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. (14,15) observed unexpectedly that exposure of individuals to'C0 sufficient to raise their levels of COHb to between 5 and 10 percent was associated with a signifi- cant fall in arterial p0 Greater fall in venous pOi was noted, but this was considered secondary to increased tissue extraction. In a recent article, Brady and Coburn (30) suggested that this COHb-induced arterial hypoxemia was due to the interaction of a number of factors. These authors noted that in the presence of veno-arterial shunts or of an imbalance in the ventilation-perfu- sion ratio, the shift in the oxyhemoglobin dissociation curve in- creased the alveolar-arterial O? gradient and resulted in arterial hypoxemia. The presence of shunts as small as 2 percent of cardiac output as well as of approximately 10 percent COHb was found to cause an increase in the gradient. Such ventilation-perfusion (V/Q) abnormalities have recently been noted even in asymp- fomatic smokers (see Chapter on Chronic Obstructive Broncho- pulmonary Disease). The increased levels of COHb found in the blood of smokers may interact with these V/Q abnormalities to further decrease available oxygen. In normal individuals, coronary flow can increase to meet the increased oxygen demands of a stressed myocardium (as that under nicotine stimulation), while in `individuals with severe CHD coronary flow cannot respond as readily. In such cases, myocardial oxygen extraction must be increased above the almost maximal extraction found at rest. Any interference with arterial oxygen levels or hemoglobin affinity could very well decrease available oxygen supplies below the level required for proper tissue func- tion. That this occurs is suggested by the experiments discussed below. Chevalier, et al. (41) exposed 10 young nonsmokers to CO con- centrations sufficient to induce COHb levels of approximately 4 percent. Taking measurements from blood specimens obtained at cardiac catheterization under resting and exercise conditions, the authors noted that the ratio of oxygen debt to oxygen uptake in- creased significantly under conditions of increased COW. Accord- ing to the investigators this implied that the same work was being done at a greater metabolic cost. These same authors, (121,162) had previously noted similar findings among smokers and observed 57 that cessation of smoking was associated with a significant im- provemeat in oxygen debt accumulation. More recent work by Ayres, et al. (15) has focused on the dif- ference in response to CO exposure between 7 normals and pi pa- tients suffering from CHD (proven arteriographically). The induG tion of a COHb concentration of approximately 9 percent in the normals was followed by an increase in coronary blood flow, a decrease in hemoglobin-oxygen percent extraction and no change in myocardial oxygen consumption, coronary sinus.oxygen tension, .&id lactate and pyruvate extraction ratios. The induction of simi- Iar COW levels in the CHD patients was followed by no change in coronary blood flow, a decrease in the hemoglobin-oxygen ex- traction ratio, and no change in myocardial oxygen consumption. However, these patients did manifest a decrease in coronary sinus p0, as well as a decrease in lactate and pyruvate extraction. The latter measures indicate that the myocardium was functioning under hypoxic conditions. Because the coronary flow could not in- crease and because the myocardium couId not extract 0, from IGO, which was under the influence of CO, coronary sinus oxygen tension decreased to a point which could inactivate certain oxida- five enzyme processes. Thus, the myocardial function of persons with CHD may be unable to compensate for the stresses induced by smoking. Although COHb levels resulting from the CO present in the atmosphere during periods of high air pollution are much lower than those due to the inhalation of cigarette smoke, these concen- trations of COHb might contribute to the manifestations of CHD. Cohen, et al. (44) studied the case fatality rates for patients ad- mitted to 35 Los Angeles area hospitals with myocardial infarction in relation to atmospheric CO pollution. The authors observed an increased MI case fatality rate in areas of increased pollution, and then only during periods of relatively increased CO pollution. An area of interest which has been discussed in previous reports concerns the presence of hydrogen cyanide in tobacco smoke. According to Wynder and Hoffmann (225), the amount present ranges from 11 to 32 micrograms HCN per puff. It is known that a significant amount of this material is detoxified to thiocyanate and excreted as such in the urine or saliva. However, cyanide is a potent inhibitor of oxidative metabolism. Such inhibition of myo- cardial oxidative metabolism may be of importance when combined with f&e other factors mentioned above- which tend to decrease the oxygen supply available and increase the need for oxygen on the part of the myocardium. 58 EFFECTS OF SMOKING ON THE FORMATION OF ATHEXOSCLER~T Ic LESIONS A number of autopsy studies have demonstrated a significant association between cigarette smoking ar.d the presence of aortic and coronary artery atherosclerosis, even in men without a his- tory of clinical CHD. The possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking are discussed in this section. A number of investigators have studied the effect. of nicotine administration, either subcutaneously or intravenously, upon athe- rosclerotic changes in the aorta and coronary arteries of animals (table A23). When administered alone, nicotine induces Cedin necrotic changes in the arterial wall. However, in combination with the administration of increased amounts of cholesterol in the diet, nicotine aggravates either subendothelial fibrosis (7.5) or definite atheromatous lesions (46, 75, 80, 130, 178). Studies by Choi (AZ) and by Wenzel, et al. (207) did not demonstrate this synergism between cholesterol and nicotine. The other major cigarette smoke component under discussion in this chapter, carbon monoxide, has also been recently implicated in atherogenesis. Table 24 presents the studies which have related exposure to CO in combination with increased dietary cholesterol to both macroscopic and microscopic aortic and coronary athero- matosis. Astrup, et al. (10) exposed cholesterol-fed rabbits to CO continually over a period of up to 10 weeks. The experimental group showed increased aortic atheromatosis over that shown by the control group, also cholesterol-fed. Kjeldsen, et al. (II&) observed that exposure of rabbits to increased oxygen concentra- tions significantly reduced the amount of cholesterol-induced atheromatosis in rabbits. Most recently, Webster, et al. (204) have extended this research to primates. These investigators found that cholesterol-fed squirrel monkeys developed significantly more coronary artery atherosclerosis when exposed intermittently to CO over a T-month period than when exposed only to room air. ReceCt discussion has centered on the mechanisms whereby CO can induce these changes (9, 212). Astrup (9), referring to pre- vious experiments in humans which had shown increased vascular permeability for albumin upon chronic exposure to CO (II), con- siders it likely that this increase in permeability allows for in- creased filtration of lipoproteins into arterial walls. This, he con- siders, is a primary cause of intimal and medial lipid accumulation and, therefore, of atherosclerosis. Another point of view has been stressed by Whereat (ZIZ), who considers the filtration theory to be an inadequate hypothesis for 59 TABUS !U.-Expdmnta evncedng the athemgmic efect of carbon monde ezpoeure and hyporia Ucldrcn X4 cutrated mde hdat dlct p!U8 X WKent Tbr uDer~mcntd1 D,V"D cxpored to hYDoxl4 lboaed kaCP?6sed ttW~OD!O UHtlS et al, rlblno rabblta. cboleateml: atberomatod# over that ahown by eontml o nim& bfkroacoDk uamtnathxI rc ID68. I. (12) control. w&d mom Intlmal and sublatin lipid dcposltlon In the o ortu of the cr~mod Dcnmrrt II. (12) continub, qry~~~m. rabbit-s than In those of the noncxwaed. The total amount of ebcltiterol dt- (117). to hypoxia: Posited In tbs sort&n of the experiment&l Om"D wan tbrn tha t&her thw h 10 DWCe"t.$ for 6 weeks. chow of tbe cootrol sroup. 8 DetCWIt Ox for 2 weeks. uetdrcn x4 ca1lrrtAd male h~ulat dlst DlUS 2 percent bhOtWODkdY, the exDerhe"tll WOUD ahowed &diCl"tb feWt StbWoUMbUI et aL. albino rrbbltr. cholcsteml: changn. Micro~coDlc~ll~, tie uperlmrntal PKIUD ~hoaed ~ignlflcant~ krr rortlo 1060. I. (12) conttc1. Intimrl liDId deposItIon. Dmmwk 11. (12) CXDOIUM t0 28 DtrCmt (JJ4). O2 for 10 weeks. Webster x2 femrb lpulrrel Diet eontalnlng 0.1 percent The uprr~mtntal proup cxpoml to trrbon moaoxldr rhowad 8 prertrt maan Wr- e &I.. moakeya. chol~~ttrol rnd 26 DUCC"t fat: eentalpe of comnar~ rrtcrlar rlth rtheruclemtlc lcalon~ rnd more lumen occlu- 1970, I. (IO) control. U.S.A. don among the &ccted arteries Them wm ~lmifluntb mom CO-treat4 11. (12) eIDdme"trk!Y UpO8d t0 monkeys than control monkcn having 11 per-ant or more o ????*? athem- (W). 200400 P.P.~. errbon monoxide AerotIc rtenorlt among the wTected arterlcr. Aorttlc atbcmrclcroaL wu &PP*~- for 20 hOWa DW week for 7 cntlv not agemwkl by exposure to CO. COHb IevcL at the md of each ewaun montha. perlad averaged 18-28 percent durlw the flnrl 24 wrnkr of tbhs apsrlment mural lipid accumulation. The author notes that when the oxida- tion of the pyridine nucleotide, nicotinamideadenine dinucleotide (NAD), is impaired, the reduced form of this nucleotide (NADH) provides an essential factor for fatty acid synthesis. Fatty acid synthesis in the aorta and heart is carried out by mitochondrid enzymes whose hydrogen donor is NADH. Substances which slow or impair the reoxidation of this compound tend to increase mite- chondrial fatty acid synthesis (and decrease fatty acid utilization) in the arterial wall. Carbon monoxide prevents this oxidation proc- ess both directly and indirectly. Indirectly, it decreases the oxygen available for diffusion into the tissue. Directly, carbon monoxide can stall the process of NADH oxidation by combining with cyto- chrome oxidase. Further research is required into this problem, ParticuIarIy in view of the fact that cyanide is also a respiratory chain inhibitor and thus may also adversely affect arterial wall fat metabolism. In the discussion concerning the epidemiologica aspects of CEID, it was noted that increased serum cholesterol was a significant risk factor for the development of overt CHD. Serum triglycerides have also been related to CHD incidence. Of concern also is the immediate effect which cigarette smoking has upon blood lipid levels. The studies concerning this immediate effect are presented in tables A 25 and A 25a. The tabIe is divided into a section concem- he studies on humans (table A25) and one concerning studies utilizing animals or in vitro systems (table A 25a). Although no consistent response was noted for serum cholesterol, serum free fatty acids were found consistently to rise following smoking, As with other cardiovascular reactions to nicotine and smoking, it appears that the fatty acid response is also mediated by catechol- amine release. This relationship has been observed in a number of experiments by Kershbaum, et al. (105,106,108,109,110) and Klensch (118). That nicotine is primarily responsibIe for this rise may be seen by reference to the study by Kershbaum, et al. (105) in which lettuce-leaf cigarettes of minimal nicotine content had a negligible effect upon serum free fatty acids in comparison with that of regular cigarettes. While attention has been centered upon nicotine as the agent inducing the immediate increase in serum lipids, recent studies have been concerned with the effect of chronic exposure to carbon monoxide on serum lipid metabolism. These studies are hated in table A26. Among rabbits fed increased amounts of cholesterol, the authors observed significant increases in cholesterol and tri- glyceride concentrations in those exposed to CO versus those maintained in a normal atmosphere. TEE EFFECT OF SMOKING ON THROMBOSIS In the study of CHD, a number of investigators have turned their attention to thrombosis because myocardial infarction and sudden coronary death frequently result from thrombotic events. A thrombus may be of either gross or microscopic dimensions, and a minute thrombus at a strategic site may precipitate a fatal-ari rhythmia. However, thrombotic and prethrombotic states are dif- ficult to detect except when gross, and the emphasis has been pri- marily on factors which can be studied conveniently. Coagulation is now thought to have a secondary role in the consolidation of an arterial tbrombus and little if any in initiating the process. The prime mechanism in thrombogenesis appears to be the reaction of the platelet. Several papers have been written about platelet re- activity in v&-o but few about the effect of smoking on platelet behavior in wivo. The assay of fibrinolysis, which may also be im- portant, has received scanty treatment. The relevant studies are listed in table A27. Many of these are discussed in the 1968 sup- plement (192) and by Murphy (140). Corroborative data are still inconclusive as to whether smoking shortens platelet survival. OTHER AREAS OF IFNEXT~GATION Certain other aspects of cardiovascular pathophysiology may be of importance in the relationship of smoking to CHD. Glucose me- tabolism and insulin response, when altered, may alter myocardial response. This topic has been covered in detail in the 1968 Supple- ment to the Health Consequences of Smoking (192). Also, .varia- Finns in. blood hemoglobin and hematocrit may adversely affect coronary blood flow. A number of studies showing a possible rela- tionship of smoking to hemoconcentration have been reviewed pre piougly (192, I%?), and the reader is referred to those discussions. CEREBROVAXKJLAR DISEASE The term cerebrovascular disease (CVD) refers to a number of merent types of vascular lesions affecting the central nervous system : subarachnoid hemorrhage, cerebral hemorrhage, cerebral embolism, and thrombosis (ICD Codes 330 to 334). In 1967 in the United States; a total of 93,071 males and 109,113 females were Wed as dying from CVD as the underlying cause (196). Epidemiological studies indicate that cigarette smoking is asso- 62 ciated with increased mortality from cerebrovascular disease, whether CVD is listed as the underlying or as a contributory cause of death. Table 28 presents the results of the seven major epidemi- ological studies. The smoking of pipes and cigars does not appear to increase significantly the risk of ,dying from CVD. The impor- tance of high blood pressure and diabetes as risk factors for mor- tality from CVD has recently been noted by Hammond and Gar- finkel (76). The data from their study, as presented in table 23, also indicate that the mortality ratio for cigarette smokers is greater for persons under 75 years of age than for older individuals. Many of the pathophysiological considerations discussed in the sections concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. In a study reported by Kuhn (~zS), 20 habitual smokers X+ frained from smoking for one-half day, and base line retrograde brachiocerebral angiograms were taken; they then smoked one cigarette, inhaling deeply, and had repeat angiograms. Those over 60 years of age failed to have significant acceleration of flow as demonstrated in carbon dioxide inhalation experiments. More recently, Miyazaki (15.2) studied the effect of smoking on the cerebral circulation of 12 moderate/heavy cigarette smokers 88 measured indirectly using an ultrasonic Doppler technique to record internal carotid artery flow. Measurements were made be- fore and after ordinary smoking and showed an increase in cere- bral blood flow and a decrease in cerebral vascular resistance in all subjects. No significant difference in response was observed between the 4 younger and 8 older (over 66 years of age) subjects. More research is needed to clarify the role of cigarette smoking in the acute pathogenesis of CVD manifestations. However, the chronic effect of smoking upon the cerebral circulation (particu- h]JT its extracranial portion) is Iikely to be similar to the effect Of smoking upon the aortic and coronary atherosclerosis. NON-SYPHILITIC AORTIC ANEURYSM Aortic aneurysm is an uncommon but not rare cause of death. In 1967 in the United States, a total of 8,448 men and 3,173 women Were listed as dying from aortic aneurysm as the underlying cause (196). Cigarette smoking appears to i_ncrease the risk of dying from this disease, perhaps by promoting the atherosclerotic proc- aaa'which underlies this type of aneurysm. As illustrated in table 29, the mortality ratios for cigarette smokers are high relative to other cardiovascular diseases in which smoking increases the risk, and the risk increases in proportion to the amount smoked. 63 TABW PL-Deaths jrma cerebruva.mdar disease related to making (Xcutdity ratIoa--actual number of death8 ahown In ~nrmthesca)~ [SM = lmokcn NS = non~mdrsnl PROSPECTIVE STUDIES Age r1rhtIon commcntr 1.060 NS . . . . . . ..l.OO (lE4) t(Pco.01). Ckarcttn SM . . . . ..tl.aO (666) Other SM . .1.26 (HO) Ciuarstter only 20 . . . . . . . 1.46 (83) Doll and ADDR~u~~Y Questlonnalrs 10 606 NS . ..,...,. 1.00 RIU 41,ObO mole md fqlIow- All SM ,,.,., 1.06 1064, Brltlsh up of death All CRlt phyrlelan~. certine*te. clgrrctta 1.12 B?ibLn l-14 . . . . ..l.lO (lob. 16-24 . ...,. 1.W >26 .,,,,... 1.26 Kmnsl 6,127 males MedICal 12 1s NS . . . .L.OO 161 Data o o~lu onlv TABLE `&I.-Deaths from cerebrovaamlar diseaee related to making (cont.) (Mortality ntlw-actual number of dwthr ahown In partnthnel)' [SM = mokcn NS = nonamokersl PROSPECTIVE STUDIES Irhn. U.S. mab Queatloonalra 6% 2,008 NS . . . . . . . . 1.00 (614) PIPU 1060. Vetm-uIl and follor- AU shl . .1.06 (82) U.S.A. 2966.674 up of death current . . . .1.60(1,894) NS . .1.00(614) (011. pmon MrufiUk Chtl-tnt CXQLW Y- dgetla . 51.62 (682) NS . .1.00(614) 1-v . . . . . , . 1.61 (88) 8M ..1.06(186) lo-20 . . ...1.42 (826) 21-89 . . . ..l.?O (216) >se .# ..*.* 1.69 (87) Elmmond 868.d64 make Quatlonn~lm 6 md 446,876 and follow- Cuflnkd, fcrmla 40-79 UP of death 196O. ,eara of we CertlIlC~tc. U.S.A. at entry. (78). 4.09D CUW#UC rcoukw duortfle 40-u Never rmoktd 1.00 l-9 . . . ...2.79 lo-18 . . ...1.14 2049 . . ...2.21 ,>40 . . . ...1.64 NeVW amoked 1.00 l-9 . . . ...1.60 IO-19 . . ...2.60 20-39 . . ...2.90 >tO . . . ..t6.70 Maksr so-se 004 1.00 1.00 1.96 1.to 1.48 tl.44 LOS 1.62' 2.40 1.72 Fcnrclkr 1.00 1.00 1.26 1.26 2.70 2.16 2.67 1.88 t6.62 - trlued on only 69 death. TO-78 1.00 0.86 0.92 1.22 to.68 1.00 0.83 to.67 1.26 T)~BLE 28.-Deaths from cerebromscular dieease veluted to smoking (cont.) (Mortrllty ratios-actual number of dtrtha ehoan In parentheses)l SY = Smoken. NS = Nonsmokers. PROSPECTIVE STUDIES Pbf?ra. 8.268 m&b IraM multi- 16 67 NSand buglt, bnoabaremhn pbdc -30, . . . . . . . ..l.OO (42) rtd. s-e4 Yea" lC~e+nltlg x0 . . . . . . . al.16 (26) 1970 of .* In and follow- U.&A. 1961. UD of death (144). ceruncrte. RETROSPECTIVE STUDY >SO,OOO male Inltlal eolleps Death Rater The 69 deaths from barper Unlvcnlty entrsnce Corer (fad, Catrok (ala) occlualvc stroke u.d ,tudrnt., medld cx- SM ,,..,.,,...,,...,..,. 46.0 81.8 (ptO per day . 20.9 11.2(P39 . . . . . . . . . . . . . . . . . 7.26 (17) Hammond 368.634 males Queationn~irc 6 337 NS . . . . . . . . . . . . 1.00 Data r~uly onlv and 446.816 femrles and follow-up 1-9 . . . . . . . . . ..2.62 toms1ec SO-69 GarRnkcl. 40-79 ye,* Of of death 10-19 .:.....,..8.86 yt.m of Lge. 1369, age at entry. certificate. 20-3s . . . . . a.... 4.64 V.S;A* >40 (76). , . . . . .._.I . ..8.00 Web ind 68,163 Callfomla Queatlannalre S-8 61 NS . . . ..,.,...* 1.00 DlInIl, tide workera and fOl!OW-Up All . . . ,. . . . . . . . .2.64 1970. E-64 ye.n ot al death Cl0 I.. ..a,. a .,.2.44 U.S.A. age at entry. crrtificste. 520 ,... * . . . . . . . 2.88 (IDS). ZSO . . . . . . . . . ...2.64 ' Unlnr ofJwrwlse 1~4fled, dl#parltlh between the total number of dsrthl and the sum of the Indlvldual cskgorlw .re due to the urclulon Sk! Include cr-amoken. NS include plge and clg~r amoken. m of elthcr oeculonrl, mlscell~neou~, mlxed, or rxamokcn. PERIPHERAL ARTERIOSCLEROSIS Peripheral arteriosclerosis represents the effects on the vascu- lature of the extremities of the pathophysiologic processes which produce coronary and aortic atherosclerosis. A number of studies have been concerned with smoking as a risk factcr in the develop- ment of this disease. Kannel, et al. (95) observed, in the Framing- ham study, that diabetes mellitus and elevated serum cholesterol, as well as cigarette smoking, were also risk factors in the develop- ment of peripheral vascular disease. Juergens, et al. (9.2) reviewed the records of and contacted 478 maIe patients with arteriosclerosis obIiterans (a severe form of peripheral arteriosclerosis), who had been patients at the Mayo Clinic between 1939 and 1948. The diagnosis of this condition was based upon certain clinical criteria: the presence of intermittent claudication, the marked diminution or absence of lower extremity arterial pulsations, and objective trophic manifestations of per- ipheral limb ischemia. Smoking information was available on 401 patients. These patients were compared with a control group of 350 Mayo Clinic patients of similar age who showed no clinical evidence of vascular disease. It was found, for males under the age of 60, that 2.5 percent of the cases and 25 percent of the con- trols were nonsmokers. However, no difference was noted between the percentages of heavy smokers in each group. The authors also impIicated high blood pressure and elevated serum cholesterol as risk factors in the occurrence of this disease. Begg (19) noted similar findings in a study of 294 male patients with intermittent claudication who were patients at the Western Infirmary in Glasgow, Scotland. .In comparing the smoking his- tories of 100 patients with this complaint with those of 116 healthy male controls, the author found that 1 percent of the patients and 21 percent of the controls had never smoked. A total of 42 percent of the patients smoked more than 20 cigarettes per day while only 24 percent of the controls had a similar history of heavy smoking. The author concluded that smoking, while not a prime cause of peripheral arterial disease, is a significant cofactor in its develop- ment in almost ali cases. The author also noted obesity, high blood Pressure, and elevated serum choIestero1 as risk factors. Schwartz, et al. (168) compared the prevalence of risk factors in four groups of subjects: 141 cases with arteriosclerotic disease of the lower limbs, 551 cases with coronary arteriosclerosis, 58 cases with both conditions, and finally an indefinite number of control individuals who h.ad been hospitalized for injuries. The in- vestigators reported that certain risk fa_ctors, including hyper- cholesterolemia, hypertension, and cigarette smoking, were signifi- 68 cant in both coronary and lower limb arteriosclerosis. The authors noted that the inhalation of cigarette smoke appeared to be an important risk factor for coronary arteriosclerosis up to age 55 while in arteriosclerosis of the lower extremities, inhalation ap- peared to increase the risk even in the older age groups. Widmer, et al. (215) compared 277 male patients with arteriaI occlusion of the limbs as demonstrated by aortography or oscilIog- raphy with 2,082 men demonstrated by oscillography to be free of arterial disease. The authors found that cigarette smoking, parti- cularly heavy smoking, was significantly more frequent among the cases with arterial occlusion than'among the controls. Increased beta-lipoproteins and systolic hypertension were also found to be more common among the cases. EXPERIMENTAL EVIDENCE A number of experimenters have investigated the acute effects of smoking or nicotine upon the peripheral circulatory system. These investigators, as listed in table A30, have measured effects in terms of alterations in skin temperature and blood flow as meas- ured by plethysmography, radioactive iodinated albumin clear- ance, or radiosodium clearance from the skin. The majority of these studies have shown significant decreases in peripheral blood flow and skin temperature upon smoking, particularly in persons without manifest peripheral vascular disease. The study of Freund and Ward (68) demonstrates the difference in peripheral vascular reactivity found between normals and patients with arterioscle- rotic changes in the vessels of their extremities. The work of Striimblad (181) on blockade of this response with automatic SYS- tern blockers indicates that the reactivity of these vessels is se& ondary to the local release of catecholamines. Most probably, the degenerative changes associated with this disease create a stiffen- ing of the vessel wall and prevent rapid alteration, particularly dilatation, in response to the catecholamines liberated by smoking or nicotine. THROMBOANGIITIS OBLITERANS Thromboangiitis obliterans (Buerger's Disease) (TAO) in an uncommon obstructive vasculitis primarily involving the arteries and veins of the extremities. Severely affected patients may even lose their limbs secondary to ischemic changes. Much discussion has centered upon the question as to whether this disease is a clin- ical and pathological entity separate froqperipheral arterioscle: r&is. McKusick, et al. (128) consider it to be a distinct entity 69 while Eisen (57) concludes that TAO is the acute inflammatory phase of severe arteriosclerosis. Clinically, it has been shown that smoking aggravates this dis- ease and cessation of smoking frequently aids in complete or par- tial remission. Razdan, et al. (153) and Brown, et al. (32) found very few nonsmokers in groups of patients diagnosed as having typical TAO. A recent study from Israel (16) involved a case- control comparison of 46 patients with TAO and 32 matched con- trols. Although the controls were found to smoke less-per day than the patients, this difference was not found to be statistically sig- nificant. However, 100 percent of the smoking patients and only 72 percent of the smoking controls were inhalers, a difference sig- nificant at the 0.02 level. CARDIOVASCULAR DISEASES SUMMARY AND CONCLUSIONS CORONARY HEART DISEASE 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physica inactivity) shows that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that-cigarette smoking may acceIerate tfle pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coro- nary arteries. 