CHAPTER 1 Introduction and Summary INTRODUCTION AND SUMMARY Cigarette smoking continues to be a major health problem in the United States today. It is still too early to tell whether the increas- ing rate of giving up smoking by adults during the years 196'7,1968, 1969, and early 1970 and the plateauing of this effect during the past year have had any measurable effect on the morbidity and mortality associated with smoking. At the same time that the major health professions, voluntary health agencies, and public service agencies concerned have joined with government agencies to reduce the magnitude of this problem through education, research efforts devoted to understanding how cigarette smoking affects biological function to produce disease continue at a high level. This report is largely concerned with reviewing the research re- ports which have become available in the past year. In this chapter, brief summary statements are presented of the state of knowledge in several areas. These are followed, where appropriate, by a "high- light" statement of significant additions to knowledge made as a result of the new research presented in