5. The cessation of smoking is associated with a decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms: a. Cigarette smoking, by contributing to the release of catechol- amines, causes increased myocardial wall tension, contraction 70 velocity, and heart rate, and thereby increases the lvork of the heart and the myocardial demand for os'gen and other nutrients. b. -among individuals \vith coronar> atherosclerosis, cigarette smoking appears to create an imbalance betlveen the increased needs of the mvocardium and an insufficient increase in coro- nary blood flow and oxygenation. c Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the a\.`ailability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hyposemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. CEREBROVASCULXR DISEASE 1. Data from numerous prospective studies indicate that ciga- rerte smoking is associated with increased mortalit>- from cerebro- vzscnlar disease. `3. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conc!usions concerning pathogenesis. However, some of the pathophgsiological considerations discussed concerning CHD may also pertain to the relationship of smoking and 0-D, particularly cerebral infarction. NON-SYPHILITIC XORTIC ANEURYSM Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. PERIPHERAL VASCULAR DISEASE 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascuiar disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. 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S?O ., ,. I.. .46.3(S) IIrnlth Survey interview. >20 . ,, .* *. *.. ,18.6 (21) U.S.A. >20 . . . . .11.6(10 with mntched (33). contm3ls from slmr I"rvCY (included there surviving Arot myocardi~l infarction). \D 0 rctrospectiuc studies (cont.) TAULE AG.-Coronaq hnrt discusc morbidity and worlulity- (Actual number OC casca ahown in pnrcnthesn)' [ SM = Smokers NS = Nonsmokers EX = Ex-smokers1 Author. year. COUntrY, rcrrrence Number nnd type of Donulntiu" Dstn collcctian Cnscs (percent) Controls (percent) Comments Rusrsk and 97 mule and 3 Interviews Tobacco ~jU cigurctkalday Psticnts Zohmrn. lcmalc coronary bs 70 percent. 35 percent. included 83 199. pntientl. Controls: authors. with chwical U.S.A. 100 healthy control3 mkucnrdiut (165). of similar "g-2. iliiairliu" sex. occupation. nnd II WlLh and ethnic origin. sngtna pcctorin. SDai" and 269 males identified 3,000 mr1es NS .,....., .30.0 (81) 29.0 (772) Nnthe", 8s hnving CHID by in New 40/day ,. .13.0 (33) 9.0 (234) (D36 . . . . . . . . . . ...21.8 (42) 2.2 (9) ciK(olrPLtc CnLcKOrir8 -Hnmburp ngr- 100.0~193) ~ 100.0(413) i"rllldP n~ihr,Ll 01 cisnr matchcvl citizens ' (only 28 were mixed (G2 wcrc mixed nr sm<,krrn ri~,ils.ulntrd selected randomly. or cigar smokers) cigar smokers1 as LLI nutnhcr cbt CLKLL. I.P~~LY No vntir,ntr or controls brnilkcd "ii'rn cxcIu5i\rly. Dbrken, 33 females up to Death cer- Cioaretlcs prr dau 1967. 44 yrnrsofngc tificotcs, 0 . . . . . . . . . . ,.... 6.1 (2) 63.?(841 (P36 . . . . ..~.. c.1 (2) of time frcam clinic without CVD or lung Lc7 CLi"CFt. P _-- TABLE A&-Coronary heasl disease morbidily and mortalily--7etro~ective studies (cont.) (Aeturl number of cum shown In ~nrenthesn)~ [Shl = Smokers NS = Nonsmokers EX = Ex.smokeral Cl3CO (pcrccnt) Cummcntl refcrcncc population Hybms 79 maln Iurvivino. Interviews NS . *... . . . . . . . 10.1 (S) 21.0 (33) et al, myocsrdial infnrc- by trained l-9 eiearettes 1967, lion. 167 age. DW3Otltl.d. perday 1.0 (6) 10.5 (13) Jkpnn matched controls lo-15 .._..., ,,,., 26.4 (18) 33.9 (42) (87). hospilalired for nan- 16-20 ,..,..., ,. .35.2 (25) 26.8 (37.) CVD but include 21-34 . . . 22.6 (1G) 17.7 (22) hypcrtenaive diaeare. >36 . 9.Y (7) 12.1 (15) AllSbl . . . . . . . . . . 100.0 (71) 100.0(1!40 - Mulcahy 100 fet"ak DSthltS Hospital sm . . . . . . . I .I., 63.0 (63) 45.6(261) Smoking on controlr et al., less than GO yesrs interviews. NS .,.....,,..,,, 33.0 (33) 45.3(2511) obtsinrd from 1967, of age admitted t0 EX . . . . . . . . . . . . . 4.0 (4) 0.1 (52) stulisticn of Ireland hospital with CHD. Total . . . ..100.0(100) 100.0(572) smoking in (IJIb. Irish I~rpulrl~c. Sudclrn dvn\h ""1 IrlCIIIIICII. Stejfa, 70 maleand Direct Plcvolcncc Of risk factora Authurs then fullowcd 19G7. female patient3 interview. Angina patient., Control DIOllD lhr 70 pnlirnts for Poland with recent onrct 60.0 3 yrnr, and rrutcd (179,. exertional angina 48,1(p>O.l) Lhnl amgaktng sinnifi. Deftotis. 54 control3 canlly inilurnr*,20 ..I. .42 0(2(13) 29.or2oiI (PI6 cigarettes .22.6 20.0 All ,, ,,. ., .EO.O 47.4 Pipe 16.5 8.8 JOUVC 1.229 CIID patients: Interview. 43.0 13.0~P<0.0001) et al., 802 malcs.427 1961. fcmsics. Controls: FranCe 743 individuals of (91). both BCXCJ: age. sex. and socinl class matcbedd. Icrst1. 275 mrde railway Interview NS . . . . . . . . . I... .ZO.O 1.55) 29.8 (82) 1969. FmploycPr UP to 65 and ex- Z-20 cigarettes or Germany years of e.gc sur- amina- UD to 6 cigars.. .32.O (88) 63.3 (82) (98). viving myocnrdial tion. >20 CigaretleS or infarction. 215 con- >S cigars. . . . . . ..48.0(132) 6.9 119) trol employees with minor circulstory diaturbanccs. ' Unless otherwise specified. disparities pween the total number of case9 and the sum of the individual smoking categories are due to the exclusion of u tither occuionrl, miacellaneoua. mixed, or ex-smokera. w - TABLE A?`.-Differences in sertcm lipids betlceen sl,iokers and nonsmokers (Aciusl number of ind\vlduslo shown in parrnthm)' [Sat = Smukcn NS = Nonsmokers] Author. year. Number and countrv. type of Results Comments Diflermcc bctu,ern S,!l and NS tSf relrrs to S~edbere ngca 90-19 Ages JO-S9 Apt-a4049 flotation unit8 of Lipid: f NS 55. SM 37) (NS 66. SM 67) (NS 17. Shl 44) centrlfugcd lil,iaproteins. tsr o-12 . . . . ,. +59.9 lJ concludu from the antl I.unrlmnn, tbvin ~:LIIS nnd of cholesterol. triRlyccridcs, and pho~pholiyid~ than nonsmokers. di!Trring 512 and DZ rc~ult~ I !I 1: G , k7 o.o5 1.362.1 I p270 ahownl significantly biphcr tng. petcni1 mg.pcrcmlt (p20 cigarettes/duy(Sll) 249.4 30.0 Van Buchem. 1967, Netherlands (19Pl. -- Quvlr ct al.. 19BM. . U.S.A. i la ) . 918 randomly chowen Strum clLolcafcrol The nuthon found no maks 40-SY yearn O-209 mg. portent PIO-249 mg. percent >250 mg. percent correlution bctwwn smokbnu of age for entry NS .,t...,.....,..... 12.4 (32) 14.0 (40 14.2 (41) and serum chokntrrol Icvela. Into prospective Ciparettc SM `lt.6(184) 67.8(213) 68.2(197) study. Other . . . . 16.0 (41) 18.2 (61) 17.6 (61) 1.10% male lnctory Snum chorcslcrd Strum Bclo-liyoprotcin Dcta-lipoprotrins were found rmaloyem 20.64 mg, pcrccllt mp. pcrccnt to increase with age. but Y*nrl Of age. NS . . . . . . . . . . . . . . . . . 243(519) smokers had hivhcr lcvcl~ SM 251(576) p26 PT~UIB 127.9 (`JO) 128.1(218) All amounta 129.1(619) 128.6 (447 I The author did notz MUX diadtoldic b&d yrcrrvrc Shf-NS blood "rcaeurr dlf- UK Lf.5.A. lcrmcm prior to 70.9 81.0 rnntrolling fur wciuht. 19.4 62.1 but nut sltcr such cuntrol. 78.6 71.3 71.6 17.1 78.7 77.8 - JS'O-J70/ Numbers in parcnthcwa Ioo-Iro(zro~ >J7sl>IJs(rs, reurewnt tatnl in blood 25.5 34.7 yrcllure group. 26.6 18.7 The nulhor noted 15.6 17.3 a stcpwiue dwrcue with 10.0 4.0 ICI,@1 01 blood pwsJ"re Tibblin. 1967. 896 m&3 In SW&tl GGtebn?, SW&J& (Jar). born in 1913. L?locd prcrr,rre J JS-145/ ~110/~70(a9) 7*95 (468) NS . . . . . . . . . . . .t. . . . . IP:O 23.0 l-14 clgaretta, *....,..... 29.2 21.2 >I6 cigar&k-a . . . . . . . . . . . 28.1 20.9 Pipe and cigar , . ,, 11.2 8.6 ditiduala and the aum cl tbc individual smoking categories are due to the excluioa of either oeeuional, mlrel+oua, mhd, or ex-smokera. TABLE A17 .-Incidence of new coronary heart disease by smoking category and behavior type for men 59-49 years of age (Numb-m in pnrentheses are number oC CHD cases in each aubnroup) Smoking group NW.3 smoked Currot and former pipe and ciynr only I-16 Cigarcttez 16-25 2C rnd over TOtAl 1.6(l) 15 8(15) 14.9(16) 9.3(461 1.3(J) 3.1 (3) 4,9 (0 3.3(18) 4.3(5) 9.3(18) 10.4(20) 6.2(63) --- -- Analysis of variance Iable Source Sum of sauark-0 d.C. `Eater nre sue-adjusted nnnual incidence per 1,000 men. *Mean SQUH~TI for "betwccm smoking groups" and "between behavior Iypea" are each computed eliminating the general mean and the other main effect but ignoring interaction. thus yicldine m eatimak al each main o f- feet unconfounded by other significant main ef?~ta. SOUKCS: Jcnkino. C. D. et al. (90). TABLE AlS.-Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age (Numbera in psrcntheaes are number of CHD cylea in cacb nubgroup) Former Current and Cigarettes BehaVlOr Never cigarette fOiTlCl' DiDC tYDC amokcd amoken and cigar only 1-16 16-25 26 and over TOlal A . ** . . . .~. .., . . . . . .,.. `12.4(K) 18.6(B) 21.8 (8) 16,4(6) 21.5 (9) 30.0(14) 20.4 (43; B .*....... . . . . . . . . . . ...,., 10.0(4) 6.1(I) 6.4 (3) 4.7(l) 21.1 (I) 19.1 (51 12.0(21) Total . ., . . . . , ., 11.1(g) 14.2(9) 14.9(!1) 11.6(6) 21.3116) Z&0(19) 16.8(70) - Analysis of variance table Wltbin eclb . . . . . ., ,#I......,.. ,....,. ,.. . . . . . . . . . . ..,. 63.627 911 0.070 Regreuion on age . . . . . . . . ..*..*.*..* ,..... ..,.,... . . . . . . . . . 0.117 1 0.171 2.64 0.111 Dctwctn smoking groupa: . . . ,.. . . . . . . . . . ., . . . .., , ~, . . . , 0.522 6 0.104 1.496 0.188 Between behavior typea 2 ..,...~.....,., . . . . . . . ,.,... .,..,,...... 0.296 1 0.296 4.24 0.040 hkr.ction . . . . . . . . . . . . . . . . . . . . . . . . . ..I . . . . . . I ,....,,.,..,.,, 0.129 6. 0.026 0.37 0.870 IFLaLpl are age-hdjuattd annual incidence per 1.000 men. cflect buL ignoring interaction, lhur yielding an catimate of each mnln rf- `Yew ~puarea for "between smoking groups" and "between behavior feet uncanloundL4 by other significant rn~~in ellectr. trpn" are each computed eliminating the general meon and the other msin SOURCE: Jenkins. C. D. et nl. (901. TAULE .420.-Expcrinrents concwning the cffccts of swoking ant1 nicotine on animal cardiovascttlar function West cl nl.. 33 norm01 1958, ndult rn0ngrcl U.S.A. rlous. (:`OS) COIOn&I-Y intro- ortcrinl nicotine: 1. 0.2-2.2 uz./ka. II. 0.04-i )ig./ks. Dttli"iW incrensc (ey3lolic). (Tctrnuthylammonium chloride b!ockcd CUF In- crcnsc.) The authors found no evidence of coronary YLBD. mnalriction In tbeuc healthy rnimala. TABLE ABO.--Ezperiments concerning the efects of smoking and nicotine on animal cardiovascular function (cont.) Author, YCIT. Number and Smoking Heart Blcmd Cardiac CCTO"tIW EO""tcJ, type of DKXCd"~C rate DXW"R OUtPUt blood Commenld rdcrence DoDulnlio" flow Forte 27 obscrvn- intravenous Definite No cbanw. No signlflcant change I" either left ventricular et nl., tiono on 8 nicotine up initial work or myocardlal oxygen extraction. 1060, dogs. I3 21.6 "lg. increase U.S.A. given 83 6-16 then 165). !.w./kg./ dccroase. minute. - Kicn and 21 adult doas Ciasrette Definite Definite Increase ERccts of cigarette smoke were duplicated by In- Shrrrod, 1960. U.S.A. IlIP). smoke under positive pressure via tracheostomy. Nicotine 20 pg./kg. intrs- ve"ou8Jy. Epinrphrine 6 w./kg. intra- ve"ausly. increaae. i"crea8e. followi"g trnvenous nicotine and eDi"eDbrl"C. incrcnse During cigarette smoke Inhalation. it WBI noted in blood that without blood pressure or output chanp+a, prC*s"rC coronary blood Row did not Incrrnse and tbnt and cardiac while adverse EKG changea were noted they COP 0"tD"t. related Marc claaeiv with decreued cardinc OXY- gel, utilization than with actual cardiac wGrk. TraVCll 14 norm"1 intravenous DCli"itC Nicotinc.induced coronary blood flow and heart CL RI., rabbits nnd nicotine increase rate increase in the atheroeclulotic nnlmals re- IICO. 1C rabbits 0.01-0.1 mg. in normals. auirrd 10 times and 2 timn. ~IIB~C~LIVCI~. thr U.S.A. with severe emwnta rwuircd in the norms1 animula. flS9). cholratwxzl- induced ather- sclerosis. TADLD A20.--6zpcrimcnts concerning the cflccts of smoki,tg nud nicofinc on animal cardiovnecular function (cont.) Numbrr and type oc raopulntion Smoking proccdurc Comments Dellet I. 10 narmol dose l"trevcnaus 1.126 percent The nuthors noted that: et al.. 11. 9 dous at nicotine. increase 1, The rCBPO"Se of coron.ry blood flow to "ica- 1962, varying in- 20 ug./kg./ II. 82.6 percent line resembled that of anoxtmia I" t(c Drrs- U.S.A. tervnls Iol- minute for l"CV?WX cnce of eoronsry i"3ufllciency. (22). lowing core- 15-20 mi"ute3. 111, 83.3 DE'K'Znt 2. The grater the induced coronary imwlrment nary artery increase the smaller the increment in coronary blood ligation. Row. III. 7 dogs with varying grndcn of srtificinlly- induced corcw nary artery narrowing. Leaders 16 adult Left anterior Nicotine and norcyinrphrine both ir\crcnacd corc- and mongrel descending nary vascular rcsiotance and myucnrdinl contrsc- Long. dogs. i"tracoro"nrY tile force (the formor mcanurcd by e. conalant- 196?, injection of volume variable~prcssurc rystem). The action of U.S.A. niwtinc or nicotine was blocked by prrtrcatment wilh hcx- (125). norepincphrine. amethonium, pmtolinium. rcsrrpinc. or I(U&~C tbidinc. Lk?-Wll 13 rdult Intravenous Definite Definite Systemic vnscular rrsiatnnce ond pulmonnrr nrten et al.. mongrel nicotine, incrcasc. incraw. and left atria1 ~rr~surca show4 biphnaic rr 1965. duga. 0.02 mg.lke.1 ?~ponoen of increase followed by drcrcsac. U.S.A. minute for (JZJ). IO-12 minutes. P TABLD A20.-&p&??~nt8 concerning t/te eflecls of smoki~tg wd nicotine ox anirrla~ cafdiovQscU~ar flt?Iction (cont.) 0 m Author. yr.r. Number and Smukina cuuntry, type of ptOC`%lUtC C"mlne"tl refrrencc population FOIL? 7 dog-a of 30 inveatleated et al.. (Rcmoinder expcrirnced 1966, cntbcterizntion fnilurra). U.S.A. (64). h'adcau and J&mm. 1961. U.S.A. (144). 26 dogs 1. Cigarette smoke inhnlntian to isolated left lower lobe and then blood perfused coronary srtcries. 11. Cunrctte smoke to rest of lunu and then blood pnascd to gcnrral cireullltion. III. Nicotine perfuocd directly into left coronary nrtery. Nicotine 0.01-10.0 pg. into sinus node artery. I. No change in cor~n&ry vw~lnr resistance. II. S/G show~~i increase in c~r~ne.ry va~ulor tesiatance due, actordine to the author. to gcncral aympathetlc nervou~l ayatem stimulation. IIt. 415 showed ~nrrcn~e in corunnry vascular rnisldnce. The authors eon- cldc that the cnrdiac eflcct~ of tobacco arise nlmotlt entlrcly from thr extracnl.rlinc actiona of smoking instend of the direct reaponae of the 111.nrt. HeurL rate showed initial slowing (due probably to vnaal stimulation) fol- lowed by r.ccelcrntiun (due probably to vagnl pnrnlyais and cntecholamine reluse~. No systrrnic blood pressure changes nuted~ 22 monurel dopa I. (IO Intrnvcnour nicotine cnrct. I. Nlcotinr pruduccd B dclinitc incrcnre In the force and vt~l~~city of left 50 irr./kg.lminutc fur 3-4 \L.~IIIC~II;II. c\jnt~actiun. minutes II. Prrtrcntmcnt with proprsnolol produced (r&live to rP3u1IP Of Group 1): II. (8) Prcpranolol pretreat- (a) A further increase in left vrntriculsr ayatolic prrsnlrr. ment, then 50 hK./kg./minute (b) A dccrensc in velocity of shortening. nicotine fur 3-d minutes (c) A aignificxnt incrtnae in lrft vrntrirular cnd.diwtolic prc*rurc. The authors CO~CIUIIO thnl proprnnolol probably lmpnira the no,rcpinrpbrirl~ like cfIccts of nicotine on the myocardium while cnhrnclng ita wriphrral ve.*oprcssor enecta. TASLD AZO.-Ezpetiments concerning Llle eflccts of smoking a,td nicotine on atiirttnl cardiovascdar function (cont.) Author, YC`T. Number end Smoklna cuuntry. type of ptOCCdUre Comments l-dcrcncc populntlon D1Iaza Bcaule dona with lesions 1. Normsb (3-6 per exveriment): I. (a) No evidence of arrhythmias; (b) A ainele or ~1 few ectopic brats Cl al.. Induced in myocardium by (a) 4 PK./kg. intravenous in Z/3 normal dogs. 1969. either: (1) IaavroierenOl nicotine. lb1 40 ,%/kg. II. Extrnsystoles noted in 2/3 animals during the firat dny nftcr cesantlon U.S.A. vrctrcatmcnt. or (2) intravenous nicotine. of the arrhythmia induced by the lesion alone. but not thcrenfter, (Id). ligation of the anterior II. Experimentnl (3), 4 )iK./kg. These and nicotine-induced arrhythmias wcrc of II abort clurution. descending ecmnar~ artery. intruvenoua nicotine Greensvan Cardiac muaeleisalated from Nicotine Z-100 ~~p./cc. in Nicotine perfusion produced: Cl 81.. the right vcntriele of 10 Tyrode'n solution verfuunte. (I) An increase In myocnrdlnl contractile force avusrently indrvcndrnt 1969. adult dogs. of adrcnergic innervation. U.S.A. (2) An increased automuticity of the Purkinje Aber ~ystcm ~lvpe.rently (74). due to release 01 catecholamin& from chromnmn tissue ~turn. (3) A dccresse in conduction velocity. The authors conclude that the latter two eirectn vrobnbly predispose to nr. rhythmia formation. Swhlr and RaPSPOrt. 1969. U.S.A. (166). 88 mongrel cats Nicotine 6-12 pg./kg. injcctrd lntrnarterially to mesenterie circulatio". I. hlesenteric injection of nicotine WLI followed with 1-2 secunda by: (a) Increased left ventricular ayatalic prcasure (LVSP). (b) Increased systemic resistance. (c) Enhanced myocvrdial performance. II. Left ventricular injection of nicotine WBB followed by: (a) Increased LVSP. (b) L1radycardia. (c) Enhanced myocardisl pcr!ormnnce grcnter than that wxn in mcrenterir-injected group. 111. Prctrcntmcnt with phcnoxybcnznmine diminished the incrcnlc in LVSP while pr~~pl`nnoli~l prctrrutmcnt diminiJhcd the tnhnncrmcnt of my- ocardial perfurmnncc while LVSP still showed D. niKnif~cnnt IIIC~PU~~. 1V. MNrntvrie sympsthctic ncrvc section led to a diminished rc*i,on~u. The nuthurs ctmeludc thnt the cnrdiovnsculnr IC'IPO~BCB to nlcntinc m&y be ncurogenic in nature with receptors distributed in ccrtnin abdominal srterica. TABLD A20.-Ezpsriments concerning the etfects of smoking and nicotine on animal cardiovascular function (cont.) Smoking procedure Comments Lrb ct al., 12 mon~rcl dov and Nicotine 100 u#.lkt. for Effecelive Corunary Flow (ECF) 11 that part of the totnl COTU"*T) IloW 1910. CBF measured with UIC of 2 mln!lLC Intravenously. (TCF) which il "ellcctivelr ' involved In nutria1 exchonec. U.S.A. Rb" and digital counter. Nicotine injection WM followed by: (J,6). (11 96.6 gcrccnt increase in TCF. (2) 61.1 percent lncrense in ECF. (3) 73.1 percent increase In mwcardial oxysen ccnaumption and annl~aia revealed that capillav flow increased almost ptovortimatcly to my- wardial oxygen consumption whereas the increase in TCF W~LI f&r In CXCCJ8. (4) Definite increases In cardiac output, hesrt rate. left ventricular work, and oorlic pressure. Ross rnd BIna. 1970, U.S.A. (160). 10 does undergoIng inatrntulcwJs COlO"r.ry arrerinl flow meuurement. Nicotine lC-100 BB. lntra- coronary injection. Nicotine injection was followed by: (11 Increurcd tontractilc force. (2) Decreawl myocardial cuntrnction time. (3) Dccrensed time RCCCJI~~Y to reach peak tension. (4, Dccreucd total stroke ustolic CBF. (5) Incrcwcd total stroke dirutolic CBF. (6 I Increased total stroke CBF. (7) Changes similar to intraarterial rDin&rine. (8) Changes blocked by pentolinium pretreatment. (9) No change in heart rate or blood ~r~rure. The authors conclude that eatecholamines released from the ventricular mywardium mediated thrae I~~FIOIIIFI to nicotine. TABLE A21.- Experiments concerning the efects of smoking. and nicotixc on the cardiovascular system of humana Author, Year. Nypy;;nd Smoking Heart Blood Electrocardiogram Stroke Cnrdiac %%" eounlry, procedun rate PttBY"te ballistocard~ugrsm volume OutDUt Commenta referrnee DODUhth, Row Rusaek I. 28 healthy 1 standard and 1 I. Incresae. Incrcaee. EKG: Denicotinircd cign- et al., male amokera denicotlnired I. 16/29 showed rettes evoked changes 1955. 21-60 yearn cigsrettc. significnnt of R lesser dcgrcc U.S.A. of age (aver- chnnaex. in normnle and CliD (ISi). ape 42). II. No sis- subjoeU, but in the II. 37 male patients II. Increeae. 1ncre.s.w. nineant latter group thcr'e with overt chansce. wc,s no aiguiflcnnt clinical CHD BCC : dilTcrcnce between 42-10 yeara of I. these change+.. .-ge (bvenge II. 18/37 showed 64) ( 6 were aiKnificnnt nonsmokers. chnnue. DIrgeron 14 of 30 healthy 1 cigarette Insinnilicsnt Increase. Dcnnite Coronary vrl8cIIIflr et al.. adult mnle vol- inhaled at increase. increase. re3i3tBncc fill 1967. untccr smokera intervals of si!pificelrtly. U.S.A. and nonrmokers 20 aeconda. Myacerdinl O3 fJ71. who underwent usage unllcrwc"l no BUCCeSSfUl aienlfirsnt chnnac. catheterization Pyruvnte extrnction 18-63 years fell slightly. of age. Authora conaldrr lack of incrcnw in heart rate u due to bascllne nl>prrhcnsive tschyrardia. F 0 TABLE A21.- Expriments concerning the eflects of smoking and nicotine on the cardiovascular s@?T?t of humans (cont.) Author, Y-r. cou"trY. NUt~pbc"o;"d Smoking Heart Dlood Elcctrocardiopram Stroke Cardiac prowlure rate pre49urc b@lliatocardloprrm volume output cYl"Y reference potNlstio" nOow Comment4 Repm et al.. 1860, U.S.A. (IS4). 7 mnlca with 2 standard DCA"lte Dcnnite Incrcaac. No aipnl- Myocsrdlal 0, conaump- bintory of cirarettn In Increase. increcae. licnnt tlon row sliuhtl,`in EKC.DWWl 26 minutes change. 3outof7. myocsrdial inhaled at The author considcra Inf~rctlo" minute that the EKG chsnrca undergoing Intervals. notrd on amokinw are cardiac ~a- probably due ICYS to theteriration. decreased coronor~, blood Row than to incrcawd worklond (oxygen "red) where oxygen supply dwcs not incrcwe. Noted no cvidrnce of myocardirl irchcmla during anwkinp. Thomas and 113 clinlcallu One rtandard Definite Definite Definite Definite Pulse yrcsaurc ahowed MUWhY, healthy young cigarette increase. increase. incrcaae. increase. a decrease. 1960, males. smoked at Smokers rrr~mnded U.S.A. own pace. slightly but sisnl- (166). Acantly more actively lhan "on- smokrra. BCC change were incrcnninfly common with incrraaing ale. wright, and serum ehulcaterol. TADLE AZl.--Experin~ents concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. YCBT, country. retcrencc Number nnd type of Dopulnlion Smoking Heart procedure rate Blood Electrocardiosram Stroke Cardiac lltC33"t.? bnllirtocardioyrnm v0lume output cti:o":w timmcntd now Von Ah", The author Cigarette Increase. EKG: Slight ST EKG changes more 1960. reviews * smoking. HCg"lC"t prominent in younr, SWCd?" arries of denreeaion clinicnlly healthy (POZ). expcrimenta nnd T-wnve aubjccla than /II performed nattc"i"c. older. hltbitunl IJCLWCC" amokcrs. Intro- 1944-1954. venou nicutinc end smuki"K ahuwrenses not de. (b) Non-inhalation lb) No No change. (IJ) No cbrnge. No change. dilutwn tvchniwc. Ennlnnd fined. 19-66 yesra smoking. change. (89). ol nw. all mod- (c) 2 standard (c) Definite Widened (c) DefiniLe DeAnire ernte-heavy cigarettes in increase. vulse, increaaae. increase. cisaretti smokers. 10 minutes. pressure. (d) NicotineO.6 (d) Definite Definite (d) Dcfinlt-e Dellnit- mg. intra- increase. increase. i"CV3.W. change. Ye"ousIy. TAOLE A21.--6ccpcri~~~ents concerning the efects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. Year. country. rclercnce Prntrcost Nut$r;nd Smoking Heart Blood Eleclrocardiosrnm Stroke Cardiac DhXFSi!J~~ rate PRSl"W ballistocnrdloeram volume OUtDUt C"d;o,n;lY Comment.8 pODUt`,tiO" How I. 14 volunteers Single ciKarette Definite Definite I. 10 21 DerCe,,t ;b"J with clinical Shelling- CIID, 13/14 l~,ril, smokers, 11164. averape *pe U S.A. 39.6. (149). II. 6 patients with angina pCCtAri.3. &it1 smokers, ave. rage age 43.4. 111. 14 Datk"tS with history ol definite myo. cnrdinl infsrc- tlon, all smok. em *"eraBe age 64.1. smoked at own increase increase geW"t incrcaw. rate in 6-l in all in all increase, minutes. ITOUDI. !JrO"DS, II. Inter- Interme- medipte dlnte change. change. III. a DCP 1 D~rG?r,t cent incresac. decreaae. Frulikl 6 male and 3 2 rtandsrd Definite No signih- No signifi- The author contrnnta P! HI., female Datients cigarettes in incrense cant changes cant this rnponse with lcKJ5, u*ith healed 10 minute3 at al rest at rest or chnngL-3 that LI~C" amo,,p U.S.A. myocardisl inlarc- rest and under and at during at rest or hcnlthy you"&! (ti?). tion 48-69 years graded exercise. exercise. exercise. during individuals. 01 age Z/8 non- exercise. smokers. TABLE A21.- Experiments concerning the e&Tech of smoking atld nicotine on the cardiovascular system of hman8 (cont.) AUlbW, year. Number and Smoking lienrt Blood Electrocardiocrnm Stroke Csrdinc CO"IltlY, 1ype of procedure rate pWSs"rC bnllistocnrdiogram volume cK,"d"v output ^ C4mmentc reference populntion 1lLlW Allison 30 healthy male 2 standard ciga- Definite Increase. Increase fol- Definite drercnac in and Roth, aubjectr. retta smoked Increase. lowed by pulmonary blwd 1969. 1949 years of In 12-16 minute decrease wulume 83 indicated U.S.A. (3): nge. period. within 20 minutes. by impwloncc mc\boda of thorocic PUIX volume. Aronow and 10 male patienta 1 low nicotine Definite Definite All patients dcvclopcd SWltOOD. with classical cigarette in increase. increase. angina moner if 1969. fingina pectoris. 6 minutes. they amoked bclore U.S.A. 32-59 yeara of exercising. (7). aye. Aronow and 10 male patients 1 non-nleotlne No chanw. No chance. No dlfiercncr natcd Swanson. with claraical cigarette in In time or onset 1969. anpina pectaria. 6 minutea. of excrcistcinduced U.S.A. 32-69 yeara of *ngir,0 bctwe,n (6). ape. anwkina and non- rmoklng prucrdurca. Mershsll et III., 1969. U.S.A. (129). 42 normotenslvc 314 of one standard Insignificant lnsignificnnt Blood prr-srurc rrB"onle healthy male cigarette. increase. increanc. to cold prwsor teat prisoner8 noled to Lw grcntrr in 13-50 yean of heavy amokcra. a!ze. Prc5~n~opnl rcnctiona 13 nonsmokera. to 40 dcgrre bced-up 16 moderate till moi-c Irruucn1 smokers. in smokers. 13 heavy smokers. TABLE A22.-.?hpeti?ncnts concerning the cgcct of nicotine or smoking on cutcchoht~inc lcuch WMlfril 22 mongrel doga Clgnrette smoking via Ile~uler ciunrette smoke evoked a atatlatically aignlflcent incrcndc In nilrrnnl vein. md Watta, trneheal cnnnula: vena cave. and femoral artery levels of eDinepbrine. CornsIlk cigarcttc amukr woked 1063, 1 cigarette/8 minutea no chnnse. U.S.A. for 36 minutes. (ZIO). Wes1fall 21 male volunteers 3 ciunrettcs smoked in Smoking nt rnte noted for 2',4 hours evoked B signlficnnt Incrcn8c In urinnry cplnc- and Wntta. ap~roximnlely 26 SO minulca. phrinc. but not norcpincphrlne Irvels. 1ec4, yenre of n*e; U.S.A. 11 nonsmokers, (II!). 10 amokem. wmtfsll et al., MOnkTVZl dOK8 Standard cigarette amokc Smoke inhalntian cvoknl R r/Be In cardloc output. atrokc volume. blood nrrw\!rc, nnd 1966, cxwsure vin cndotrnchcnl plarmn catccholnminc levels. Prctrcntmcnt with prvprnnolol diminial~cd the cnrdinc U.S.A. tube. Smoke lnhnlntion output and ntrokc volume reeponsn but increased the blood prcsaure rrsponsc-the (209,. every third inspiration for latter cflect llue to the release of alpha-receptor activity by betn.bloekade. 3 minutes. E TABLE A23.-Experiments concerning the atherogenic eflect of nicotine administrution m Author. ye.,, couotn. Number and tyDe Procedure Results rercrciee cl mlmal~ Adler et al.. Rabblb Nlcotlne 1.6 mg. IntravenouaLv in 6 oercent The authors noted an artcrionecrosir of the aorta. anectins mainly the 1906, U.S.A. (2). mlutlo" 6 O! 7 dnya per week for more than 4 munthr. inner muscular 18ycrs. hlocrorcopicslly. early changa consisted Of ,mall nrens of calcnrcuus ridging nnd aneur~smsl dilatation without notable fatty degeneration or intimnl discontinuity. hlicroucopicnlly. rarly changes appeared in the muscle cells of the media. and "chalky" depositi wcrc noted between the elastic Rbcn. HUWW. 1943. U.S.A. (SS). I. 6 moni~el donr. Nicotine subcutaneously. lncreaaing dosage up I. O/G ~njmn1s died of infection nnd showed marked cdcmo. n!ld f0Cnl UP to 2.6 cc. 013 percent solution fur 1 hynlinizntion of the mcdin of the e.ojin and lnrgc clustic nrtvriL*. month. 216 nn,mnls wcrc sncrificed and show4 thickcninn and hynlinizo- tion of the WSH~ of the mronory artcries nnd cdcmn uf the mcllin BP well as ondothclial prulifelntion of other aIzc.ricB, II. 60 rati. Increaalne doses UP to 1 cc. of 1 percent II. Much It-15 *ortic involvement than that found in thr doga: inlrc- solution for 1 month. quent r,rteriolnr changes consisting of Rbrosia and thickcninu of the media. MS6lOVa, Rabbi& I. (10) Nicotine aubeutaneously 1 percent I. Aorlic wall---acute swelling of claxtic fibem with loco1 frognlenta- 1966, solution 0.2 cc. daily for 116 days. lion and partial disintegration-no intimal lot deposits SCC~. USSR Coronary vessels-thickening 01 thr vessel wall-no fat deposits. (130). II. (14) Nicotine ~1~s 0.2 grams cholesterol II. Aorta-"massive" deposits of "cholesterol" in the intlma nnd YLLSIL per day. vniorum with "lcmsening" of the aotiic wall. Cotonnry VMSVII- the larger vcsscl~ showed mticrntc fnt depositlou nnd the ~mllllcr ve~scls showed swelling of the cliuLicn. III. (IO) Cholesterol only. III. Aorta--i.olatd lipid deyusition in the arch snd a.vccndinv. portiune only. Coronary vessels-no fat dcpusitiun. -- Czochra- Rnbbita I. (10) 1.0 g. cholesterol/day for 100 ln~irx uf nul-tic lnion density (cholesterol inr~ltrstion): Lysanowicr dnye. I. 2.5. et al., Il. (10) Cholesterol plus 0.0015 g. nicotine/ II. 3.4. 1969. day intrnvenourly. U.S.A. 111. (4) Nicotine only. III. Nu nurtic lcsiono noted. (46). Author, year, CO""lrY. Number and type I'rllcrilurc RcvultJ rcfcrrncc of nnimnl -- Wcnzrl Pl al.. Rabbits I. (12) C,~ntwl untlcntod. Gcncrni Rn~l!n~`s: Mnrkul .sorlic nntholonic involvrmrnt w'ns noted in nil 1050. II. fl U.S.A. (frn7). III. IV. V. 12) Cs~ntrul ,licl plu3 I percent cholcstcrl,l nnd 5 ,icrccnt cuttanseed oil nddcd 12) Cnnlrol diet plus oral nicotine 2.2H mp./kC./dny. 12) Rraimen 11 plus oral nicotine 2.2R ma./ha./day. 12) Regimen 11 plus oral n&line I.42 mu./ks /~lny. Thicncs 1960, U.S.A. VI. (12) IleKimcn II plus oral nicotine 0.57 mg /ka./dey. Newborn rata nnd Nicotine subcutnncousiv un to 5 mg./kg. No nnrrini pathology noted. hledinl dwrnwntion wcn more Irn~unltiv mice. twice daily by the end of 1 month. Animals autonsied at 1 year. hlale rabbits I. (10) Nicotine subculnncounlv 0.16 Sicnilicont diflcrcncn in aorlic subrndothrilnl fibrail brtwwn control Sncrificcd at GO days. i= TABLE AZ?,.--Eccperimenls concerning the QtherOgeniC cfCct of nicotine administration (Cont.) OJ Author. year, countw, Number and type Procedure Reaulb rcfewnce of animrl Hua cl al., Male rabbits Nicolinc Diet Vilomin D 1966, I. (8) Conlrol CO"ltOl Control I. Infrwucnt medial calcific disease without llpid localization. U.S.A. 11. 17) Control Cholrsterol Cuntrol II. No medial calcific disease but Ireguent intimal atherurna formation. (80). III. (14) Nicotine CU"ttOl CO"ttUl III. Rare cnlcilic medinl degeneration; no intimal athcro"bntous dlscost. IV. (15) Nicotine Cholcslerol Control IV, The Iaw=t number of ntheromataus lesions. V. (91 Control Cholesterol Vitamin D V. No medial calcific diseaae. VI. (14) Nicotine Cholesterol Vitamin D VI. Conslrtent medial calcific disease. (Sacrificed at various times) Control-no treatment. Nicotine-subcutaneous injectiona in oil- increasing amounts 2 times per week. Vitamin D--subcutanwus injections up Lo 6-8 x 1w III. Cholesterol--260-500 mg. cholesterol sdded per 100 g. diet. Choi. Albino rabbita I. Nicotine l-5 mg./kg.lday intraperi. I. Increasing nicotine dosages were aswciatcd with dccrcnscd athcroma 1961. t0"MllY. formation (findings not statistically significant). Korea Cholesterol 1 g.1dr.y (in varying II. Nlcotinc ulone prcduccd no nthcruma formation bul WBJ usur,ciatI prOCCd"rC fatty ncidr cholrstclol triglyccridcs ottlcr Comments rerrrcnce wpulotiou hlurchiron 0 melt and 4 2 cigarettes I. Dclinitc Nu rhngc. Nu chan~c. Uoth regular nnd sham amokers and fcmnle mod- in 15 minutes. incwose. shawcd significant incrcn.4cs FYIIZ, mate smokers I. Lit-cign- II. No change. No ClLmKe. No chnnw, in conccntrntion of IcNm I'JGC. with various rc1tes. oieic acid nnd SLgnlfirnnt Scotland discnses 31- 11. Unlit-cign- dccrcnars in conuvlltrl~tion of (139). 67 ycnrs of rettcs. ~crum Pnllnitic acid. age. Kerrhbaum 6 normal et .I., heavy 106i, cipnrette U.S.A. amukcrs (105). 20-15 years of nE!e. Vnrlous types of cigarettes of known nicotine content. llrsulai. cigarcttrr. filtrr ciKnrrttes. chmcllnl-filtP, ciunlcttcs. pipe tobnccn PI\B cignreltes nil showed similnr increiw in FFA. Lcltuce Ical cimrettes hnd negligible eRect. ANIMAL AND IN VITRO STUIlIES Kerrhbaum 20 adult I. 0 reccivcd I?4 nicotine et al., 1 II c 5 , U.S.A. (107). TABLE AZ?.Smoking and thrombosis -- Author. wlmle Partial Rexaleif~ed YtiT. Numbrr and Expcrl. blood Pro- thrombc- Dlrrsma Plotrlet Platelet PlaL?let Platelet ctiuntt-y. type of mental clotting pInstin clotting adhrsive- count SUlViVal turnover Other Comments rcrcrcnte populntion conditions ' lime ":Ein tlme time "~88 -_-___- - Blnck- 16 dUlL 12 individuals PloU"U burn achizo- rmokcd 2 llypvtn et al., phlwnic hlph. time 1053. pnticntn. 8 nicotine (-) U.S.A. university atsndard (25). atud,,ntr. nil trR,id ii"!1 with cithcr IlflCr clumping Murphy. CVDur periods of time l%i3. COI'O. Dli nbstinence (-) c--j (-) (-) (-) (+) (4-l (2) U.S.A. hrn\y or cuntinua- dacrenae increase (Ill,. smokers 35- Lion of 72 YPBi-5 of smoking. aYe Ambrus 20 hoolthy Deep inhala- Thromboplaslir~ 2 studrnts and mule nr,n- tl"n of one yc,lmltlon I~~~plmc ill, Ml"k. smukinv nonfiltered 1-j (-) f--j (`c) C-J 1imr Rvomen: while filtered cxgarettrs showed respective decreesa of 11 nerwnt and 2, percrnt. Stromb!ad. 1959. Saedcn , Ii, ,. 11 mnie and femnle subjects (smokrrs and nonsmokers) were studicd for the eilect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by veno~~l occlusion plpthysmozraphy. Increasing doses of nicotine were asso- ciated with increasing nombers of individuals manifesting vase- constriction. The vasoconStTxtive eKec!s of nicotine were abolished by the prior administration of either hexamethonium or Dentolinium. Bmnetr and Boake 9 male patients with intermittent clsodication (`I were heavy smokers) 1960X"srnlia 118,. were studied ior the cKect of smoking on blood flow to the leg a5 measured h,- vc11ous occlusion plethgsmogr-aphy. Smoking an un- filtered cigarette was found not to p:-educe aray consistent changes in blood Row to the caLf or foot of the affected leg. Freund and Ward. 1960. U.S.A. (68). 15 male prkon inmates (less then 35 years of age) and 14 male patients with peripheral vascular disease la~~roximatcly 65 years of ape, were studied ior the effect u: smoking on digital circulation as rwasurrd by skin temtxrsture. plc:hysmoglsphy, and radiosodium CIPP~R~CC from the skin. Smokina WRS iound to adversely affect the fib;: and third ~FISUIP~ in a stp~iricant manner (while plethva- montaphic valurs weac rsr-isb!r) only in the healthy prisoners and not at a,, in the Sargent group. Roth and Schick. 100 normal tndividuals undrruent 425 cxperlmcntal procedures con- 1960. U.S..4 (161). cerntng the eflrrt 01 srnok~~~ on the petipheznl circulation. Smak- ing II-Z, found to be as.oclsted with a drrrrxe in extremity skin tP"De**t"*C. 129 130 Chapter 2 Cardiovascular Diseases Part II 131 CONTENTS Page Coronary Heart Disease (CHD) .............................. 135 Introduction ..................................... Cigarette Smoking as 3 Major Risk Factor for -135 Coronary Heart Disease .......................... .136 Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease .................. .137 Hypertension ............................. .137 Cofflee Drmking _ _ _ . _ _ _ _ . , _ _ . . _ . ,141 Ventriculx Premature Beats ................... .142 Carbon hlonoxide .................................. ,142 Introduction ................................. -142 Sources of Carbon hlonoxide Esposu re and Human Absorption ......................... .143 Effects on Healthy Individuals ..................... .148 Effects on Persons With Atherosclerotic Cardiovascular Disease ....................... .I49 Studies on the Pathogenesis of Cardiovascular Disease ................................. .150 Nicotine ....................................... ..15 1 Acrolein ....................................... ..15 1 Cerebrovascular Disease ................................ .,.151 Effects of Smoking on the Coagulation System .................. .154 Summary of Recent Cardiovascular Findings .... , ... , ........... .155 Bibliography .............. _ .......................... .156 133 List of Tables Table I. - Age-standardized blood pressure changes (mm tlg) at followup for continuing cigarette smokers and quitters according to weight clrsnges _ . . . _ _ 139 Table 2. - Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...140 Table 3. - Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race . _ . . _ _ . _ _ . . _ . _ _ 144 Table 4. - Alean percent of carbosybemoglobin saturation in smokers and nonsmokers by employment status _ . . _ . 14.5 Table 5. - Median percent carbo~yl~enloglobln (COHb) saturation and 90 percent range for smokers and nonsmokers by location _ . . . . . . . . . _ . _ . 146 Table 6. - Alean percent carboxyhemoglobin (COHb) saturation in cigarette smokers I hour after last cigarette . . . . 147 Table 7. - Age-standardired death rates and mortality ratios for cerebral vascular lesions for men and women by type of smoking (lifetime history) and age at start of study . . . . . . . . . . .._...____...._____._______.____ 153 134 COROXARY HEART DISE,\SE (CHD) itirrodlrcliorl Coronary Heart Disease (CHD) is the most frequent C`XUSS of death in the United States and is the most important single c3use of excess mortality among cigarette smokers. The evidence relatins smoking to CHD has been reviewed in previous reports on the health consequences of smoking (61. 62. 63. 64. 65. 66. 67. 6Sj. The following is a brief summary of the relationships between smoking and CHD presented in these reports. Cigarette smoking, hypertension, and elevated serum cholesterol are the major alterable risk factors for myocardial infarction and death from CHD. Cigarette smoking acts both independently as a risk factor and synergistically with the other CHID risk factors. The magmtude of the risk increases directly wi'th the amount smoked. The excess risk of CHD amon? smokers has been demonstrated in some Asian, Black, and Caucasian populations and is proportionately greater for younger men, especially those below age 80. Cessation of cigarette smoking results in a reduced mortality rate from CHD compared with the mortality rate for those who continue to smoke. Pipe and cigar smokers have a slightly higher risk of death from CHD than nonsmokers. but they incur a much lower risk than ciga- rette smokers. This has been attributed to the lower levels of inhala- tion that characterize most pipe and cigar smoking. Data from autopsy studies have shown coronary atherosclerosis to be more frequent and more extensive in cigarette smokers than in nonsmokers, and experimental work in humans and animals has suggested several mechanisms by which smoking may influence the- development of atherosclerosis and CHD. The formation of carboxy- hemoglobin, release of catecholamines, creation of an imbalance between myocardial oxygen supply and demand, and increased platelet .adhesiveness leading to thrombus formation have all been demonstrated in smokers and proposed as explanations for the excess CHD mortality and morbidity among smokers. 135 Cigarette Stnot?ittg as a .Ilajor Risk Facror for Corottary Heart Dherrse The evidence establishing smoking as a major risk factor in CI1D has been reviewed in previous reports (lil. 62. 63. 64. 62. 66. 67. 6s). During the last year new epidemiologic data have been published on the relationship between coronary artery disease and smoking. Bengtsson (9. 10) studied the smoking habits of women with myocardial infarction (hiI) in Goteborg, Sweden. He found that smoking w3.s significantly more common in a group of 46 women (80 percent smokers), ages 50-54, who had a myocardial infarction than in ;1 control group of 578 herllthy nonhospitalized women (37.2 percent smokers). Other investigators examined the effect of cigarette smoking on sunrival of people with acute myocardial infarction. In a study of 400 patients with documented myocardial infarction who survived to he admitted to a coronary care unit, Helmers (26, 27, 2s) found no significant difference between the percentages of smokers and nonsmokers among survivors studied after ihe first 24 hours. from 2 days until discharge, and from discharge to 3 years. Reynertson and Tzagournis (53). in a 5-year prospective study of 137 patients with documented CHD at age 50 or less, were also unable to find sny relationship between CHD mortality rates and smoking habits. Smoking habits after entrance into the study were also considered and again rio difference in mortality rates was found. The Coronary Drug Project (17) found an effect of cigarette smoking on mortality after myocardial infarction. This group studied 2,789 men ages 30-64 years for 3 years after myocardial infarction and found a statistically significant correlation between cigarette smoking determined 3 months after a myocardial infarction and mortality (t-value of 2.94). None of these studies (Z 7, 26, 27, 28, 52) were able to examine the smoking habits of the group of people who die suddenly as a first manifestation of CHD, and therefore may have excluded that group in which there is the highest excess mortality due to cigarette smoking (31). Additional data from the Swedish twin study of Friberg, et al. (23) have been reported. They found an excess CHD mortality among smokers in dizygotic twins with different degrees of smoking, but no similar excess in monozygotic twins. Although the numbers \vcrc too lrnal1 to be significant, the authors suggest that this tends to >uppc>rt the theory that both smoking and CHD are constitutionally 136 determined. These data must be viewed with caution. however, since the difference was demonstrable only in the older age group (born 1901 - 1910). \J'hen the younger age group (born 191 1 - 19?5) ~3s considered, no excess CHD mortality was seen in the dizygotic group but a small excess was noted in the monozygotic group (three CHD deaths in the high smoking group and one in the low smoking group). Also the difference in cigarette consumption between the t!igh and low smoking groups was rslativeiy small (seven cigarettes per day). Consequently, data from this study are not sufficient to warrant the conclusion that both smoking and excess CHD mortality are constitutionally determined rather than smoking being a cause-of the excess CHD mortality. Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Dbease Cigarette smoking, elevated serum cholesterol, and elevated blood pressure are generally accepted as the three major modifiable risk factors for CHD. However, there is less agreement concerning other CHD risk factors - obesity, physical inactivity, diabetes mellitus. elevated resting heart rate, psycholopic type A behavior, etc. The following studies present recent evidence on the relation- ships between smoking and hypertension, coffee drinking, and ventricular premature beats. Results from several studies have shown that smokers on the average have slightly lower blood pressure than nonsmokers. Some investigators have attributed this finding to the fact that smokers on the average weigh slightly less than nonsmokers. Three current studies (24, 36. 55) discuss this relationship. Gyntelberg and Meyer (-74), based on their evaluation of 5,249 men ages 40-59, were of the opinion that lower blood pressure in smokers could not be accounted for by differences in weight. age, or physical fitness. Kesteloot and Van Houte (36), in a study of 42.804 men, performed a multiple regression analysis on age, weight, and height and found that cigarette smokers had lower blood pressure than nonsmokers; however, When they included serum cholesterol values in the analysis, the difference in blood pressure was reduced to approxi- mately I mm Hg. Although tllis difference was statistically signifi- cant based on the large population. the actual difference in blood pressure was too small to be of clinical importance. 137 Seltzer (55) studied 794 men selected for their initial good health and normal blood pressure (below 140 systolic and 90 diastolic) and followed them for changes in cigarette smoking habits, weight. and blood pressure. During the S-year period of the study 104 men gave up smoking. For every age group except those over 55. there was a significantly greater weight gain (8 lb) among the "quitters" than among the continuing smokers (3.5 lb). Blood pressure increased 4 mm Hg systolic and 2.5 mm Hg diastolic in the quitters with no change in systolic and a slight reduction in diastolic (-1.1 mm Hg) in persons who continued to smoke. in order to examine blood pressure changes in relation to weight change, both continuing smokers and quitters were grouped according to their weight changes during the period of study (Table 1). The most significant finding was an increase in the systolic blood pressure (+ 1 .77 mm Hg) among the quitters even in that group with significant weight loss. In contrast, the continuing smokers with significant wei$t loss had a decline in systolic blood pressure (-3.28 mm Hg). Diastolic blood pressure in quitters showed an increase with weight gain and no change with weight loss, while continuing smokeys showed a decrease in diastolic pressure with weight loss and no change with weight gain. The data on subjects whose blood pressure had increased to hypertensive levels (systolic > 1.50 and diastolic > 9.5) were evaluated, and it was found that quitters had a much higher frequency of becoming hypertensive than continuing smokers (Table 2). Seltzer, in interpreting these data, suggested that cigarette smoking tends to inhibit blood pressure increases, with only minimal pressure rises occurring even in instances of substantial weight gain. When this inhibiting effect of cigarette smoking is removed as in the case of the quitters, sharp rises in blood pressure become evident. He cautioned, however, that the development of hypertension in some quitters may have been responsible for decisions to lose weight and that his data do not allow an evaluation of the degree of blood pressure changes according to how recently cigarettes were given up. The results of the ischemic fleart disease study by Kahn, et al. (34) raise additional questions about Seltzer's data. Kahn followed 10,000 Jsraeli male civil service employees for 5 years to determine what factors were associated with an increased incidence of hypertension. He presented no data concerning persons who stopped smoking, but he did show that the incidence of hypertension increased with age and that the age-adjusted incidence of hyper- tension in smokers was over twice that of nonsmokers (76.9/ 1000 for smokers versus 35.4/1000 for nonsmokers). Seltzer reported no 138 TABLE 1. - Age-standardized blood pressure changes (mm IIg)l at followup for continuing cigarette sn~nkers and quitters according to weight chofrges Weight Change (LB) Significant No Significant Modcrate Smoking Clas wt LOS Wt Cl13ngc WI Gain II) lb lb NO. -25 to -5 No. -4 lo +4 No. +5 IO +12 Mean systolic BP changes; Continuing smokers 32 -4.00 84 -1.52 71 2.85 Quitters 13 1.77 27 2.22 27 4.04 Mean diastolic BP changes: Continuing smokers 32 -3.28 84 -2.04 71 0.13 Quitters 13 -0.31 27 -1.96 27 4.30 `Standardized on basis of age distribution of current cigarette smokers. Source: Seltzer, C.C. (j-5). Significanl WI c;ain II) - No. +I3 IO +30 24 I .sll 32 3 69 24 -0.04 32 3.94 TABLE 2. - Number of subjects who hod developed hyperrensiorl at followup for contirruhg cigorettc smokers and quirters Blood preaure Continuing cigarette snnokers Quitters levels Number Percent Number Pcrccnt Systolic blood pressure lSO+ 6 2.8 9 x.7 Systolic blood pressure 160+ 2 0.9 5 4.8 Diastolic blood pressure 9S+ 3 1.4 5 4.8 Source: Seltzer, C.C. (55). data on the incidence of hypertension in nonsmokers, and the age distribution for his group of smokers (the original source of the quitters) is heavily weighted toward younger age groups .(with only 33 of 214 men age 50 years or over). According to Kahn's data, this age group would be expected to have a lower incidence of hypertension, and, in fact, Seltzer found only small numbers of men who developed hypertension (eight with diastolic hypertension) (Table 2). Making interpretations based on such small numbers is hazardous; for example, the difference between current smokers and quitters in the incidence of diastolic hypertension could have been produced by only three men quitting smoking because they developed hypertension. Coffee Drinking The Boston Collaborative Drug Study (12) recently reported a correlation between coffee drinking (> 6 cups per day) and myocardial infarction that persisted after controlling for the effect of cigarette smoking. This was a retrospective study of 276 patients with a hospital discharge diagnosis of myocardial infarction and 1,103 age, sex, and hospital-matched controls discharged with other diagnoses. In addition to the usual limitations of retrospective studies, this study has several characteristics that make interpretation difficult. In controlling for the effect of cigarette smoking, the investigators divided the smokers into those who smoked one pack or less per day and those who smoked more than one pack per day. Because cigarette consumption is highly correlated with coffee consumption (29, 39), it can be expected that within such broad smoking categories those who were heavy coffee drinkers tended to be heavier smokers than those who consumed smaller amounts of coffee. It is also possible that the hospitalized controls represented persons who drank less coffee than the general population because of serious chronic illnesses. These characteristics of the study design do not allow firm conclusions to be made concerning the extent to which the relationship between coffee drinking and myocardial infarction is independent of the relationship of both variables to cigarette smoking. The question of the independent nature of this relationship is also dealt with in a prospective study by Klatsky, et al. (39) of 464 patients with myocardial infarction who previously had had multi- phasic health checkups. Both ordinary controls and CHD risk factor-matched controls were drawn from 250,000 people who had undergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee drinking and myocardial infarction when risk-matched controls were used. 141 The Framingham Study (I$) recently published data on coffee drinking based on a I?--year followup of 5,209 mrn and women ages 30-67. An incrensed risk cfdeath from all causes was demonstrated in coffee drinkers, but this relationship was accounted for by the associ- ation between coffee consumption and cigarette smol;i,g. No association between coffee drinking and myocardial infarction or between coffee drinking and the development of CHD, stroke, or intermittent clsudication was demonstrated. Heyden, et al. (29) also found no relationship between excessive coffee consumption (> 5 cups per day) and atherosclerotic vascular disease. Vettrrictrlar Prmratrtre Beats Ventricular premature beats have been shown to be a risk factor for sudden death from CHD. Vedin, et al. (69). in a study of 793 men 111 Goteborg, Sweden, examined the frequency of rhythm and COl~dUc~iOJ~ disturbances at rest and during exercise. They found no statistically significant correlation between cigarette smoking habits and the presence of supraventricular or ventricular premature beats at rsst or during exercise. CARBON MONOXIDE Itrtrodrictiott Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemo- globin levels below 15 to 20 percent were thought to have little effect on humans. Currently there is considerable interest in determining the effect of chronic exposure to low levels of carbon monoside (65. 66, 67, 68). Carbon monoxide is present in concentrations of 1 to 5 pelcent of the gaseous phase of cigarette smoke (II, 45). The concentr%tion varies with temperature of combustion as well as with factors which control the oxygen supply such as the porosity of the paper and packing of the tobacco. The amount of carbon monoxide produced increases as the cigarette burns down. Carboxyhemoglobin levels in smokers vary from 2 to IS percent depending on the amount smoked, degree of inhalation, and the time elapsed since smoking the lrtst cigarette. Carbon monoxide, which has 230 times the affinity of oxygen for hemoglobin, impairs oxygen transportation in at lcast Iwo ways: 142 First, it competes with oxygen for hemoglobin binding sites. Second. it increases the affinity of the remaining hemo@obin for osyfen. thereby requiring a larger gradient in Paz between the blood and tissue to dsliver a given amount of oxygen; this increased gradient is usually produced by a lowering of the tissue Po2. Carbon monoxide also binds to other heme-containing pig ments, most notably myoglobin, for which it has e\`en a greater affinity than for hemoglobin under conditions of low Paz. The significance of this binding is unclear, but may be important in tissues, such as the heart muscle, which have both high oxygen requirements and large amounts of myoglobin. Sources of Carbon hlonoxide Exposure and flumarl A bsorpriorl Several researchers (13, 32, 35. 57. 60. 70) have estimated the relative contribution of cigarette smoking and air pollution to the human carbon monoxide burden as measured by carboxyhemoglobin levels (COHb). Kahn, et al. (35), in a study of 16,649 blood donors. determined that smoking was the most important contributing factor, followed by industrial work exposure. Nonsmoking industrial workers had COHb levels of 1.38 percent, and nonsmokers without industrial exposure had levels of .7S percent. Cigarette smokers. on the other hand, had very high levels. Smokers with industrial exposure had levels of 5.01 percent, while smokers without industriai exposure had levels of 4.44 percent (Tables 3 and 4). Stewart, et al. (57) found similar results in a nationwide survey of blood donors and noted marked variation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However. in all areas, smokers still had COHb levels two to three times higher than nonsmokers and had increasing COHb levels with increasing level of cigarette consumption (Table 6). Similar findings were reported by Torbati, et al (60) in a study of 500 male Israeli blood donors. Nonsmoking workers exposed to atitomobile exhaust - London taxi drivers (32) and garage and service station operators (13) ~ have higher baseline levels of carboxyhemoglobin than nonsmokers of the general population. But even in these high exposure occupations smokers have markedly higher COHb levels (8.1 and 10.8 percent) than nonsmokers (6.3 and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed to an average of 63 ppm CO with peak exposure levels as high as 217 ppm CO: cigarette smokers still maintained much higher COHb levels (5.01 percent) than nonsmokers (2.93 percent) (8). 143 TABLE 3. -Mean percent of carbo.~yhemoglobit1 saturation in smokers and notwnokers by sex alId race Total Sample 1 Nonsmokers Smokers1 No. jz+s,- NO. x+q No. 2 +s, Total Sample 16,649 2.30 t 0.02 10,157 0.85 2 0.01 6,492 4.58 t 0.03 hlalc 10,542 2.66 + 0.03 5,888 1.00 + 0.01 4>654 4.76 + 0 04 Female 6,107 1.68 + 0.03 4,269 0.64 + 0.01 1.838 4.10 + 0.06 White 15,167 2.28 to.02 9.474 0.85 f. 0.01 5.693 4 66 + 0.04 htale 9,669 2.65 f 0.03 5,508 1.00 * o.o\ 4,161 4 tl3 * 0.04 Female 5,498 1.63 f. 0.03 3,966 0.64 * 0.01 1,532 4 19 + 0.06 Black 1,429 2.59 5 0.06 641 Male 829 2.91 *0.10 347 Female 600 2.15 c 0.09 294 `Smokers are defined as those who smoked on the day of giving blood. NOTE. - % = mean percent: ST= standard error of mean percent. Source: Kahn, A., et al. (35). 0.86 t 0.03 788 4.00 f 0.08 1.07 2 0.05 482 4.24 + O.lC 0.62 + 0.04 306 3.63 f 0 12 TABLE 4. - hfearz percerzt of carbo.~.~llzt~rnoglobin saturation in smokers arzt! Izutzwzokers by euzployrnerzt statzis I Nonsmokers Smokrrs' xiss; I No. I.38 t 0.04 I 1,738 5.01 t O.OG G.955 0.7M f 0.0 1 I 4,224 4.44 f u.u`l Persons not employed 1,678 0.6 3 +_ 0.02 531 4 24 f 0. I I `Industrial workers are employed in either durably or ~mndur,~bls good> manufacturing (craflsmen. operalives. or I~borrrs). Smokers are defined iis those who smoked on lhe day UC giving I~lood. NOTE. - i = mean percent; S, = stnnd.lrd error of mean percent. Source: Kahn, A., et al. (35). TABLE 5. - Median percent carbo~yylrerrloglobin (COHb) saturation and 90 percetrt range for smokers and wmtnokers by location Location Anchorage Chicago Denver Dciroit rlonolulu Houston Los Angeles hliami Milwaukee New Orleans NW York PhOWlX St. Louis S.111 Lake City Slin IFruncisco SeJttle Vermont. NW Ilampshire Washington, DC Cigarette Smokers Nonsmokers . Median Range 4.1 0.9 - 9.5 5.8 2.0 - 9.9 5.5 2.0 - 9.8 5.6 1.6 - IO.4 4.9 1.6 - 9.0 3.2 1.0 - 7.8 6.2 2.0 - 10.3 S.0 1.2 - 9.1 4.2 1.0 - 8.9 5.5 2.0 - 9.6 4.8 1.2 - 9.1 4.1 09 - 8.7 5.1 1.7 - 9.2 5.1 1 5 - 9.5 5.4 1.6 - 9.8 5.7 1.7 - 9.6 4.8 1.4 - 9.0 4.9 1.2 - 8.4 hlcdian K3llge 1.5 0 6 .- 3.2 I .7 I.0 - 3 2 2.0 o.!, - 3.7 1.6 0.7 - 2.7 I.4 0.7 - 2.5 1.2 06-35 1.u I.0 - 3.0 1.2 0 4 - 3.0 1.2 0.5 - 2.5 1.6 I.0 - 3 u 1.2 0.6 .- 2 5 1.2 0.5 2 5 1.4 0.9 - !.I I.? 0 G 2,s 1.5 0 h 2.1 1.5 0.M - 2 7 I.2 0 K - ?..I s 1.2 0.6 2.5 l-- Source: Stewurt, K.D., et III. (57). TABLE 6. - Mean percent carhoxyl~emoglobirr (COiIb) saturation in cigarette smokers I hour after bst cigarette Location Nonsmoker Packs of Cigucttcs Smoked Per day CK %-I I 1 5i 2 hlilwukuc Now Htimp\hirc, Vermont New York City Washington, DC LOS Angclcs Chicago 1.3 3.0 4.2 5.3 6.2 4,7 1.4 3.3 4.4 5.1 67 5.3 1.4 3.1 4.3 4.1 5.x 63 1.4 3.8 4.6 5.2 5.x 6 6 2.0 4.0 5.2 6.0 1.4 7.5 2.0 4.x 5.4 6.3 7. I 1.1 Source: Slewart, R.D.. et al. (57) Studies on the CO burden of each cigrette have determined the body burden of CO per cigarette to be 7.10-S.66 ml (40). and the increase in COHb level produced by smoking one ci_rar?tte to he .94 to I .6 percenr after I:! hours of abstinence (40. 33). The hali-life for the washout of CO in healthy college smokers (40) was catculated to be from 3 to 5 hours. Several studies have been published on the effects of carbon monoxide on healthy individuals. Small doses of CO (COZb levels 2.4-5.4 percent) were found to have no effect on heart rate (56). Raven, et al. (5f), in a study of young men exposed during exercise on a treadmill to 50 ppm CO (COlIb levels 2.5 percent in nonsmokers and 4.1 in smokers), found no decrease in maximum aerobic capacity when the subjects were tested at 25" C. In a similar experiment conducted at 35" C by the same researchers (20). there was a decrease in maximum aerobic capacity in nonsmokers exposed to SO ppm CO, but not in smokers despite an increase in the carboxyhemoglobin levels of I.5 percent in both groups. They postulated a possible physiologic adaptation of smokers to carbon monoxide. Ekblom and Huot (22) studied five young men who inhaled CO to reach given COHb levels. They reported that as COHb levels increased, there was a decrease in maximal oxygen uptake and lower heart rates at maximal treadmill exercise. Sagone, et al. (54), in a study of 9 cigarette smokers and I8 nonsmokers ages 20-32, showed significantly higher values for COHb, red cell mass, hemoglobin, and hematocrit in the smokers. Levels of 2,3 DPG were unaltered while oxyhemoglobin affinity I'50 and A'fP levels were significantly lower in the smokers. The three smokers with highest red cell mass had normal arterial blood gases and one smoker had very high values of red cell mass which returned to normal after he stopped smokin,. 0 The authors interpret these data-as evidence of tissue hypoxia. Millar and Gregory (43), in a study of both fresh heparinized blood and ACD-stored blood from a bIood bank, showed a reduction in the oxygen carrying capacity of up to 10 percent in the blood of cigarette smokers; this reduction persisted for the full 21-day storage life of blood bank blood. Cole, et al. (16), in a study of pregnant women, found COHb levels in the fetus to be 1.8 times a~ great as those in the 148 simu!taneou,ly measured bloat! ot t!1t` m0tI1rr. Fct31 l~100d \v3s exposed to carbon monoxide in vitro. and Iztd! h~mo~!ol~in \vas found to 113~2 a shift of the osyh~mo~obin disassociation curve to the left as occurs \vit!l adult !lemo_clobin. The !li$ler fetal CO!!b levels were attributed to tile lower fetal Po2 and a resultant decrease in the ability of oxygen to compete for t!X fetal I~emoglobin. It was felt by the authors that the hi& COHb levels may be responsible for the lower birth wei$t of infants born to mothers who smoke. Effecis ofi Persons wirll A rheroscleroric Carrliovascdar Disease Aronow and Isbe!! (5) and Anderson, et a!. (I) have shown a decrease in the mean duration of exercise before the onset of pain in patients with angina pectoris exposed to low levels of carbon monoxide (50 and 100 ppm). Carboxyhemoglobin levels were significantly elevated (2.9 percent after 50 ppm; 4.5 percent after 100 ppm) and the systolic blood pressure, heart rate, and product of s>.stolic blood pressure times heart rate (a measure of cardiac work) were a!! significantly lower at onset of angina pectoris. In a continuation of this work. Aronow, et al. (2. 3) studied eight patients durin: two separate cardiac catheterizations, one during which each patient smoked three cigarettes and one during Lvhich each patient inhaled carbon monoxide until the maximal coronary sinus COHb level equalled that produced by smoking during the first catheterization. All eight had angiographically demonstrated CHD (> 75 percent obstruction of at least one coronary artery). Smoking increased the systolic and diastolic blood pressure, heart rate. left ventricular end-diastolic pressure (LVEDP), and coronary sinus. arterial, and venous CO levels. No changes were noted in left ventricular contractility (dp/dt), aortic systolic ejection period. or cardiac index, and decreases were found in stroke index and coronary sinus. arterial, and venous Pq When carbon monoxide was inhaled. increased LVEDP and coronary sinus, arterial, and venous CO levels were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and decreases in left ventricular dp/dt, stroke index, cardiac index and coronary sinus. arterial, and venous Paz were found. .These data suzoest that carbon monoxide has a negative inotropic effect OR m;&ardia! tissue resulting in the decrease in contractility (dp/dt) and stroke index. \I'hen the positive effect of nicotine on contrac- tility and heart rate is added by cigarette smoking, the net effect is increased cardiac work for the same cardiac output. in the heart with 149 coronary artery disease there is a greatly restricted capacity to increase blood flow in response to this increase in cardiac work. The result is early cardiac decompensation manifested by elevation in LVEDP and angina pectoris. Aronow, et al. have also shown decreased exercise time prior to onset of angina pectoris in persons exercised after riding for 90 minutes on the Los Angeles Freeway (4). In a related study, they demonstrated a decrease in exercise time before claudication in a group of patients with intermittent claudication who were exposed to 50 ppm CO (6). Studies otr the Putlrogertesis of Curdiovascniur Disease In a review of some of their work on carbon monoxide, Astrup and Kjeldsen (7) noted that in cholesterol-fed rabbits exposed to I70 ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to 310 ppm for 2 weeks, the cholesterol content of the aorta was 2.5 times higher than that of cholesterol-fed, air breathing controls. Groups of cholesterol-fed rabbits intermittently exposed to carbon monoxide for 13 or 4 hours per day produced three- to fivefold increases in the cholesterol content of their aortas. Cholesterol-fed rabbits made hypoxic at IO and 16 percent oxygen had 3 to 3.5 times tlie aortic cholesterol content, while those exposed to 26 and 28 percent oxygen had a considerable decrease in cholesterol aciumulation. Theodore, et al. (5s) studied the aortas of monkeys, baboons, dogs. rats, and mice fed a normal diet but exposed to very high levels of CO (COHb levels 33 percent) and found no atheromatous changes in their aortas. Further work by Astrup and Kieldsen (38) revealed that in rab- bits fed normal diets but exposed to 180 ppm carbon monoxide for 2 weeks, there were local areas in their hearts of partial or total necro% of myofihrils; in the arteries there was endothelial swelling, formation of subendothelial edema, and degeneration of the myocytes. When the aortas of these rabbits were examined (37), the Iuminal coats showed pronounced changes characterized by sevcrc edematous reaction with extensive swellin, 0 and formation of srrbendothelial blisters and plaques. The authors postulate that carbon monoxide increases endothelial permeability to albumin which results in formation of edema leading to changes indijtirl~Ir;il,,lt~l~ from early atherosclerosis. 150 Evidenc2 that this mecllJnism rnsy occur in Ilunlans is provided by the findings of Panins (50) \vho showed an increased trans- capillary escape rat2 for 13 1 I- labzlrd albumin in humans exposed to .-I3 percent CO (COHh 20 p2rcent) for 3 to 5 hot115. hut not in thoss mad2 hypoxic to an altituti? of -I300 mrters (I~emoglobin 75 percent saturat2d). By exposing rabbits to different conccntmtions of carbon monoxide (SO. 100, and 180 ppm) for varying periods (.S, 2. 4, 8, 24. and 48 hours), Thornsen and Kjeldsen (59) were able to show a threshold of 100 ppm of CO for myocardial damage. The demonstra- tion of damage at this level of CO (COHb 8-10 percent) is possibly explained by the ratio of carboxyrnyodobin to carboxyt~erno_elobin which is about 3 to 1 in myocardium at ambirnt POT. Thus, a COHb level of 10 percent would be accompanied by a cnrboxymyo- globin level of 30 percent in heart muscle. This ratio is even greater under hypoxic condltlons with a ratio of 6 to I when the arterial Paz is below 40 mm Hg (15). Nicotine In a study of the effects of smoking cigarettes with low and hi* nicotine content, Hill and Wynder (30) noted increasing serum epin2phrine levels with increasing nicotine content of the smoke. but serum nor2pinephrine levels were unchanged. However. increasing serum epinephrine levels with increasing number of low nicotine content cigarettes smoked were also noted. Acrolein Egle and Hudgins (21) did inhalation studies with acrolein on rats. Inhalation of this aldehyde at concentrations below those encountered in cigarette smoke resulted in a significanj increase in blood pressure and heart rate in rats. CEREBROVASCULAR DISEASE There has been conflicting evidence on whether there is an increased risk of cerebrovascular disease due to smoking (61, 62, 63, 64. 65. 66. 67, 65). A prospective study by Paffenbarger, et al. (4s) of 3,991 lon&oremen followed for I8 years showed no correlation between fatal strokes and smoking. However, both the Dot-n study of 151 U.S. veterans (3-i) and Hammond's study of one million men and women (175) showed a small but slgniticsnt increase in tile death rates from cerebrovascular disease among cigarette smokers. The Framing- ham i&year followup of men ages 45 to 54 (32) and PafTenbar~er`s study of men who entered IIarvard between 1916 and 1940 (49) also showed an excess risk of cerebrovsscular disease associated wit11 cigarette smoking. TWO recent studies provided more data on this topic. Ostfctld. et al. (46, 47), in a study of 2,748 people ages 65-74 receiving old age assistance in Cook County, Illinois, were unable to find any relation between cigarette smoking habits at the start of the study and incidence of new strokes or prevalence of transient ischemic attacks. Nomura, et al. (44), in a study of the population of Washington County, Maryland, ages 25 and older, were unable to find any relation between cigarette smoking and either mortality or morbidity from stroke. Nomura noted that "in atherosclerotic strokes the Framingham study and Paffenbarger's investigation of former college students included a great percentage of stroke cases under the age of 55. Because these two studies found an association between cigarette smoking and atherosclerotic strokes and the present study did not, it may be that the association is age-dependent." Hammond (25) provides some data which may clarify this relationship. Analysis of his data shows that the difference between cerebrovascular death rates in cigarette smokers and nonsmokers increases as persons get older except in males ages 75-84 (Table 7), indicating that the excess death rates associated with cigarette smoking increase with advancing age. The ratio of the death rates for smokers and nonsmokers (mortality ratio), however, decreases with 3ge. reflecting the fact that cerebrovascular disease death rates attributable to other causes increase with age more rapidly than death rates attributable to smoking. Cigarette smoking may well be a risk factor for stroke at all ages, but other causes of strokes become proportionally so important in older age groups that in studies not based on very large populations the risk due to cigarette smoking%' masked by the large total number of strokes due to other causes. 152 CVL Death Rates per 100,000 Person-Years hlen Never woked regulxly Pipe. cigx Clgtirctlc and other Clgarettc only 28 92 349 25 100 369 2x 129 36 I 42 130 477 Total 35 116 Never smoked regularly Clg;lrcllc Tot;11 18 38 25 57 X8 64 391 22x 315 238 1,3sti 1,371 9'10 l,lbY I.272 I .0X! I.277 I ,09 I CVL hfortalitv Ratios Never smoked regularly I 00 1.00 1.00 I .oo Pipe, cigx 0.119 I 09 I .06 I .o I Clgarelle dnd other I .oo 1.40 1.03 0.72 CigJrclle anl! 1.50 I.41 1.37 0.X6 Women Never smoked regulxrly CIprectc NOTE. - (`VL = Crruhrdl vtiscul~r Ies~ons. I .oo 1.00 1.00 I 00 2.1 I I.54 I.!X I Iii EFFECTS OF S.\lOKISG ON THE CO.AGULATION SYSTEM Several studies have contributed to an understandinq of the role of smoking in thrombogenesis. Lri,inr l-J/), in a controllc`d double blind study, showed that smoking a sin~Je cigarette increased the platelet's response to a standnrd a:_crqatin g stimulus (ADP). This phenomenon did not occur when lettuce lca11` cigarettes were smoked and was independent of a rise in free fatty acids in the plasma. The author postulates that this may be due to increasing epinephrine Jcvelr. These data may have relevancrt for two other studies. In the clinical trial of the possible prevention of heart attack by hyperlipidemic drugs in Newcastle, En~lnnd, (19) it was found that cigarette smokers were at increased risk of sudden death. This increased risk was not present in smokers treated with clotibrate. Llowrver, the researchers were unclble to relate this reduction in risk to any effect of clofibrate on st`m~n lipids. Kscfntly Carvaiho, et at. (13) evaluated 79 patients with familial i~yp~rbetslipoproteintlniia and noted that their platelets had an increased sensitivity to aggregating stimuli (ADP). Treatment with clofibrate returned the ADP sensitivity to normal without significantly altering serum lipids. This demonstrated effect of clofibrate may provide some insight into the Newcastle study. The reduction in the escess risk of sudden death could be due to a clofibratr induced reversal of increased sensitivity to aggr-egating stimuli produced by smoking. 154 SUJIhlARY OF RECEST C:\RDlO\`,ASCL'LAR FINDISCS 1. Data from one recent incidcncr: study suggest that ciCarc't;-? smokers are more likely to develop hypertension than 3ri nonsmokers. There is some evidence that suggests that stoppir.: smoking may be accompanied by a rise in blood pressure. 2. Cigarette smoking has been shown to be the major sourc< of elevated carbosyhemoglobin levels, with occupational esposnrs and air pollution being far less important in most circumstances. Carboxyhemoglobin levels in cigarette smokers are two to three times the levels in nonsmokers and increase with the amounts smoked. 3. Elevated carboxyhemoglobin levels have been shown to decrease maximal oxygen uptake in healthy people as weft 3s to decrease the exercise tolerance of persons with angina pectoris and intermittent claudication. The carboxyhemoglobin levels at which these effects take place 3re well within the range productld b!: cigarette smoking. 4. Carbon monoxide at levels of exposure commonly reachi`d by cigarette smokers has been shown to decrease cardiac contractlfitb, in persons with coronary heart disease. 5. Carbon monoxide has been shown to produce changes Iik? those of early atherosclerosis in the aortas of rabbits. 155 BlBLIOGKAPHY ANDERSON. E. W., ANDEL5IAN. K J.. 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Alherosclero~~s 16( 1): 67-82, July-August 1972. 38 KJELDSEN. E.. THOMSEN. H. K., ASTRUP, Y. Eit&ts of carbon monoxide on myocardiurn. Ultrastructural chsnrrs m rabblls sfter moderate. chronic e\powre. Clrculstion RL`search 34(3): 339.348. March 1974. 39 KLATSKY. A. L, t RILDXIAN, C. D., SIECELAUE. A. B. Coffee drinking prmr to acute myocardlal mfxction. Journ~J of the American hledrcal Association 226(S): 540-543. October 29. 1973. 40 LANDAW. S. A. The effects of cigarette smoking on total body burden and excretion r3tes of carbon monoxrde. Journal of Occupatmnal Medicine 15(3): 231.235, 5lxch i 973. 41 LE\;INE, P. H. An acute effect of cigarette smoking on platelet function. A possible hnk between smoking and arterial thrombosis. Circulation 48(3): 619-623;. September 1973. 42 \l&EE. D. Section 28. The probability of developing certain cardiovascular diseases in eight years at specified values of some characterrstics. In: Kannsl, W. B., Gordon, T. (Editors). The FramIngham Study: An cpidemiolorrcal investigation Of cardiovascul.u disease. U.S. Departmt-nt of Health. Education. and Welfare. Public Health Service. Natmnal Instrtutes of Health. Publication No. (NIH) 74-618, May 1973. 152 pp. 43 MILLAK, R. A.. GRI-,(;ORY. I. C. Reduced oxygen content in eqwhhrated fresh hrp,rrinrzed and ACD-stored blood from cigarrttc smokcrc. Bntlsh Journal of Anarsthecta44( 10): 1015.1019, October 1972. 44 NO\lURA. A.. CO\fSTOCK, G. W., KULLEK. L. TDS.\SCIA. 1. A. Qurettr making and strokes. Stroke 5(4):4X3486. July-August 1974. 158 46 OSTFELD. A. hf., SHEK;EI.LE. R. B.. K;1..\\1',\SS. H L. Tr~nwnt icchrrnlc .~llxk\ and risk of stroke m an elderly poor popul.~lion. Stroke 4(h): 9809Yh. November-December 1973. 47 OSTFELD. A. M., SHEKELLE, R. B.. KLAWANS. H , 1 U10, H. hl. Epidemloloey of stroke in an elderly welfare population. American Journal ol` Puhllc tlealth 63(S): 4SO--l58. May 1974. 48 PAFFENBARCER, R. S., Jr. Faclors predisposing to Patal stroke m long>horcmen. Preventive Medicine i(4): 522-525. December 1972. 49 PAFFENBARGER, R. S., Jr.. WING. A. L. Chronic disease in former college students, XI. Early precursors of nonfaral stroke. American Journal of Epldemlology 9-t(6): 524-530, Drcember 197 I. 50 PARVING. H. -H. The effect of hypoxia and carbon monouldr exposure on plasma volume and capillary prrmcabdity to albumin. Scandinavian Journal of Clmical and Laboratory investigation 3U( 1): 49-56. September 1972. 51 RAVEN. P. B.. DRINKWATER. B. L., RUHLING. R. 0.. BOLDUAN. N..TAGUCtll. S.. CLINER. J., HORVATH. S. ht. Effect of carbon monoxide and peroxyxetyl nitrate on man's maxmmt aerobic capacity. Journal of Applied Physiology 36(3): 288-293, hlarch 1973. 52 REYNERXON, R. H., TZACOURNIS. hl. Clinical and metabolic characterislics. Effects on mortality in coronary disease. Archives oi 1ntern.d hlediclne 132(5). 649653, November 1973. 53 RUSSELL, hl. A. H. Blood carhoxghaernoglobin changes during: tobacco \moklng. Postgraduate Medical Journal 49(576)' 684.687, October 1973. 54 SAGONE. A. L., Jr., LAWRENCE, T., BALCERZAK, S. P. Effect of smoking on tissue oxygen supply. Blood 4 l(6): 845.85 1. June 1973. 55 SELTZER. C. C. Effect of smoking on blood pressure. American lfrart Journ.rl 87(S): 558-564, May 1974. 56 SHEPHARD, R. J. The influence of small doses of carbon monoxide upon heart rate. Respiration 29(5/6): 516-521. 1972. 57 STEWART, R. D., BARETTA, E. D., PLATTE, L. R., STEWAKT, E. B.. KALBFLEISCH, J. H., VAN YSERLOO, B.. RIXlM. A. A. Csrboxyhemogobm levels in American blood donors. Journal. of the American hledlcal Association 229(9): 1187-l 195, August 26. 1974. 58 THEODORE, J., O'DONNELL, R. D., BACK, K. C. Toxicological evaluation of carbon monotlde in humans and other mammalian species. Journal of Occupstlonal hiedicine 13(S): 242-255. hfay 1971. 59 THOMSEN. H. I<., KJELDSEN. K. Threshold limit for carbon monoxide-Induced myocudlal damage. An electron muoscopic study in rabbits. ArchIves oi Environmental Health 29(2): 73-78. August 1974. 60 TORBATI. I.D.; HAR-KEDAR. I.. BEN-DAVID. A. Carbo\yhcmoglobin Icvelr in blood donors in relation to c~garel!e smoking And to orcupstlonal expowre to carbon monoxtde. Israel Journal ot blcdwal Sc~encrs lO(3): 241-244, hIarch 1974. 159 61 US. PUBLIC HtAI.TH SERVICE. %nokin~ ..d Ilralth. Kcport ot the ~d\,wry Committee to the Surgeon General of the Public tlralth Service. Wsshinpton. U.S. Department oi Health. Education, and Welfare. Pubhc IlcJlth Setvice Pubhcatwn No. 1103. 1964. 387 pp. 62 U.S. PURLIC HEALTH SERVICE. The Health Conwquences of Smoking. A Public 63 US 64 U.S Health Sew~ce Rcwew: 1967. U.S. Dcpartrncnt of Health. Education. And Welfare. Washington. Public Health Serwce Pubhcatlon No. 1696. Revised January 1968. 227 pp. PUBLIC HEALTH SERVICE. Ihe Health Consequences of Smoking 1968. Supplement IO the 1967 Public Health Scrwce R&ew. U.S. Dcpartmcnt of Health. Education. and Welfare. Washington, Public Health Service Publwation 1696, 1968. II7 pp. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking 1969. Supplement to the 1967 Public Health Sew~ce Review. U.S. Department of Health, Education. and Welfare. Warhington. Public Hrslth Servrce Publtcafion 1696-Z. 1969. 98 pp. 65 U.S. PUBLIC HEAL.rH SERVICE. The Health Consequrnces of Smokmg. A Report of lhe Surgeon General: 1971. U.S. Drputment ol Health. Educatmn. and Welfare. Washington, DHEW Publication No. (fiShi) 7 I-75 13, 1971, 458 pp. 66 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smokmg. A Report of the Surgeon General: 1972. U.S. Department of Health. Education. and Welfare. Washingron, DHEW Publication No. (HSM) 72-6516, 1972. IS8 pp. 67 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 1973. U.S. Department of Health, Education. and Welfare. Washington. DHEW Publication No. (HSM) 73-8704. 1973. 249 pp. 68 U.S. PUBLIC HEALTH SERVICE: The Health Consequences of Smoking: 1974. U.S. Department of Health, Education. and Welfare. Washington. DHEW Publication No. (CDC) 74-8704. 1974. 124 pp. 69 VEDIN, J. A., WILHELMSSON, C. E.. WILHELhtSEN. L.. BJURE, J.. EKSTROhl- JODAL. B. Relation of restmg and exercise-induced eclopc beats IO other ischemic manifestations and to coronsry risk factors. Men born in 1913. American Journal of Cardiology 30(l): 25-3 I, July I I. 1972. 70 WALLACE, N. D., DAVIS, G. L., RUTLEDGE, R. B.. KAHN, A. Smoking and carboxyhemoglobin in the St. Louis Metropolitan population. Theoretical and empIrica considerations. Archives of Environmental Health 29(3): 136-142, September 1974. 160 Chapter 3 Chronic Obstructive Bronchopulmonq Disease source: 1971 Report, Chapter 3, pages 135 - 230. 161 Contenfs Introduction ......................................... Epidemiological Studies .............................. COPD Mortality ................................. COPD Morbidity .......................... .._... Ventilatory Function. ............................ Genetic Factors ................................. Alpha,-antitrypsin ........................... Air Pollution .................................... Occupational Hazards ............................ Cadmium. .................................. Pathological Studies ................................. Experimental Studies ................................ Animal Studies ................................. Studies in Humans .............................. Studies Concerning Pulmonary Clearance .......... Overall Clearance ........................... Ciliary Function ............................ Phagocytosis ................................ Studies Concerning the Surfactant System ......... Other Respiratory Disorders .......................... Infectious Respiratory Diseases .................... Postoperative Complications ...................... Summary and Conclusions ........................... References .......................................... FIGURES 1. Percent of lung sections with Grade IV or V fibrosis . . . 187 2. Percent of lung sections with Grade II or III emphysema 188 LIST OF TABLES (A indicates tables located in appendix at end of chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios.. . . _. . _. . . . . . . _. . . . . . _ . . _ . . . . . . . . Page 165 .167 167 171 172 174 176 178 179 180 180 184 184 189 190 190 190 191 198 198 198 200 201 202 168 163 LIST OF TABLES (Continued) (A indicates tsbics locstetl ~n :~ppendix at end of chapter) A2. Smoking and chronic obstructive pulmonary disease symptoms-percent prevalence. _ _ _ , . _ . . . . . . . _ _ . A3. Smoking and ventilatory function . . . . . . . _ _. _ _ . . _ AJ. GIossary of terms used in tables and text on smoking and ventilatory function.. _ . _ _ _ . . . . . . . . . . . . . . . _ 5. Cessation of smoking and human pulmonary function AG. Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD) . . A7. Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease. . . _ . . . _ . . 8. Studies concerning the relation of human pulmonary histology and smoking . . . . . . . . . . . . . . . . . . . . . . . 9. Experiments concerning the effect of the inhalation of cigarette smoke upon the tt,acheob~.o2lc)lial tree and pulmonary parenchymn of animals . . . . . . . _ _ . . . . . AlO. Experiments concerning the effect of the chronic in- halation of I\`O? upon the trncheobronchial tree and pulmonary parench>-ma of animals _ . _ . . :. . . . . . . 11. Experiments concerning the acute effect of cigarette smoke inhalation on hutnnn pulmonary function. . 12. Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance. . . . . . . A13. Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function . . . . . . . . . Al4. Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension . . . ATS. Studies concerning the relationship of smoking to in- fectious respiratory disease in humans . . . . . . . . . . A16. Complications developing in the postoperative period in patients undergoing abdominal operations - .-. . A17. Arterial oxygen saturation before and after operation Paw 221 232 241 175 242 244 181 185 246 192 196 247 251 252 256 256 ISTI?ODLCTIOS Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lungs. The term COPD refers to three common I-espiratory ailments: namely, chronic bronchitis, pulmonary emphysema, and reversible obstruc- tive lung disease (bronchial asthma) .* Chronic bronchitis has been defined as the chronic or recurrent excessive mucus secretion of the bronchial tree. It is characterized by cough with the production of sputum on most days for at least three months in the year during at least two consecutive years (217). Pulmonary emphysema is that anatomically defined condition of the iung characterized by an abnormal, permanent increase in the size of the distal air spaces (beyond the terminal bronchiole) ac- companied by destructive changes (217). Patients can suffer from both of these conditions simultaneously. The symptoms as well as the abnormalities in pulmonary function observed in the presence of the t1v-o ailments may be quite similar. Patients with chronic bronchitis suffer from productive cough with or without dyspnea (breathlessness both at rest or on exertion) while pulmonary emphysema is characterized mainly by dyspnea. COPD comprises a spectrum of clinical manifestations; thus, it is frequently diffleult to determine nhether a particular patient is suffering from one of the two specified diseases alone or which one predominates when both are thought to be present. COPD is responsible for significant mortality in the United States. In 1967, a total of 21,507 men and 3,885 women were re- corded as dying from chronic bronchitis and emphysema (221). This figure does not include a sizable number of individuals fol whom COPD was a contributory cause of death. During the past two decades, a major increase has taken place in the mortality from COPD in the United States. In 1949, the death rate from COPD was 2.1 per lOp,OOO resident population, Tvhile in 1960 it was 6.0 (zz?), and in 1967, 12.9 (2'1). Although 165 much of this rise is probably due to changes in certification and recording methods as well as to an increased interest on the part of the medical community, an appreciable proportion is also gen- erally accepted as reflecting a real increase in disease. Similar in- creases over the past 20 to SO years have also been observed in Canada (7) and in Israel (3L). The lack of a similar increase in Great Britain, a country with an extremely high rate of COPD, may be the result of a number of factors including improved therapy and decreased air pollution. Moreover, it is also likely that the diagnosis of COPD has been made more commonly and ac- curately in Great Britain for a longer time than in the United States, or elsewhere. Furthermore, the British definitions of bron- chitis and emphysema have differed in the past from those used in the United States. The mortality from and prevalence of COPD is probably under- estimated. In a study of death certificates, Rloriyama, et al. (170) reported that COPD is often omitted as a contributing cause of death. In a study of more than 350 autopsies, hlitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe cIinica1 airway obstruction. Hepper, et al. (110) observed that ventilatory test re- sults were abnormal in 10 percent of 714 patients in whom no symptoms, signs, or past history of pulmonary disease were noted. They concluded that severe degrees of ventilatory impairment may be undetected by history and physical examination alone. Boushy, et al. (40) evaluated clinical symptoms, physiologic measurements of airway obstruction, and morphologic bronchial and parenchymal changes in 90 males with bronchogenic carcinoma. The authors found that when either clinical, physiologic, or pathologic evidence of COPD was used alone, one-third to one-fourth of the patients were considered normal, but when all three criteria were used to- gether, only one patient was free of COPD. The importance of COPD as a contributing cause of mortality is now beginning to be more fully recognized. Clinicians have long observed that the `majority of their patients suffering from COPD were cigarette smokers (1, 150). Epidemio- logical studies have validated this impression by indicating that cigarette smokers are at a much greater risk of developing or dying from this disease and that the risk increases with increased dosage of cigarette smoke, reaching in the smoker of two packs or more a day a level as high as 18 times that of the nonsmokers (132). The salutary effect of giving up smoking has also been borne out by clinical observation and epidemiological studies. In a number of studies, smokers were found to suffer more fre- quently than nonsmokers from pulmonary symptoms including 166 cough, cough with production of phlegm, and dyspnea. By a variety of PUhIIOnar?- function tests, .cmokers were sho\\-Il to ltave dimin- ished function as compared to nonsmokers :ind also to have 3 steeper slope of the espected decline of function lvith age. Tests of ventilation./perfusion relationships in the lung have revealed ab- normal function in smokers. Autopsy studies have indicated that smokers dying of causes other than COPD have significnntl3~ more changes characteristic of emphysema than nonsmokers. Several recent studies have validated the clinical impression that among patients who undergo surgery, cigarette smokers run a greater risk of developing complications in the post-operative period than nonsmokers. Abundant experimental evidence of the role of smoking in bronchopulmonary disease has been obtained from experiments employing animals and tissue and cell cultures. Recent work has demonstrated, in dogs trained to inhale cigarette smoke through a tracheostoma, that emphysema, pulmonary fibrosis, and other path- ologic changes in the pulmonary parenchyma and bronchi develop and that these changes are proportional to the total dosage of cig- arette smoke inhaled. In vice and in vitro studies have sho\vn that whole cigarette smoke, or certain fractions thereof, inhibit ciliar) activity of the bronchial epithelium, adversely affect the mucous sheath, and inhibit the phagocytic activity of the pulmonary alveolar macrophage. These abnormalities lead to retarded clear- ance of inhaled foreign matter including infectious agents from the lungs, thus predisposing the individual to respiratory infec- tions. Evidence also exists that pulmonary surfactant may be ad- versely affected by cigarette smoke. The convergence of these lines of evidence, which will be de- scribed in more detail in the body of this chapter, leads to the judgment that cigarette smoking is the most important Cause of COPD in man. EPIDE31IOLOGICXL STUDIES COPD MORTALITY Numerous epidemiological studies, based on a variety of pop- ulations and carried on in a number of countries, have investi- gated the association between cigarette smoking and COPD. They have shown a greatly increased mortality and morbidity from COPD among smokers as compared to nonsmokers. Results from the major prospective studies relating smoking and CQPD mortal- ity are presented in table 1. The majority of the studies separate 167 TA~LD l.-Chronic obstructive broncltopulmonary disease mortality ratios (Actual number of deaths shown in pnrcntbewa)' SM = Smukcrs. NS = Nonsmokers PKOSFECTIVE STUDlF;S Author. yc.r. Number and Date Follow.up Number CiRnrcttcs/dry Cbr0tlk countly. type of collection Yeal.8 of deaths PlucJ. cignn bmnchitir Empbyaema Other rdcrence po9ulntion Hammond 187.783 white Queatiannaire 31/j 33s Ciporcltrr bnd maim in 3 and follow-up ShI ., ,308 NS ,. .I. .l.OO (30) Horn. e.te.te3 50-69 of death NS ., ,, 30 ?O . . . . -3.64 (40) Ail ,.. . .2.151231) Pipw h's ., .I.00 (90) sn ...I..1.77 (23) Cigar, NS ,., . ..I.00 (30) Shl . ..I 1.23 08) Doll and Approximately Qucationnnire 10 ___..-.. 292 Hill Ciporctfca 41.000 male Ciiinrt.llvY and follow-up Chronir 1964 NS , .I.00 N .s Llritish . . . ..I.00 of death bronchilit l-14 .6.80 Great 1 I4 . . ..O.GS phssicians. certificate. 111 Drilnin 15-24 ,12.80 15-24 ,l.OH Other >zs .21.20 >ZG .ucn (70). 181 All . . ...11.60 All . . . ..U.til I'ilwr art11 I'ijt,,a ct PIII Cif7orr (`i!,o ra sat .3.00 S>I ,....UiH --.---__---- _-_- --.. Author. )`cnr, Nu,m$;nd DlIln Follow-up NUttlbCt Cip.nrrttcs/doy Chronic country, eollcction YPtlTS of denths pipes, cignrs bronchitis Emphysema Other rdcrcnee 909ulntion PROSPECTIVE STUDIES net. Approximntelr Qucstionnairc 6 IOGG. 78,000 mole nncl follow-up Conndn Cnnndian of dcnth (JO). vctcrnns. certificate. Hammond. 440.568 males IntPrriews by 4 IIGG. 5li?.GiI ACS volun- U.S.A. icmnlcs twrs. (103). 35-M years of ape in 25 3taLes. 124 Cionrcttea NS , ,I.00 20 . . ..I4.G3fIZ) Al, 11.42(781 Pill0 Shl ,, ,. .2.11 (5) CipClr8 Shl 3.57 (1) Ciporcltra NS ,..... 1.00 ?O .G.03 (7) All .5,Y5(3?1 Pijlc.4 Shl ,,..,.. 0.75 (2) C10flta Shl .,...,, 3.33 (1) 380 nloicr Sbl . . . ...369 NS ., .l.OO (20) NS . . . . ..?a SM (nge 45-60 , .6.65(114) S!l! (age 65-79) .11.41(175) Kuhn. U.S. male Questionnaire S?l, Hronciiitis NS 1966. . . . ..I.oo (31) Cunc7lt cign- Currmt cigo. veterans snd Shl 64 U.S.A. AIlShI . ..6.49(348) 2,265.674 rtttcr odv rcltea ml/v fOUOW-Up NS . ..I3 Current ciga. (1J:l. NS .,..,. l.OO(l3) NS 1.00 (18) person years. of death Emphvacmo rette .10.08 (229) 1-O . . . . . 3.63 (5) l-9 ,.,.,.. 5.33 (10) certificate. ShI . . . ...284 Pipe8 IO-20 .4.61(22) 10-20 .14.04 (93) NS .,...., 18 Shl ~.2.36 (9) 21-39 .,,. 4.5i(12) 21-39 . ,. .17.04 (62) Cipora >a9 . . ...8.31 (4) >39 ,. .26.34 (171 Shl . ...,. 0.70 (6) All .I.... 4.49(43) Ail ..:...14.17(186) w m r, 0 Wickcn. 1,189 moles. Personal inter- 1,188 obtoincd 1066. view with rctrosncc. North- relntives of tiveiy. err1 individuals Shl .1,064 lrelsnd listed on NS . . . ..I24 (227). death register. `Unless otherwise specified, disparities between the total number of deaths and the mourn of the individual smoking cntcgoriea are due to the exclusion Ciyarcltcs odu NS ,...., LOO(124) I-10 ,,, .2.95(245) II-?? . . ..3.43(300) >?3 . . . ..4.44(168) hlirrd Shl . . . ..I.55 (62) I'ipca or ciynrr Shl ., . . .1.84(ZB9) - of either occasional, miscellnnwus. mixed, or ex.smokcrs. 2 NS includus aijic and cigur smokwr: SXl includes rx-rmokcra. the findings for chronic bronchitis and emphysema. Such specific VJUPing Of the mortality data should be viejved with some reser- vations in the light of the difhculties mentioned above in dis- tinguishing the two diseases clinically. The dose relationship of increased mortality ratios with increased Consumption of cigarettes is indicated by the results of all the studies which present rates for different Ievels of smoking. Kahn (13-3), for instance, noted that those smoking only 1 to 9 cigarettes per day incurred an emphysema mortality ratio of 5.33 while those smoking over 39 per day incurred one of 25.34. Pipe and cigar smokers were found in some studies to have slightly elevated mor- tality ratios in comparison with nonsmokers although other studies did not show this. The risk of dying from COPD among cigar and pipe smokers appears to be much less than that incurred by cigarette smokers but may be somewhat greater than that among nonsmokers (table 1) . The effect of stopping smoking on COPD mortality is reflected in the results of Doll and Hill (70, 71) in their study of British physi- cians. They found that during the years immediately following cessation of smoking, mortality ratios remained elevated and did not begin to decline below the level of continuing smokers until nearly a decade later. This delay in response is probably due to two factors: the presence in the ex-smokers' group of many who quit for reasons of ill health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (131') also noted that the age-specific mortality ratios for es-smokers were lower than those for continuing smokers of cor- responding amounts of cigarettes. A better estimate of the potential effect of stopping smoking on COPD mortality can be gained by studying the death rates in a population in which a high proportion of smokers have stopped smoking to protect their health rather than as a response to ill health. Among doctors age 35-64 in England and Wales, many of whom have stopped smoking cigarettes, there was a 24 Percent- reduction in bronchitis mortality between 1953-57 and 1961-65, as compared with a reduction of only 4 percent in all men of the same age in England and Wales, among whom there was no reduc- tion of cigarette smoking. (84). COPD MORBIDITY Many investigators have studied the prevalence of bronchopul- monary symptoms (including those of chronic nonspecific respira- tory disease) among smokers and nonsmokers. These studies are outlined in table AZ. Their results indicate that the cigarette 171 smoker is much more likely to suffer from respiratory symptoms such as cough, sputum production, and dyspnea than is the non- smoker. Such symptoms, particularly cough and sputum produc- tion, increase with increasing dosage of cigarette smoke. Table A2 also sholvs that pipe and cigar smokers experience COPD symptoms more frequently than nonsmokers although not to the degree found in cigarette smokers. These morbidity findings are similar to the mortality findings presented above. Similarly, cessation of cigarette smoking has been shown to be associated with a decrease in symptom prevalence. Nitchell, et al. (168) studied 60 patients who succeeded in stopping smoking and 84 continuing smokers. Among the ex-smokers, more than 70 per- cent reported improvement in their cough while less than 3 percent of the continuing smokers did so. Wynder, et al. (2.37) followed 224 ex-smokers of cigarettes and noted that 77 percent reported cessation of persistent cough and an additional 17 percent reported definite improvement. Hammond (102) reported similar results concerning cough and shortness of breath in a study of a large group of ex-smokers. VENTILATOKY FUXCTION Another type of quantification of the effects of smoking on the bronchopulmonary system has been obtained by those groups of investigators who have studied pulmonary function in various gIWUpS. Results are presented in table A3, and a glossary of the terms used in the various tests is presented in table A4. The pa- rameters investigated have included maximal breathing capacity (maximal voluntary ventilation), expiratory flow rates, forced expiratory volume, and vital capacity. Although certain of these parameters appear to be more sensitive measures of pulmonary dysfunction than others, the overwhelming majority of these stud- ies have shown diminished function among smokers. An increase in the expected age-diminution rate in smokers has been observed in those studies which employed either repeated examinations or examinations at many different age levels. Higgins, et al. (117) conducted a nine-year follow-up examination of 385 male residents of a British industrial town who were age 55-64 at the beginning of the study. Among the survivors who were tested initially and nine years later, the average decline in FEV,.;, was smallest in non- smokers, slightly greater in ex-smokers, and greatest in smokers. As with COPD mortality and symptom prevalence, the impairment of pulmonary function shows a dose-reIationship with increasing amounts of cigarettes smoked. The data contained in table XX provide two di;?erent kinds of information. The majority of the studies \vere conducted on un- selected populations, which probably include a number of individ- uals with clinically manifest COPD. Therefore, these studies re- flect the prevalence of COPD-related dysfunction (as determined by pulmonary function tests) in relation to smoking. However, some studies of younger individuals have revealed that pulmonary function tests are abnormal in clinically asymptomatic smokers. Krumholz, et al. (140) and Rankin, et al. (189) have sho\vnthat pulmonary diffusing capacity is impaired in young asymptomatic smokers when compared with age-matched nonsmokers. Similar impairment in other pulmonary function tests was noted by Peters and Ferris (182, 183) in an asymptomatic college-age group and by Zwi, et al. (241) and Krumholz. et al. (lS0, 142) in groups of young asymptomatic physicians and medical students. Several investigators have employed tests which measure the relationship of ventilation and perfusion (V/Q relationships) in the various pulmonary segments. These tests are predicated on observations that some segments of the lung may he relatively under or overperfused and that, likewise, segments may be under or over-ventilated. Anthonisen, et al. (IO) investigated pulmonary function in 10 male smokers with clinically mild chronic bronchitis, all of whom had smoked cigarettes for at least 30 years. Regional pulmonary function was studied using radioactive xenon. Despite the fact that overall pulmonary function was nearly normal in sev- eral patients, all had depressed V/Q ratios in some lung regions with the basal areas being those most commonly affected. The au- thors suggested that significant disease in the peripheral airways may exist in patients whose chronic bronchitis is clinically mild and who show no present impairment of ventilatory capacity. The radioactive xenon test may reveal severe compromise of local gas exchange when usual studies of ventilatory capacity do not reveal any impairment. Similar results concerning peripheral airway ob struction in bronchitic patients with normal, or only minimally in- creased pulmonary resistance, have been observed by Woolcock, et al. (234). These authors also noted that their patients demon- strated frequency-dependent compliance lvhich was unaffected by the administration of bronchodilator aerosols. Strieder, et al. (214) have recently investigated the mechanism of postural hypoxemia in 2.1 asymptomatic smokers and non- . smokers. They found that standard ventilatory tests and lung vol.- umes were normal in both the smoking and nonsmoking groups. However, the arterial ~0' measured in the supine position was significantly lower among the smokers and alveolar-arterial oxygen gradients, while breathing room air, were larger in smokers than in 173 nonsmokers (more so in the supine than in the erect position) _ The increase in alveolar-arterial 0: gradients I\-as rrenter for heaq than for light smokers. The authors concluded that mnltlistribution of ventilation and perfusion accounted for the observed hyposemin. They also felt that this mild diffu5.e air\\-a>- disease among asympto- matic smokers is physiologically significant mainly because of in- volvement of small bronchi, as expressed by maldistribution unac- companied by gross airway obstruction. X similar ventilatory distribution abnormality among smokers has also been observed by Ross, et al. (198) with the mere severe alterations found in the long-term smokers. Although of concern in the consideration of COPD, such dis- turbances of the V/Q relationship may also have adverse effects upon cardiac function depending upon the level of hppoxemia (213). The discussion in the section on Coronary Heart Disease noted that carbon monoxide has adverse effects on both oxygen transport and alveolar-arterial exchange as well as on osygtn debt developed with exercise (50). Further research is needed on the joint effect of these pulmonary and carbon monoxide induced h>-poxemic influences. A number of other studies have provided further evidence con- cerning the adverse effect of smoking on ventilatory function. Table 5 presents those experiments which deal with the effect of cessation of smoking on pulmonary function. Among the param- eters which have been noted to improve after stopping smoking are: diffusing capacity, compliance, resistance, maximal breathing capacity, and forced expiratory volumes. These parameters shelved improvement within 3 to -1 weeks after cessation of smoking. GENETIC FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogtnesis of COPD. Earlier studies (127. 147) had noted the existence of kindreds with high incidenres of chronic bronchitis, emphysema, or both diseases. In addition to the presence of genetic susceptibility, Larson, et al. (1:7) also observed that all but one of the 11 symptomatic individuals in their two kindreds were smokers. They postulated that the susceptibility of some smokers to develop emphysema may be, at least partially, genetically detemined. More recently, Larson, et al. (1;8) studied 156 relatives of COPD patients and 86 control individuals. The subjects underwent pul- monary function testing, including forced espiratory volume and residual volume./total lung capacity measurements. The authors observed that pulmonary function abnormalities were most prev- alent among the relatives who smoked and least prevalent among 174 Krumhulz 10 physicians F&lowing J wecka abslincnce FoUowinp c weeks obalincxcc (6 tubjocts mily)t ! All subjcets were >E Dock eL al., 25-33 ycara Lung volumes--no significant ehnnae. Lung volumes: per ycnr smokcra 1965. or hKC. Pcnk e&pirntory flow rntl-incrensc Insplrntury rcscrvc volumcinerease (p- (.we below). In addition, nonsmoking reIati\.es and -;nroking controls were observed to sho\v approsimntely the same pre\.:llence of :tb- normalities. However. due to the large proportion of females in the nonsmoking relative group and to the clustering of tuo-thirds of the affected relatives in 10 families, firm conclusions cannot nt present be dralvn from this study concerning the relative contribu- tions of smoking and of heredity to the pathogenesis of COPD. In order to determine the relative significance of smoking and heredity in the pathogenesis of COPD, Cederlof, et al. (;;s, ;c) have used the twin-study methods on registries in both Sweden and the USA. The specific details of this method are described in the sec- tion on Coronary Heart Disease. As may be noted from a summary of their work at the end of table A 2, the authors compared the symptom prevalence among monozygotic and dizygotic twins who were both discordant and concordant for smoking habits. The\ observed that the h~~permorbidit~ for COPD symptoms related to smoking persisted even after controlling for zygosity and concluded that a causal relationship of smoking and COPD symptoms iv-as sup- ported. HoLvever, genetic factors were still found to have an appre- ciable influence. Lundmann (1.59) has applied this method to the study of pulmonary function. He studied 37 monozygotic and 62 dizygotic tlvin pairs, measuring forced expiratory voiumes and nitrogen washout gradients, and matched the various pairs for smoking discordancy. He observed that both of these parameters were adverseI>. affected in txvins ivho smoked and that these changes were correlated \vith cigarette consumption. The results are out- lined at the end of table X3. AZr,I~a-,-a,~ti~~.~~sin (X,XT) -Of more recent note and discus- sion has been the discovery of an association between a hereditary predisposition to COPD and the relative or absolute absence of alpha,-antitrypsin, a serum glycoprotein enzyme. Eriksson (78) was the first investigator to observe a relationship between the presence of markedly decreased serum trypsin inhibitory capacity and panlobular emph!-sema. Since Eriksson's paper, much added research has been published concerning many facets of this intrigu- ing area. It appears that X,-XT deficiency is inherited as an autosomal recessive trait (~8, 2IG) although Kueppers (IL') considers the transmission to be by an autosomal codominant allele. It hlis been estimated that up to 5 percent of the general population may be heterozygous for this gene (1.51) although full cross-sectional studies of the population remain to be done. Homozygous or severe deficiency of this enzyme has been asso- 176 ciated with a particular type of pulmonary emphysema. \Vhile the majority of lungs of cmphysematous patients reveal ~UIIOLIS or centrilobular deformities, particularly of the upper lobes, this hereditary disorder reveals a panncinar change, most severe in the lower lobes (101, 215. 226). Patients with emphysema who are found to have the homozygous deficiency have been observed to include a greater percentage of female patients than is usually ob- served in the general emphy-sema population. Their disease begins earlier, is more severe, is characterized by dyspnea rather than cough, and frequently is unassociated with a history of preceding bronchitis (101 , "~5, ~6) _ Radiographic studies of A,AT-deficient patients have revealed decreased vascularization of the lower lobes and increased vascularization of the upper lobes (101, 21.1). It is estimated that between 1 and 2 percent of patients with COPD have this homozygous deficiency (78 , 216). In family studies, it has been found that almost all the homozygous individuals are symptomatic by the age of -10 and that those ivho are not usually show alterations in pulmonary function studies. Guenter, et al. (38) studied 7 per- sons with homozygous deficiency. Of the five symptomatic individ- uals, .I smoked and all had abnormal timed vital capacity. Neither of the two asymptomatic individuals smoked or had this change in vital capacity. All 7, however, were noted to be hypoxemic at rest and to have decreased pulmonary diffusing capacity. It has been suggested (I.?;) that the lack of this proteinase in- hibitor in the serum of homozygous patients predisposes them t.o emphysema in the following manner: Leukocytes present in the blood contain significant amounts of proteinase enzymes as part of the overall defense mechanism against infection ; the breakdown of these cells during acute infection releases proteinases into the pul- monary tissues and these, \vithout the presence of a normal inhib- itor, may contribute to the breakdown of the structural proteins of lung tissue. Heterozygous individuals have been defined as those who show levels of X,AT intermediate between those of normals and those with homozygous deficiency. At the present time, there is much debate about whether or not heterozygotes for A,AT are at a greater risk of developing COPD than are A,AT normals. A major dificultv is the lack of a precise definition of heterozygosity. At Present, the best method for the determination of the level of A,AT appears to be that of crossed serum immunoelectrophoresis he- cause levels of trypsin inhibitory capacity (TIC) have been shown to rise acutely with infections. Welch, et al. (26) feel that heterozygotes do not show an in- creased susceptibility to COPD. The heterozygotes tvhich they studied showed symptoms of bronchitis and did not present the 177 lolver lobe perfusion defects frequentI>- noted in homozygotes. The>- also fo~~nd no difference in the number of COPD patients among the heterozygotic and the gtner:\l population. Other inve~iiigators, no- tably Lieberman, et al. (I.,;, I.;.;), Rueppers, et al. ( IAL), and L;irson, et al. (I.;$) found significantly increased percentaF;es of COPD patients among those lvith heterozpgous deficiency as com- pared with the general population. Lieberman, et al. (~55) ob- served that the percentage of heterozygdtes among a group of healthy industrial xvorkers was 1.7 percent while that among a group of patients with emphysema was 18.1 percent. In a recent re\,iew, Falk and Briscoe (79) considered that the available evi- dence points to an increased prevalence of COPD among hetero- zygotes. Of more central interest to this discussion, however, is the pos- sible relationship of smoking to the predisposition of disease among the heterozygote population. Kueppers, et al. (IL-$) studied three populations: younger controls, older controls, and a group of COPD patients. They observed that of the 25 heterozygotes with COPD, only 2 \vere over 70 years of age, both were female and non- smokers. The remaining 23 were cigarette smokers. Nevertheless, studies which adequately sort out the factors of genetic susceptibil- ity and cigarette smoke exposure have yet to be reported. An important question is to \vh.at extent the relationship between smoking and COPD is influenced by identifiable genetic factors. At present, it is possible to identify what appears to be only a very small group of susceptibles for whom genetic factors may be para- mount in the pathogenesis of their ailment. Of greater public health import is whether lesser degrees of genetically identifiable suscep- tibility interact with cigarette smoking m account for a significant proportion of the problem. AIR POLLUTION Numerous epidemiological studies have been conducted in order to examine the effect of air pollution on human nonneoplastic res- piratory disease. Three major types of studies have been utilized : observation of the mortality and morbidity due to an acute episode of increased air pollution, observation of the day-to-day variation in mortality and its relation to air pollution levels, and geographical comparisons- The majority of studies fall into the third category, and these are detailed in table A& A number of studies did not show an association among air pol- lution, respiratory symptoms, and pulmonary dysfunction (81,205). More recent studies which evaluated the factors of smoking, social class, and air pollution separately noted a greater prevalence of 178 COPD symptoms, pulmonary ds,sfunction, and COPD mortality in areas of high pollution (21, 122, l;li, 2,;s). Lambert and Reid (146) observed that in the absence of cigarette smoking the corre- lation bet\\-een COPD symptoms and air pollution was slight and suggested that the two factors may interact to produce higher rates of disease. The evidence which has accumulated in the past 7 years gives further support to the conclusion of the Surgeon General's Ad- visory Committee on Smoking and Wealth as stated in its 1964 Re- port that: "For the bulk of the population of the United States, the relative importance of cigarette smoking as a cause of chronic bronchopulmonary disease is much greater than atmospheric pol- lution or occupational exposures." Exposure to various dusty occupational environments has been shown in many studies to be associated with the development of various forms of nonneopiastic lung disease. Lowe (158)) in a re- view of the relationship of occupational exposure and chronic bronchitis, noted that among workers exposed to dust significant increases in COPD mortality were observed. These occupations included coal mining, tinning, galvanizing, riveting, and caulking. Commenting on a previously unreported study of more than 20,000 steel Jvorkers, he observed that the relationship betrveen mean dust exposure levels and COPD prevalence was much stronger among smokers than among nonsmokers. Alore recently, Bouhuys and Peters (37) reviewed those specific industrial exposures related to lung disease. COPD was found to be associated with exposure to coal dust, asbestos, bagasse dust, iso- cyanates, various irritant gases, and textile dusts (cotton, flax, or hemp). Studies which have investigated the interrelationship between smoking, industrial exposure, and COPD are listed in table A?. Act; ditional compounds, not listed in the table, but which also appear to be related to COPD, are chlorine ($9) and washing powder dust (!?7), Cigarette smoking and harmful dust exposures appear to act in a combined manner in the production of COPD. Although an increased prevalence of COPD is found with cer- tain occupational exposures, in none is the relationship as strong as that between COPD and cigarette smoking. To demonstrate an increased occupational risk, careful analysis of smoking habits is required. The relative importance of cigarette smoking appears to be much greater than occupational exposure as an etioIogic factor in COPD. 179 Cad,,zilc,)r-CC:hl.onic industrial esposure to cadmium in man has been found to induce pulmonary emphysema without significant accompanying chronic bronchitis (32, 35, 210) Nandi, et al. (177) recently investigated the contribution of the cadmium in cigarette smoke to the pathogenesis of emphysema. Analyzing \I-hole cigarettes, ash. and filters, the>- found that an average of 69 percent of the cadmium present in the cigarette (ap- proximately 16 microgram5 20 cigarettes) is inhaled in the smoke. In a related study (2.53). these investigators showed that the level of cadmium in water-soluble liver protein on autopsy was three times greater in those patients with a history of chronic bronchitis; emphysema than that found in those without such a history. Un- fortunately, no smoking histories were available. PXTHOI~OGIC~I~ STUDIES The relationship betn-een smoking habits and pathological changes in the bronchial tree and pulmonary parenchpma has been investigated by se\-era1 groups of lvorkers. Xetaplastic changes, although found in nonsmokers, are much more common in smokers (table 10, Cancer Chapter), and a dose-relationship of increasing metaplasia with increased smoking has been evident in many of the studies. Pathological studies which deal primarily with pulmonary parenchgmal and non-metaplastic bronchial changes are presented in table 8. Goblet cell distention, alveolar septal rupture, thickened bronchial epithelium, and mucous gland hypertrophy have been found to be more frequent in smokers than in nonsmokers. Auer- bath, et al. (17) noted a dose-response relationship between the amount of smoking and the degree of septal rupture. Anderson, et al. (;, 5) studied the difference in the type of emphysema shown by smokers and nonsmokers. In their study, listed in table 8, they noted that the group of patients with panlobu- lar emphysema was comprised of equal numbers of smokers and nonsmokers while of patients with centrilohular emphysema, 98 percent \vere smokers. Xore recently, the same authors studied lung macrosections from 80 nonsmokers. While most were normal, 24 demonstrated parenchymal dilatation and disruption consistent with panlobular emphysema. Thurlbeck, et aL> (217) have also ob- served that centrilobular emphysema rarely occurs in nonsmokers. 180 hlcgnhed 50 male patients Mucous eland hupcrlrophu et II.. with chronic Pcrcm& 1967. bronchitis under- NS . . . . . . . . . . . ..~........ PO Egypt (2/7) goinK bronchial ShI . ,. ,, .I., ., I 77 (33/431 (P40 cigarcltn/day (66) . . 1.3 1.4 31.6 45.3 20.6 ' Numerourr experiments dttailing changes in bronchial epithelium ore dctoilcd tnbulnrly in the Cnnccr chapter. ESPERI.\IESTXL STCDIES Xsrsrx~ STUDIES A number of investigators have studied the effect of the inhala- tion of cigarette smoke on the macroscopic and microscopic str-uc- ture of the tracheobronchial tree and Pulmonary parench>.ma of animals. Studies dealing with metaplasia and cellular atypism of the trachea and bronchi are listed in table Xl6 of the cancer chap- ter. Studies more directly concerned with the pathology of COPD are listed in table 9. They show that cigarette smoke exposure is associated with changes similar to those found in humans vvith COPD, i.e., bronchitis, parenchymai disruption, alveolar septal rupture, alveolar space dilatation, and the loss of cilia and ciliated celIs in the bronchial mucosa. The investigations of Auerbach and his coworkers (15, 16, 88) have demonstrated by the use of both light and electron microscopy that dogs \vho inhale cigarette smoke through tracheostomas de- velop progressively more severe lesions of the bronchi and paren- chyma lvith increased exposure to cigarette smoke. In electron microscopic studies of specimens taken from the lungs of dogs thus exposed to cigarette smoke, the following changes were observed : In 5 dogs sacrificed after only 44 days of smoking exposure, there was a proliferation of goblet cells as well as a partial loss of cilia in the lining cells, and in 5 dogs sacrificed after 120 days or more of esposure, the num'ber of cell layers in the bronchial epithelium was found to be twice that of the nonsmoking dogs. Goblet cells and ciliated columnar cells were no longer present; instead, the surface was lined with columnar and cuboidal cells with stubby projections in place of cilia. 3Iitotic figures were frequently observed in the basal cells. These findings may be relevant to carcinogenesis as well as to the development of COPD. In a long-term experiment, carried out by the same group, dogs were exposed to varying doses of cigarette smoke. Details of the experimental procedure have been outlined in the section on Pul- monary Carcinogenesis. The animals were separated into non- smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex- posure groups. The dogs were "smoked" for 87.5 days, or approxi- mately 29 months. The animals which died during the experiment and the animals sacrificed after day 875 \vere examined for Pul- monar3' psrenchymal changes as well as for bronchial epithelial alterations. As seen in figures 1 and 2, dose-related pathological changes, including fibrosis and emphysema, were found in the lung parenchyma of the exposed dogs. These changes were similar to those seen in the lungs of humans with COPD. 184 IOO- --__- 91.7 a0 - 20 - 17.9 I.- 57 0 00 GROUP N: GROUP f: GROUP L: GROlJP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (% 25 many clpretter) as Gro"D H Several investigative groups have exposed rodents to various ambient concentrations of nitrogen dioxide over prolonged periods of time. This gas is found in cigarette smoke and in some indus- trially polluted air. The results of these studies are outlined in table A10. It is clear that chronic exposure to low levels of NO? is capable of inducing lesions in the bronchial tree although the rela- tionship between these changes, cigarette smoking, and the devel- opment of COPD remains to be determined. Rosenkrantz, et al. (196, 197) have recently undertaken experi- ments dealing with pulmonary cellular metabolism. They exposed Swiss albino mice to cigarette smoke or its vapor phase for varying lengths of time. On autopsy, animals exposed to cigarette smoke showed elevations in the levels of lung DNA, lactate, and glycogen which the authors conclude reflect hyperplnsia and macrophage infiltration. Similarly, a dose-related increase in lung hydroxypro- line was observed. This was considered to be due to increased fi- broblastic collagen synthesis. 187 GROUP N: NONSMOKING GROUP F: GROUP L: GROUP H: FILTER-TIP NO FILTER NO FILTER (`A as many cigaretb) a* Group H FIGURE Z.-Percent of lur:g sections with grade II or III emphysema. SOURCES Hammond, et al. (104). Aviado and coworkers have performed a series of experiments on live animals and in heart-lung preparations to study the effect of cigarette smoke on pulmonary physiology and structure (18, 19, 20,21, 22, 179, 180, 199, 200,201, 202). The authors observed that cigarette smoke causes acute bronchoconstriction both by the re- lease of histamine and the stimulation of parasympathetic nerve pathways in the lung. Bronchial arterial injections of nicotine were found to cause reactions similar t,o those observed after cigarette smoke inhalation. The hronchoconstriction was usually followed by bronchodilatation which the authors attributed to sympathetic stimulation. As mentioned in the Chapter on Cardiovascular Dis- eases, nicotine has been shown to induce the release of catechola- mines. Experiments by Aviado and coworkers as well as other authors (66, 99) using guinea pigs showed that exposure to cigarette smoke was associated with increased bronchopulmonary resistance and decreased pulmonary compliance. The authors related these changes to the bronchoconstriction of terminal ventilatory `units. 188 Similar experiments in dogs shelved that the increase in resistance following either cigarette smoke exposure or intravenous nicotine could be blocked by pretreatment ivith atropine. Xs a parasympa- thetic blocker, atropine would decrease the acute bronchoconstric- tive phase. Nest recently, Xviado and his colleagues (00, 130) have at- tempted to induce physiologic and anatomic changes similar to those found in the lungs of patients with emphysema. They ex- posed male rats to cigarette smoke, the introduction of the enzyme papain, as we11 as to partial tracheal ligation. In 10 rats exposed to cigarette smoke tlvice daily for 30 minutes over a period of 10 weeks, no changes in pulmonary compliance or resistance were noted. Also, no abnormal histological changes were observed in the group exposed only to cigarette smoke. However, animals who underwent tracheal ligation as well as smoke exposure showed in- creased numbers of enlarged air spaces and increased pulmonary resistance when c\ompared with animals who underwent only tracheal ligation. STUDIES IN I-TUhIhNS The acute effects of cigarette smoke inhalation on bronchopul- monary function in man have been investigated by a number of workers. The results of these studies are presented in table 11. The majority of studies, particularly the more recent ones, found that the inhalation of cigarette smoke is associated with an acute in- crease in pulmonary resistance and a decrease in pulmonary com- pliance. Chapman (&8) also observed decreases in pulmonary dif- fusing capacity and arterial 0, tension. Chiang and Wang (51) noted changes in nitrogen washout time and alveolar dilution fac- tor, alterations which reflect impaired alveolar ventilation and gas mixing. James (131) examined the effect of prior smoking on the mul- tiple breath nitrogen washout test in 41 pneumoconiotic miners and 5 normal young males. Prior smoking of a cigarette in the subject's normal manner was found to adversely affect the indices of dis- tribution in 20 percent of the miners and in all of the 5 normals who smoked within one hour of testing. The author suggests that smoking be prohibited prior to any series of pulmonary function studies. Anderson and 1ViIliams (9) studied the acute effect of cigarette smoke inhalation upon the ventilation-perfusion (V/Q) measure- ments in the lung in normals and in patients with COPD. Cigarette smoking was observed to cause acute changes in the V/Q measure- ments, and the COPD patients were found to be particularly liable to these changes. 189 Finally, Robertson, et a1. (194) studied the effect of unfiltered and filtered cigarette smoke and cigar smoke upon bronchial re- activity in 19 of the most reactive persons in a group of 91 heavy smokers. They observed that bronchial reactivity was significantly reduced by increasing the retention efficiency of the filter and that reactivity to inhaled cigar tobacco was no less than that to cigarette smoke. They concluded that differences in inhalation account for the difference in COPD prevalence observed between cigarette and cigar smokers. STUDIES CONCEKNING PULMONARY CLWRANCE Owercdl Gkarance The ability of the lqng to rid itself of inhaled particles that can- not be easily exhaled is dependent upon a number of physiologic mechanisms including ciliary activity, the mucous sheath, and the pulmonary alveolar macrophage. Studies concerning the effect of human cigarette smoking and the exposure of animals to cigarette smoke on this clearance system are presented in tabIe A13. LaBelle, et al. (145) and Bair and Dilley (23) observed no change in clear- ance following the exposure of rats, rabbits, or dogs to cigarette smoke. The latter authors noted, however, that normal clearance rates obtained prior to smoking were too low to reflect any sig- nificant change except complete cessation. Albert, et al. (3) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (185) obtained similar results in rabbits. In a related study, Albert, et al. (2) studied the bronchial ciear- ante times of 9 nonsmokers and 14 cigarette smokers in a total pop- ulation of 36 subjects. The rates of bronchial clearance were slower on the average in the cigarette smokers when compared with the nonsmokers, although a wide variation was present in each group. In relation to their study mentioned above, they also noted that the shape of the whole lung clearance curves seen in smokers (with markedly prolonged 50 percent clearance times) was similar to that developed in the donkey following acute exposures to suIfur dioxide or cigarette smoke. Numerous experiments have shown that cigarette smoke or cer- tain constituents of cigarette smoke adversely affect and can even bring about a cessation of ciliary activity in respiratory epithelium in vivo and in vitro in cultures of ciliated microorganisms. The re- sults of a number of these experiments are presented in table 12. 190 CiliarY acti\`it?: has been shown to be affected bp particulate matter as me]] a.~ by the gas phase components of cigarette smoke. The re]- ative importance of these tno large classes of components of smoke in producing ciliastasis is presently a matter of some discussion. Dalhamn and Rylander (63, 6J) consider the particulate phase to be of greater importance while Battista and Kensler (~8, 29) con- clude that gas phase components are more important in the induc- tion of ciliastasis. Studies investigating the effect of cigarette smoke on the morphology of the tracheobronchial tree in animals have noted a decrease or absence in the number of cilia in smoke-exposed ani- mals. Recently, Kennedy and Elliot (1.31) studied the effect of the direct exposure of cigarette sinoke upon the electron microscopic structure of protozoan mitochondria. After 42 minutes of exposure to mainstream smoke, they noted destruction of the internal mem- brane structure of the mitochondria. Thus, cigarette smoke has been shown to be tosic to ciliary func- tion by pathological (including electron microscopic) and physio- logical methods. Phayocytosis The effect of cigarette smoke upon pulmonary alveolar phago- cytosis, one part of the clearance mechanism, has been studied by several authors. Masin and hlasin (162) observed increased varia- tion in the size of lipid inclusions in sputum macrophages obtained from smokers as compared to those obtained from nonsmokers. They attributed these differences to a combined effect of irritation of the alveolar lining, increased turnover of alveolar cells, and in- creased injury to the macrophages. Green and Carolin (96) noted that cigarette smoke inhibited the ability of rabbit a]veo]ar macro- phages to clear cultures of S. au?-eels. This effect was noticeably reduced by filtration. Similarly, Yeager (239) exposed rabbit alveolar macrophages which had been induced by M. botiis to cigar- ette smoke and observed a dose-dependent decrease in protein syn- thesis. This alteration occurred at smoke solution concentrations that did not affect cell viability. The alteration was only partly rc- versible and was due mainly to gas phase components. LMyrvik and Evans (175) observed similar protein synthesis alterations in macrophages exposed to NO,. Roque and Pickren (19.5) obtained alveolar macrophages at thoracotomy from 17 smokers and 4 nonsmokers. They found a decrease in the activity of oxidoreductases and hydrolases in the macrophages of smokers. The reduction in the enzymatic activit? was directly proportional to the amount of stored fluorescent ma- terial present in the macrophages. This material was thought to 191 rcfcrrn-ci pop;lallon smoking Blckerman I. 66 mslc and A. Pulmonary and 26 Icmale function. Reaultd Commentd Vi&d ctlmcib (VC) I. lo/91 dccrcaae. Maximal brcafhing capacity 9/91 patient8 showed lo/e1 dccreaae. VC LIICTPLWC due to BBnzh, paLlent B. 3 cigarettes. II. No aignlficant change. No aign(flcnnt change. ClebrlnCC of apcrc- 1954. with chronic C. 30 minutes. liona. All mild cr U.S.A. nontubcrculous mdcratr enwkcra. (11). rCSpira\OV di3eam (avernge ego 601. II. 20 male snd 7 female normsl aub- jecta (average age20). Elcb. I. 31 patients with A. Esophrgwl bslloon Mc4.n uiru,ay rcriatawc Mean airwov compliancs ct al.. obxtrucllvc twhnisuc to 1. Stntiatlcolly ai~nincant No chsngc. 1917, Pllllnlmnry m~1p~s11rc Dulmonnry InCrNL?IP. U.S.A. eml'hyncma. com~~llnt~rc nnd II. No chnnuc. No change. (76). ll. 14 normul rusiatnncc. III. No chsngr. No change. subjwtd. 8. 1 cigarrttc. III. 6 patients with C. Undcfind. respiratory cumplainls. All habitual smokcn. -- Chupmon, I. 12 normal A. Pulmonarv function 1. All showed P dccrcnse In diRtwing ca~acily. lDGS, volunteer. Artcriul blood II. 4/b--aiynlficont dccrrnac in artcrinl O1 tcl~sl00. Ireland (nil smokera). atudiea. No change in vilnl cnpacily or FEV. (48,. 11. 6 pnticnla with B. I ciulrctre. chronic non- C. Undelirrcd. apccilic lung dieeaae. McDermott I. 32 normnle. A. Body Dlcthy. Afcon oirwav rcairtatwc Light amokcra ahowcd nnd II. 28 with chronic smosrnl,hy. I. Siu~iflcnnt incrcnac. prrnter chnrlu~n 1hnn COlliM. bronchitis B. Cigercttc. II. Sigoificnnt lncresse. hc.vy amokrrd. 1966. (All ciyn- C. Undefined. WDler rctte smokera (160). 3560 years of ace.) Author. A. hlcthod ' year. Number and ,3. Mnlcrinl J country. type or C. Durnliun of Result-4 COlll~Clila rcIcrmu! Dopulation emuking Miller and 10 normal A. Eaovhsuenl bnllwn DUWl77tic Inapimtory at-d Suroule, cignrcttt tcchniaue. FEVo 6 compliance cxyiratorv rcaiatanec 1966. smokcn l3. 1 cigarette. No signiicant Significant Significant U.S.A. (40 yeara C. One inhnlntion chnnge dccrcnae. increuse (166). al age). evcrY 30-60 seconds. Sterling, 11 "ormal adulta A. Body plethy- Airway rceidtance 1067, (8 smokers, smouaphy. Significant increase (Return England 3 nonsmokers). B. 16 inhalationa. to nom-al in 30 minutes). (113). C. 6 minutes. Cbiang and 7 male normal WanK. nonsmokers 1970, (c-48 yeat FWlTl03a of rae). (61). A. Pulmonary function Nitrogetr wnahout Nitrogen washout. time B. 2 cigarettes. Significant c. Undefined. iricrease. Guyatt 710 nubjecb: A. Ilodr plethy- et al., 608 smoked amograDhu. 1910. betwe?" mens- B. 1 cigarette. Englnnd urm 202 `2, Undefined. (100). did not smoke. w `All the exucriments listed concern studies of pulmonnry function b+ z iore and after smoking the epecifled number of cigarettee (unless otber- wise soeeifLd). Author. YCLI. cuunlry, rclcrcnee Subjccta Method LaUrCnXl Swiss-Webster Xlicc exposed to Significnnt incrcjbsc in S. ourcu8 rctcntion in mice cxp+8c%l to: CL nl., male mice. nermul of s. DurcuI (n) hyrruxin-retention ratio 2.5 (IO prrccnt 02). 196% and ancrificcd at (b) cignrcttc smuhc-rctintion riilio 4.5. U.S.A. Intcrvnla following (149). CXwrure 10 vilrious stimuli. LSDCIIC Albino female Silver idideor 17-30 hours uf cx~~wrc to cirrnrvttc amukc caused no change In pulmunnr/ et al.. mbbib. colloidnl gold elenrnnce ns cumjlnrcyl with controlr breathing room air. 1966. intrntrachellly. U.S.A. (1151. Bair and SpraaudJhwlw Radioactive aer&. Acute cxposurc to cignrctte smoke hnd no proo, oflect on clenrance. Chronic Dillcy. frmale rata, erl>orurc tu ciplrrctte rmukc cut) to l&20 cigarettes/7 hour day/6 dnu wwk L967. mule beogle dep. Radioactive aerwol. for "1, to 420 doye) hod no ubscrvnblc rllcctr. The authors noted, however, U.S.A. thnt normnl clrnrance rntcx were too low to rcflcct anything but complete (05). cerse.tion. so pcrcmt 90 pcrcrnt t ADproximntc villuc3. clcaronce CICOIUIICe None of `I nonamokcrs Albert 3G subjecta Radlonctive tagged Number oj "lvcraoc time time hnd GO pc~ccnl time-a et al.. undergoing 117 FeOZ particles subjcctr aoe (minulcr) (mixuterI over 200 minu(cY or 1969. uperimcnts. mensured with Nonsmekerr . 0 28 88 367 90 p~,rcmL limes over U.S.A. Scintillation All smokers ,. ,. . , , . 14 33 172 1406 600 ntinuta while (2). counter. `X+20 cigarettcs/dny ..,,,... 7 23 191 t519 6/14 am,>kws cxcwlcd 30-40 cisorettes/day ,.._,.,.. 7 36 163 1474 both thcsc limits. Uranium miners ,. 3 62 310 b80 Cigar nnd ~ipc smokrra ,..... 4 46 07 3'76 Emphywmu patients . . 2 66 330 G7G TAEZLE le.--E'zperinamts concerning the effect of cigarette smoke on human and animal pulmona~ clearance (cont.) Author. Y-r, CO""tl-7, rcfcrence Subjects MOtbOd nesuita COnlml?ntn Albert Donkey8 exwsed Radioactive tagged AVWQ7C Tmchoel franail Thmc donkeys CxDoacd et al., to CiKF,Rtte FcOz particles number lime to the KrCnl`-Bt 1969. smoke by nasnl measured wilb cigarcllca in Percent clcara?lcc Ilaltlime clmrance emount of smukc U.S.A. catheter. Scintillation z-hour period COnlrOl CiQ~rclle Cotllrol Cioarclle Conlrd Cigartile showed rczidunl (3). CO"nter. 1n-24 5.3 GO 1.2 1.9 0.G I.? Impnirmrnt of 3c 5R 64 1.0 3.4 04 6.8 clrsrnnrc fur nt h.nt 2 month3 afkr ucuk CXpW"rC. Helms. Rabbits ' CP' monodisperse Ihmsurc tu Irrsh ciaurct~c smoke (1.6 cc. nulTr, 40 puiTsl8 minxten) caured 1069, (nncsthctlrcd). PolYstYrcne n "sianificnnt" increnrc in lung retention 10 minutes followinK cessation of U.S.A. aer0301. eX,lOS"rC. (IIS). originate in tobacco smoke. The authors suggested that the tobacco smoke may have induced abnormalities in the mitochondria of the macrophage. In a study of pulmonary macrophages harvested by endobronchial lavage from smokers and nonsmokers, Pratt, et al. (187) observed that the mncrophages of smokers contained an ab- normal pigment. These studies indicate that the function of pulmonary clearance carried on by the macrophage and ciliary systems is adversely af- fected by cigarette smoke. STUDIES CONCERNING THE SURFACTANT SYSTEM The surfactant system of the lung consists of various biologically active compounds such as phosphoiipids and mucopolysaccharides which are present in the alveolar lining. Normal pulmonary func- tion is influenced and partly determined by the integrity of this system (103). The purpose of the surfactant system is to main- tain the proper amount of surface tension in the alveoli so that the expansion and contraction of the alveoli are facilitated. Studies concerning the effect of cigarette smoke upon the sur- factant system and the surface tension of the pulmonary alveoli are presented in table Al4. Exposure of rat and dog Iung extracts to cigarette smoke has been found to induce a notable decrease in the maximal surface tension demonstrated by the extracts (94, 165, 224). Cook and Webb (57) observed that surfactant activity was diminished in smokers and in patients with pulmonary disease when compared with healthy nonsmokers. Scarpelli (203) in a recent review, concluded that the lowering of maximal surface tension by cigarette smoke has been demon- strated reasonably well. The relationship of these findings to the pathogenesis of emphysema is unclear at this time. OTNER RESPIRATORY DISORDERS INFECTIOUS RESPIRATORY DISEASES Several studies have examined the question of whether ciga- rette smokers are at an increased risk of developing infectious res- piratory and bronchopulmonary disease. Table A15 presents a summary of these studies. Lowe (157) observed an excess of smokers among 705 tuberculosis patients, but Brown and Campbell (4s) in a similar study found that the difference was not present when the cases and controls were matched for alcohol intake. More recent studies have been concerned with the frequency of upper respiratory infections among groups of smokers and nonsmokers. A number of investigators (1U8,181,183) have reported increased 198 rates of respiratory illnesses among smokers. Finklea, et al. (8~) studied a male college population (prospectively) during the 1!XS-F9 influenza epidemic. They found that smokers of ail amounts experienced more clinical illness than did nonsmokers and that this r&tion was dose-dependent. Similarly, smokers required more bed rest than nonsmokers. A survey conducted by the National Center for Health Statistics (290)) involving approximately 134,000 persons, showed that male cigarette smokers reported 54 percent more cases of acute bron- chitis than males who had never smoked cigarettes, while female smokers reported 74 percent more acute bronchitis than did females who had never smoked. MaIe cigarette smokers reported 22 percent more cases of influenza than did males who had never smoked cigar- ettes, while the female smokers reported an excess of 9 percent. Experimental evidence in support of this relationship has been noted by Spurgash, et al. (211) _ Mice were tihallenged with h'lcbsiclla pneumoniae or Di$ococcw pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke eshibited a decrease in resistance to respira- tory infection, as shown by an increase in mortality and a decrease in survival time. Preexposure to cigarette smoke was found to have no significant effect on resistance of mice to influenza infection initiated by aerosol exposure. However, exposure of infected mice to smoke resulted in significantly higher mortaiity, thus suggest- ing that cigarette smoke can aggravate an existing respiratory viral infection. In the light of the experimental evidence presented above con- cerning the effect of cigarette smoke on pulmonary clearance, phagocytosis, and ciliary function, it seems reasonable to conclude that such changes in tracheobronchial physiologic function would predispose a person to respiratory infections or aggravate already existing ones. Further evidence is derived from the work of Henry, et al. (109) and Ehrlich, et al. (75). These investigators exposed sWirr& monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen dioxide. They observed that this exposure increased the suscepti- bility of the animals to airborne Klcbsiellu pneumoniae as demon- strated by increased mortality and reduced lung clearance of viable bacteria. Infectious challenge with influenza virus 24 hours before exposure to 10 p.p.m. was fatal to all monkeys within three days. Infected controls shoxved symptoms of viral infection but did not succumb to the infection. The extent to which the various oxides of nitrogen present in cigarette smoke contribute to the increased sus- ceptibiljty to respiratory disease noted in smokers is presently undefined. 199 POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers run an increased risk of developing postopera- tive PUhonarY complications over nonsmokers undergoing similar operations. Morton (173) reported on a study of more than 1,100 patients undergoing abdominal operations in which he found that cigarette and mixed smokers were significantly more likely to develop hron- chitis, bronchopneumonia, or atelectasis during the postoperative period than nonsmokers (table A16). Wiklander and Norlin (229) examined the incidence of post- operative complications in 200 patients undergoing laparotomy in the winter months when it was expected that pulmonary compli- cations would be at their maximum. These authors found no sig- nificant differences between the frequency of complications in smokers and nonsmokers. No information about the definition of a smoker and no data on dosage of tobacco smoke were reported. Piper (186) observed the prevalence of postoperative pulmonary complications in 150 patients undergoing laparotomy. Of the total sample, 66.7 percent developed pulmonary complications during the first postoperative week. All patients considered in the statis- tical analysis as having pulmonary complications had radiographic evidence of disease. Of the cigarette smokers, 73.5 percent had complications as compared to 55.5 percent of the nonsmokers. When the smokers were divided according to dosage, heavy smok- ers being those consuming more than 10 cigarettes per day for the previous six months, 55 percent of light smokers and 88 percent of heavy smokers were considered to have postoperative compli- cations. Piper also reported that stopping smoking for Up to four days preoperatively had no apparent effect on the incidence of complications. Wightman (228) reported on the incidence of postoperative pul- monary complications in 455 patients undergoing abdominal oper- ations and in 330 patients undergoing other operations. Of the cigarette smokers, 14.8 percent developed complications as com- pared to 6.3 percent of the nonsmokers. The substantial difference between these figures and those of Piper (186) is due to the latter's use of radiographic criteria alone. Wightman utilized only clinical criteria. Morton (172) has recently reported a study of postoperative hypoxemia in 10 patients, 5 of whom were cigarette smokers. Four of the smokers had chronic bronchitis. He found that the smokers had a more pronounced decrease in arterial oxygen saturation, Per- sisting into the second postoperative day CtabIe A17) -. 200 In summary, the majority of studies so far reported indicate that cigarette smokers run a higher risk of developing postopera- tive pulmonary complications than do nonsmokers, corroborating a long-held clinical impression. The risk of developing such com- plications appears to increase with increasing dosage of cigarette smoke. SUNNARY AND CONCLUSIONS 1. Cigarette smoking is the most important cause of chronic ob- structive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma although it may increase the frequency and se- verity of asthmatic attacks in patients already suffering from this disease. 2. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. HOW- ever, exposure to excessive atmospheric pollution or dusty occupa- tional materials, and cigarette smoking may act jointly to produce greater COPD morbidity and mortality. `7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilator-y function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. 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American Review of Respiratory Dis- eases 89(l) : 73-81, January 1964. 217 RRONCHOPTJLMONARY APPENDIX TABLES 219 TABLE AZ.-,Smoliing and c/Lronic obslrrrctiua pttlwonar~ discase su'ttptonls'-percolt prevalence (Numbcn in garcnthcwe rcprcscnt tolnl number of individusl in yatiiculnr smoking group) Shl = Smokera. NS = Nanamokcra. EX ; Ex-amokere. Author, ycllr, countl-Y, Nutt$rO;nd Drcnlhl~~snns Cowh Sputum production or dyspnea Chest illncssses Other Commenle rcfcrcnce DoPUhtiOn ____ Short 2,031 male and NS I... 1.6 (496) NS ,, .ID.O C.hril illnrssra Oswnld 3,602 male nnd Chronic Bronchilir Chronic and 2.2*12 femnle nfh brrducLllln. PhilliDe 1.274 mnle NS `2.0 (461) et al., fnctor~ workcn sm . ..Gl.O (823) 1966. wiLhout overt U.S.A. pulmonary (185). dircnsc or hcnrt failure. Higgins 301 male nnd Ccmoh and spufum Chronic Bronchilia 1957, 280 ffmnle hfolcs Malea `41&l Malts Enslnnd i-oral dwellers NS . ,, 7.1 (28) NS..........7.1 NS . . . ..I... a.6 NS I,,.... 3.6 (II?). 26-74 yeDrS of SM . ,. ,. 63.9 (222) 531 ..I. . . . ...19.8 Shl . . . . . . . . . 17.1 Sbf , ., I.. 9.9 we. FtWU21.24 Ft??7l~fGJ FO7I&# FL-?Mlt-, NS ., ,, 4.6 (176) NS .,I. . . . ...21.6 NS . 9.7 NS . ,, . ., 3.4 sm ,... 17.2 (93) sm . , . 9.1 Shf .a . . ..16.1 Shl . . . . 8.6 k r T,\nr.~ A2.-Smokhg and chronic obstructive pulmonary, disease sl/jliptotlis +m+xnt pcvalence (coral.) (Numbers in pnrcnthcvrs rcyrescnt tatnl number of individunl~ in vnrticular smoking nroUV) Sbl = Smokers. NS = Nunsmokers. EX = Ex.amokrra. and 92 frmnlcs Cochran. randomly chosen 1958. (members of an England agricullurel (114). commur*itu.) Edwards 1,131 male out- et al.. ImticntY on 1959. lists of Ennlnod lmlcral prnc- (74). titionera >60 YCPci of DBF. Cammrnta Couoh and sputum NS .,... . . . . ...33.3 NS I..,. 0.0 hlalca NS (6) S!d . . . . . . . . . ...29.3 SH 16.0 NS . . . . . . . 0.0 Sbf ., ..24.0 (151 FtWIalW Femdcs SM . . . 6.7 NS ., ,, 3.1 (G4) NS . . . . . ...46.3 NS . 10.9 FCrntllC# Shl .I ,I 3.0 (20) SH ..,.., .20.0 Shf ..I 10.0 NS . ,,,, .` 0.0 S.M ,,....I 6.0 Chronic bronchilir NS .,, ,, 1C.6 (151) Cigarette8 29.1 (778) l-9 . ...23.4 (236) lo-19 . ...31.2 (361) >20 . . . . . 33.7 (176) Pipe . . . 18.6 (340) - Flick 222 mnle NS . . . . . . . 10.0 (61) NS ..,,,.... 26.0 (49) NS . . 30.0 (47) and pntitnts not sm ,. ,. ..66.0 (167) Sbl ,, ..66.0 (1.66) SM . . . 60.0(138) Pnton, auffvrina from 1359. avert rnnlio- U.S.A. D\lllilOnF.~y (86). dincnac. ZO..OO r*rnofopc. Hiuuina 716 maln In Couoh and c~ulutn Chronic bronchitis et al., VR?/OUI SM ,. ., ., ,. 7.1 (86) NS . ,. . . . . .a.., 0.4 NS s I. . . 7.1 SM , ,,.., 14.3 106D. OCCUD~UO~~ NS ,. ., ,. 36.0 (1176) SM ,, ,, ,, ,. ,, .24.9 SM .a .a 20.2 NS . . . . . . 3.b England 26-64 yc(~rc, (IIS). of age. -- Liebnchuetr,l47 male NS ,. ,, ,. 0.0 (621 lC59, soldiers Shi ,. ., ,. 13.0 (83) Elsland 20-30 years tl.76). of ogc. - -- Ashford 4.014 male Et al., Rcnpiraloru ayrn~,lomr Rwpirntov coal workers. NS . . . . . . 103 (677) symplumn- lQC\. EX . ,. ,. 19.6 ,England (123) "bronchitis and/or (11). Cignrcttes 21 1 (1,604) Pipe only 36.1 (202) uthmn". Nu Cizarcttn duua 1.<,1>,- 3 and DIDC 37.1 (90) tionslaip AIlShI 21.7 (3,210 f"Ul-ld. t4 TAllI E A2.- .Ytt~okin~~ 117rtf chrouic obstricclilrc prtlt~lcr?rcrrl~ tliucccw .ul/~Jr/J~o~~lY'-- td ],c:rcclll /murlfcm: (CWll.) IP (N\,,,,~,Q~ ,n ,,nrcnthws rrprcucnt t,,tuI n,,n\l~cr of l,~dlvldunl~ in ~nrtlcufnr amokinv k!:ro'JD) SM z= Slnok~rr. NS ~1 Nunanwkvra. 1,:~ := Ex.smokurs. Author, YPUi-. NumLcrnnd Urcnthlc~sncas country. type uf Cough Sputum prduction 01 dyapnea Chest illnesses Other Comment.9 rrfcrrncc nnpulntion -______- -- Dnwcr. 06 malt nnd NS . . . . . . . . 4.1 (49) NS .,. . . ...20.4 NS . . . .31.7 Cheat lllnws- 1861. 11 lcmulc Shl .#. .27.0 (76) Shl . . . . . ...34.2 Sht ,,.,.I 88.2 clllY!t COllll U S.A. bnuk om~~loycoa l'lvc, clunr 1. (19) l'inc. clgor lG.4 I'il~c.cluar duringcach 01). 40.10ycnrs 63.0 01 Ilint z of I,YV. Wlr~tPIR. - Flrtchvr nnd 3G3 mnlc I.w~don -- NS . , 8 , (80) NS ..,..,.a., 8.7 NS . . . . . . . . . .I NS . . .a. 4.S Tlukcr, trQnalwrt t-14 g./dny 16.6 (1GC) I-14 a./dny ..ZI.U 1..14 n./dny *. 8.2 1-14 n./doy lOGI, Cm[ll"Yl'L* >lS . . . ...27.0 (110) >lG . . . . . . . ..aO.D >lG . . ...*.. 8.0 8.2 Ynulnnd 40 GoYchrI >lS . ...10.7 185). 01 DPB. Read 170 malcand M&a and 132 Iernnlc NS ..,..s.. 4.4 SCIIJY. indlvldunla SM . . . . . ...23.1 1961. lntervicwed EX . . . . . ...21.2 Auatdlr inanoub FHlt.llC~ (191). Datient NS , 4.9 clinic (not SM . . . . . ...18.6 all paticntsl, BIlebum 1.461rnale NS . . . . ...10.2 (263) NS..........ll.O NS.......... 9.8 et al.. llaht SM . . . . . . ..23.3(1.108) SM ., . . . . ...30.4 SM . . . . . . . ...14.6 IDVZ. Industry 60 .,. . . ,, .29.0 PO . . . ..GO.O (24) X0 *..II... 62.0 ?`,\uLE AZ.-Slnoking and chronic obstwclil~e pulmomr~ discasc' .S~III~~O~II.S `-.-pcrcoil prcunleuce (co?it.) (Numbers In ~nrentbrsw re~resrnt tutnl number ol individunls in ~nrticular smoking aroun) SM = Smokcra. NS = Nonsrnoken. EX = Ex-smokers. Author, YCPT, Number snd nrenthlcssnns countrY, type of Cough Sputum Drduction or dyspnea Chest illness- Other Commcnte refrrencc population - Boucot 6,137 mslcs NS . . 13.0 (806) et Ill.. 1862. cnroliina SM .31,6(6.331) U.S.A. in pulmonary (36). neoplasm project. Ftrria 90 male and Chraic Nonrpccific CL &I,. 71 female Reepiralory Dbcosc llC2. Rnx mill- n1a1ca Frtlld20 .63.1(32) GO.0 (4) Fenis 642 male and Chronic Irorkchilir hgc-,prcifir and 6?5 frmnle ?lrnlCI r*tm. AlldCrWn. wnidcnts of NS . . . . . . 13.8 (126) 1962. New Iinmpshire EX . ,, ,, ..lI.O (77) U S.A. town chosen Cianrcttcs 40.3 (340) IElI. by randurn l-10 . ...218 rumpling of 11-20 . .34.2 CC"S"S. 21-30 . 4?.3 31-40 G1.1 >:I ., .SG.3 F'cnlol~, NS . 0.4 (97Lo El . 10.8 (37) Cignrcttn 19.8 (208) I-10 .13.1 II-20 ..I. 22.2 21-30 31-40 .27.3 F=: >41 .` u -- (Jf6). e. Finnish 1-14 .,.., 31.6 (108) commun*l 15-24, . . . ..4O.S (191) region, >25 .,.... 42.4 (86) 40-64 yearn Femah of age. NS . . . . . ..I 4.6 (709) EX . . . ..13.3 (30) 1-14 . . ...10.4 (77) 16-24 .*,.,. 43.0 (6) >26 .,....# *. (1) TABLE AP.--Smoking and chronic obstructive pulmonary disease s~?~ipto?t~s `-percEnt prevalence (cont.) (Numben I" Qarcntbu.~ reQreaent total number of individuals in ~articulnr smokinn p.rOUD) SM = Smokers. NS = Nonsmokers. EX z Er-amokera. Author, y-2.r. Numm:ri"d Brcnthlrss"ess CO""W. Cough SQUh" prcductic.n or dyepnes Cheat Illnessw Other Commcntd refcrcnce QoQularloa Goldsmith 3,381 wtive Respiretory et al., or retired cotiditiona 1862, longahoremcn. NS U.S.A. hI"d6;;;;;h$:y (74" (9s'. smokcn 43.0 (1,298) Co&lea 1,342 male and Covgh and chronic phlcotn Current et al., 242 female NS . . . ..ll.Z (747) NS 14.7 NS . . . . 4.0 smoking 1966, Detroit poet l-14 , ..12.7 (266) (not LiK.) 1-14 .28.2(Q26 . . . 36.4 (170) (P25 . .a4.i(D26 . . . . . 26.8(Q26 . . . . . .42.4 FC7WJlC8 NS . . 4. .:-.. . 16.6 `ix . .24.8 l-14 . . . . ,* .2G.O IS-24 ,,,..... 26.2 >25 . ., .31.8 FOdC8 NS . 6.9 NS ., ,, . . 29.2 EX **.... . ..13.3 EX . . >. .33.3 l-14 . . . . . .10.4 1-14 * ,,..... 14.3 Molcl NS . . . . 6.7 EX . *. . . 16.3 1-14 , . . I 38.0 16-24 ,...41.4 >26 ,,... 40.0 FCTdU NS . . . 4.6 EX .,, . . 13.3 x-14 . 10.4 16-24 >?6 I . . .67.0 lb-26 >= . . ...67.0 Author, YCBT. Number and BreathlnsnpJs count-Y, type of Cough Sputum production or dyopneu Chest illnesses, Other Conlmvntd reference populntion Wynder 316 male New York Cily et al.. patirntr in NS I.., .14.0 (44) 19G6 Nrw York City Pipe. cigar 33.0 (64) U S.A. and 316 male Cigrrcttcs: (PSB). patient3 in l-10 . ..46.0 (44) California. 10-2.0 . .46.0 (88) >20 . ...67.0 (86) Catifornia NS .~ . . . . 22.0 (69) Pipe, cigar 30.0 (32) Cigarettes: l-10 .46.0 (64) lo-20 . ..74.0 (91) >20 . . ..`?4.0 (69; --.- FIPOID 1.066 randomlv Clinical aipna ot TABLE A2.-.%tokinn and chronic obstructive pulmonary disease syltlpto,t~s'-percent prevalence (cont.) (Numbcra in parentheses represent t&l number of individuals in particulbr smoking group) SM = Smokera. NS = Nonemokem. EX = Ex-amokera. Cough Sputum production Dreatblwsness or dyapnea Chest Illne4ace 0ti-M Commenti DCllWlI 6,ais IIW& POI(rrl PCWld Poltd Dyepnca a &I., and 7.29 1 NS ..a ,. ,. 7.0 (908) 13.1 IQ.8 rcurcscntcd 1967. fernah POStAl Pipe, clgsr 12.4 (628) 11.4 24.8 by Grade 11 U.S.A. snd ban&It Clgarettrs OIIIY. (88). worken. only . a. .27.0(2.687) 28.9 31.7 Transit Transit Tromit NS . . . 6.4(1,012) 9.6 11.7 Pipe, cigar 10.6 (766) 14.1 14.2 cigucttea onlr , . . .23.6(8,`746) 23.7 21.9 Efggins 926 white NS .I,,... 16.4 (162) NS . . . . . . . . . . . 31.1 NS , . . , , ,. 6.0 et al., de A- l-f ..a . . ..47.2 (61s) SM , ,a ., ., .4&Z snl . ., ,* . ,* ..10.7 1968. dents of EX s.,,.,. 19.9 (144) EX . . ,... 28.6 EX . . . . . . . ..16.8 U.S.A. hlatlon (116). county, West Virginia. 26-69 ycsn of age. Holland 8,788 mrlc Nolcr Fcmolcs N&I FVdC# snd and female NS . ,, . . , 8.8(1,000) 9.2(3,137) 2.4 2.1 Elliott, lChOOl SM . . . . . . . 6.3(1.038) 6.9 (664) 6.1 8.3 1968. ebildrcn. EX . , . . . . . 2.9 (1,782) 4.3(1.161) 3.9 4.2 England 5 *.,./ . . . . . . . . . . . . ..# . . . . ..9.`3(142) 18.3 Commenls Austrnlin. niminnton 41,723 mnic prcvnlrncc 01 di,WgC chronic bronchilia RlO20 , 20.6 FC,lltll~# NS .,.... 3.4(12,361) EX ,..... 38 (D69) PiDc . . 00 Cigarcttcs (8.986) 1- 9 ,.. 6.1 lo-19 . 10.6 >20 * I. 18 6 Chronic bronchilir rt al., G&54 yesra NS . . . 1.0 (88) 1IEl. of nac rnndomly EX , . . . * 3.0 (67) Swcdcn snmplcd irom l-14 grnms/ (231). Pu~~uIc.tloI\ day ., 6.0 (04) uf Guhborg. >16 ,.,., 17.0 (GO -. TAULE AZ.--Smoki?lg and chronic obstructive p~tlnmm~ discasc sutttptol,ls'-pcrcolt preuahce (co7lt.J (Numben in parentheses represent total number of individual* in wrticular amokinn `?rouP) SM = Smokers. NS = NonsmLkcrs. EX = Ex-smokers. Author, YCBT, Number and Drcnthlcssneas countw, type of Cough Sputum production or dyspnca Chest illnesses 00.X? Commcnta rctrrcnce DoPulation Pcrnistent couph otldphlcgm Mnlcr nclc rtuc Aoc Age ss-IS is-55 65-05 M-48 NS It... 7(?27) G("OU1 ll(171l 1 (01) ES . . . . . I(3031 11(3GBl 16(33G) 18(14Y) 20 . . ..27(1481 26(1X) 42(121) 26 (12) Fcmalcr NS .I.,. 31600) 4(G37) K(O26) 6 (211 EX 311271 al1281 1 (041 1 1411 <20 . . . o;mz; 13(472) 16(3OC) 11 (CGi 20 . . . . ..lC(1281 27(122) 31 (711 14 (7) izo . ...23 (22) 26 (301 43 (7) . . (11 LCfCW 310 male Agc.rlondardizcd roka Excluded from rnd Phuriciens of chronic rer~~irot~rv examokcra Wonnacott. in London dircaae nt~' thvac 1970. and Ontario, NS . . ...**. t. 1.0 (881 clgurctk Cnrda 26-74 yerAT EX ..*,,. .*.. 6.0 (61) amokcn who (151). of am. SM .,,....,.. 34.0 (101) now Bmoke Plpr, clgsr , .12.0 (aa) pipn or clnrn. ' Data collected by either dlrcct lnteylw, puntionnnirs. rcvicw of medical records and/or medical cxamlnation. TABLE A23 .-S9rloltirlg and chro~~ic f~bslr~rlcliuc lI~tltilu7ictrU tlisvclsc s~~tl~~Lo~~is'-~l~l'cc,lt prmlcncc LNumbcra In parrnthcszu rcprrscnt tutol n~~rnbcr of individunb in pal-ticunr smoking group) Shl = Smnkcra. NS = Nurlsnwkrw EX = Ex-emokcrs. Author, YCLLT. countty. Nutm$:,;nd Cough Bronchitis Commcnta rcfcrcnce popuation Ccdcrlol 9.319 twin Obacrved/ Obscrvcd Explnnotion of nnsl~nes for All ex.snrokcrs ir~cludcd et .I., paira czjectcd IIupcrmorbidilu cxllcclcd Ilyyermorhidity rc3pirotory eymplorn with smnkcrn. 136G, rcairtcrcd Croup A: C(IICII ratio COlCd ralio VNV8lCliCC: MZ--monorYKotlc Swcdcn in Swcdcn hlnlcr . . . . ...393/151.9 2.c 157/60,8 3.1 Croup A analyale-using each pPlr8 (46). 01 12,RRB FC?YIL?les . . . ..lW 49.4 2.8 a/11.2 3.8 flr~tbom twin an one proup DZ-dizynolic ueira availuble. Grau~ II Shl/NS: In sn unmntchcd relat!onshlp Author concludes thnt hlZ Males , , 14.6/1.1 1.9 G.C/ 1.1 6.0 (274) to each urcondborn twin. ~llnee hypcrmorbldltv Females . . l&6/7.6 1.8 3.0/ 2.3 1.33(264) Group I.3 annlysis-uuiop each for amsklnr pcraista DZ Mnlcs , . . 12.3/6.6 2.26 4.6/ 1.8 2.5,1(733) twin set BJ matched pair. in bmukinil-ill~rur,lrlnl Females , , . 14.6/6.? 2.67 LB/ 1.6 3.0 (663) AU compnrisons in Groups A hlZ popuIe:ion. o and B circ bctwwn smoking CBIURI rcIntio~~~tI/~ ot discordnnt pain. smokmn nnd brnnrho- DuhOt,lltY B,"lDt"",l IS luyD"rtLYl. Cederlol 4,379 twin Prevalence of reapiralceu symptoms No cx.amukcrs lnciuilcd et al.. pairs (all Group A: in Croup II an0ly~11-1. 1969. U.S. veterarls) NS . . ., ,, ,. 4.3 4.3 1.G Group A--as above. The nutliurr conclude U.S.A. in U.S. l-10 . . . . . . . . 6.4 6.4 2.7 Grouv B--n3 above. that the dntn indiente 145). National 11-30 . . . . . . . . . . . . . . 16.3 18.3 8.0 *strong probability Academy of >31 . . . . . . . .27.1 27.1 16.6 of rh cnu~al connection Sciences Twin Pipe, cigar . . 7.1 7.1 2.1 with amokinK. Even RegistrV (of Group B: NS sn1 NS snr thcsc a)`m,~t,rm~. 9,000 avial. hlZ . . . . . . . . . . . . . . . . . . . . 2.6 6.4 1.6 4.6 able), howcvcr. acem to be DZ . . . . . . . . . . ..., .,., ,..,, ,., 2.0 9.8 1.6 9.1 influvrrccd by gcnctic factors. ' Dab collccted'b~ either direct interview. questionnaire, review of medical records and/or mcdicnl examination. N (Numbers in parcnthcscs rrprcuunt total number of individuals in ynrticulrr amokinx R~QUD) NS = Nonsmokers. Shl = Smokers. EX = Ex-amokere. EFR FEV vc bliaccllancour Commcnb rorcrcncc pop"lution -_.. - Chivcl-s. 463 m.lc Ilcight-in-inchca tblrn" EFII 1069. rmlhyrcs Cigcuettes/dny: 64" 66" 680' 70" I" lltcm Ennland of olknline &rJ . . . . . . . . . . . . *. t97(28) 91 (35) 108 (91) lOl(21) par minute. (51). industry 6-20 ..~....,.......... R9(60) RR (75) 101 (112) 1w (76) RCgrl3Ul"" plnnt. >7.0 ,..... ,.. .,, ,,, 63 (6) RR.6 (9) 92.6 (9) llS(lZ) annl,als of dn~n rcvralvd L 8iPiiincsnr r* h,tionahiv bclwc-z" smuking and dc crceviny function. Hlgglnl 773 male3 26-64 65-64 cxprcsanl Et al., Invarious NS 146 (66) 101 (29) FE"o.75 DEB n>c~n indlrcct 1969, occupstionl EX 143 (31) 89 (62) MUC. England (25-34 and 1-14 grnms (116). 66-64 YeFall .140(193) 87(167) of age). >I6 Drnml ,183 (89) m(ia6) - WilSO" 28 male RV/TLC et al., residenta of NS . . . . 6.69 (14, NS . . . ,. . . 21.1 1960 nnllsa, Sbf ,..,I `4.44 (IO SM . . . . . . . `27.01 U.S.A. TCXBS. 1?32). former rural dwL4en; mntched for body aurrare. all.?. and height. TOLD A3.--Smoking and vmlilatcq function (cont.) (Numberr In parentheeca reprcscnt total number of individunls In gnrticulnr omoking group) NS :: Nonsmokers. Shl = Smokas. EX = Ex-enwkera. EFR FEV vc blleceunneoua Comment.4 Ashford 4.014 mnle et LI., coal workera Age: FNESVl .o snr lD61. at 3 Scottish co . ..2.88 (42) 2.21(297) Dnta rcprcjent reaulb nfter correction fur dtti"E hCiKht. SM lncludcs ylpc smoker. Datr on cx.amokcr not Included. FEV,,O found r,ipnlllcs"t: lower for Shl tbsn NS. Fletcher a63 male Mean peak EFR and London NS . . . . . ,.. 670 (SO) Tinker. CT!l"PPti l-14 prune 637(166) 1961, employees. >I6 grams 628(116) Ensland EX ,....,.. 666 (61) (85). Franklin 213 male llcavy smoker and factow FEV1.0 FEVo".;: y.;; LOWdl. workcra FIenVY 2.670 3,dll 2.71; Light . . 3.703 (69) rcyrcecnta 8" ListIt `2.489 amount wusl lOGI. 40-60 ycrlrs `2,666 `2.284 mnvy .~3,678(100 to or "lure U.S.A. of nw. thsn 30 pack (87). YEIIII. 240 . , I 307.63 (67) 2.90 blsrlt. 73 healthy 1962. medical per- DLC# Smukcn ,luRnrrl U.S.A. aanne with. NS . , . . ., , . a3.10(30) a* `hurt y'n"kinc (IS!). out signifi. SLI <6 yce.n .`28.40 (8) >zo ciKurcllcu/ eant we 6-lOyears . ..JZB.ZO(lO) dny for varying diflcrence >I0 YEB,S .`24.00(26) pcriuds. between smokers and nonmoken. TABLE A3.-Smoking and vmtilatory /unction (cont.) (Numberr In DatentheSer tepre~enl total number of individuals in particular smoking group) NS = Nonrmokrre. SM = Smokers, EX = Ex-smokers. AilthOr. YC@.i-. C0"thll-Y. MBC ,efCtenCe PWUltItiOtl EFR FEV vc Mfacelkneou8 Comment4 Revotakle 1,130 male et al., and 1.813 FE"I.O Data prcacntrd M&l Fmah 1862, female in tcrma of NS U.S.A. relidtnti In . . ...0.98 (66) 0X18(255) ratio of (IPI). Cigsrettes/dny: Framinp- obaervcd to ham par- l-10 .0.97 (90) 0.99 (92) 9rcdlcted 10-29 ticipating .0.91(163) O.OS(167) valuca. >30 in the pro- ..0.90 (81) 0.01 (22) spective study. KrumboL 18 physicians MEFR et al.. 24-37 yee.ra NS . en . . . . 660 (9) hftan DL lB64. or *ge. U.S.A. Shl ..,.., ,. `690 (9) NS SN Rat . . . . . . . . . 36 `81 (ILO). Excrclre: 2mlnuta ..60 `41 4 minutes ..60 148 8 mlnuks zwi 20 medical port exrrclae 39 `86 *t PI.. MNEFR ntudcnbor NS . . . 187 (lo) Authors found 1964. graduate 4.84 6.17 Sbl aa.1193 (10) a signitlcont diRercncc U.S.A. uhysicisns. `6.09 `6.63 bctwecn Shf and (P&l). NS for RV/TLC. complinnce. nnd non- CO&b, 1.342 male et al.. and 242 1966. female 9oat U.S.A. oNice (5-J). emDloYecs elastic realslance. FEV,.O Timed VC' Age: NS >25 o'oldau NS >tS/dau FEVI,/VC NS >fS/daU ID-44 `2.08(186) 2.86 (60) 3.89 3.86 `0.17 0.14 46-49 `2.96(170) 2x4 (42) 3.92 3.83 2 0.74 0.70 60-64 `2.X(116) 2.62 (22) 9.71 3.74 `0.74 0.70 2.44 (18) 3.64 8.61 `0.14 0.68 h) >roueste Of *gc. 65-59 `2.64 (64) k.i G&64 l2.36 (63) 2.30 (8) 3.30 3.33 `0.12 0.70 TADLD A3.Stnokitlg and vmlilator~ funcliotr (cont.) (Numben In percnthcacn rcprcacnr total number of lndividu8ls In patilcul~r lmDkln# E~OUPI NS = Nonsmokcre. SM = Smokcra. EX = Ex-amokera. Author, YCU, LO"lltlT. NuttAi-;nd MLIC EFR FEV vc Ml,cell*nmu Commrnta Xrumholr 20 mrls Pulmonwy cmnpftime'a Mean body surfnce et d., medlcd NS , ., ,,,, ,, .0.241(10) .rca for 2 ~1'0uUfl 1961, ltuden(a or SM , ,.., . . .~0.177(10) ~08 not hnifl- U.S.A. graduate Compliancr/FRC eanlly d,Rcrrnt. (14:). Dhyalclms. NS ,,,...,.,. 0.064 Smokcls arc those SM . ,* ,. .*. .`0.042 wit11 rc~unl to or g,ratr,' Ihhn 5 pack ycor history. RankIn 126 malea NS ,., 118.1 (68) et al.. nlthout a SM , ..`111.7 (67) FEV1.0 DL DL/ NS Includea pipe NS .,..,,.,. . ..106.6 NS . . ..Sl.l d"eo,ar .",I CiYLII. arnl)krrs 1066, P-t SM . #, *. . . *. * .`102.7 SM . .`26.9 volume snd ox-smoke~a ot U.S.A. hlatarq ~l'26 20-69 years . . . . . . . . a.ao(m) of .p?. w" w rrfrrcnec pOpil&Nl Sluia- 633 white 35-44 G-54 >SS Fh"J.O 1 cignrrtlc z CRWWr mnlc NS S63(106) 627(101) 444(H) ss-44 45-54 >Gs 1 gin",. . . . . . . . . and fflctorv Grams/day: 3.70 3.22 2.76 1 D""PC lobocco = Sichcl. workers l-14 . . . . . . 657 (2C) 619 (17) 410 (7) 3.c4 3.31 2.24 2c grrtms. 19&P. over 36 15-24 . . 632 (94) 446 (36) 401(13) 3.66 2.94 2.28 1 cigar = 2 10 6 South ycrsrs of >?5 t52a (66) t494 (31) t380(10) 3.54 3.05 12.12 grnms. AirkCl .ge. t Derivnl BIUIIPI (tw). found sunifi- ranlly dillcrcnt frurn 0. SlBlM_CU 87 male bus FE"1.o Nifrogcn gradient et 81.. drivers: Younper OIdcr YouQ?er Old&-7 Younger Older 1968. 27 anrd NS ,.I.. 4.470(14) 3.310(40) 6,126 4,?90 1.63 2.49 Rumania 20-26. 60 Shl . . . ..`4.5OOl131 `3,200(20) '6.285 '4,290 Il.47 83.77 BYIll"lQmB. DenWl 6.281 male FEV, n FEV exprcaacd 111 et &I., 1969, U.S.A. (69). postal and 7,213 mole transit workers in New York City. A." POSlOl 1Slritc 3.29 (666) 3.11t2.340) 3.14 (1.292) 3.06 (1.038) Tronait ll'hitc 3.39 (620) 3.11(2,941) 3.16(1,929) Non-white 3.05 (2041 2.04 (768) 2.96 (699) 2.93 (161) Na-vhilc 3.08 (298) 2.99(1.041) 3.00 (691) 226 gramaldey ,. ,. . . , . . . . 3.0?(1,011) 2.96 (149) (Numbers in parentheses rcprcscnt totul number of individunh in Dnrticular smoking group) NS = Nunsmukrrs. Shl = Smukcrr. EX - Ex-smokcru. EFR FEV vc Miscellanwu Commcntr PEFR vc 1963 vnlum only. NS . . . . . . . . . . . . . . . . . . . . . . . 1. 626(88) FEVl,O 3.17 4.83 EX . , . . 631tb7) 3.69 4.77 1-14 grams/day .,., . . .., 621(90 3.62 4.83 >I6 grams/day ., ,I. .., ,. 492(GO 3.31 4.66 -- NBIFR NblFR hua Lccn NS , . . 4.09 (88) ;;;I.0 ~lnnllnrdlrcd for Cignrrtte ogc nnd hciuht. amokers. 3.64(101) 3.11 EX , 3.99 (61) 3.38 Pipe, cigar 4.17 (33) 3.17 TAELE AS.--Smoking and vent&tory function (cont.) (Numbs-8 In psrenthcaea rcprcacnt total number of lndivldurb In pw-tlcular amoklnr WJuD) NS = Nonsmokers. Shl = Smokers. EX = En.smokem. AUbX, Year, countl-y, FEV Miacellsneoua Commcnta rtfcrcncs Lundmnn. 87 hlZ and FEV, n N. wanhout nndicnt hlZ = monorygotle. 62 DZ twin prim aelectcd from Swedlrh Twln.Pair Rerl1tty. Slgnlftcant dlffercnccs between smoklnp discordant twin DltIl found for: 1. G~OUD A MZ males and fern&e. 2. Group n DZ malea, 8. Gmuu ADZ nudes. Slgnlficant diFferencea between smoking dls- cordant twin pain found far: Grouu B DZ malee. DZ = dirygotlc. The author concludea that the danwe of ventllrtlon II mcssured by N, w&shout was correlated with cigarette conaumptlon. Tbr FEY,,, WBI aignlficrntly lower for amokera and tbcre wns a ecrrelstiuti with clgsrette consumutlon. Explan&tlon of rnalysea for rnplratow wnptam prevalencr: Grouu A nnrlvsls-u~lnn each Aratborn twin " ona PIO"P In .n unmatched relstlcnshlp to each wcondborn twin. Group B w~alyala-wing ekfb twin set u mstcb*d unlr. All comp~rlson~ In Grour, A rnd B are bctwetn nnoklw-dlscor dant DllrI. ' Not lignlflcnnt Cdlflerence OI trend), : DtO ye~n of age) (59). (lime md xxi- sxs ruociated with decrcued PEFR v~lua. Mb uposum~. Fiireins 300 mak miner. Miners showed incrra~ed prevalence of symptoms and de and and 300 mak creased MBC value which remained even after standard- c"cbrwne. nonminer 3-4 iration for smoking habits. 1961. yea13 of .KF. Torrl dust cxmure wm not dirvcthr correlated with these Engbnd hndiwx. (115).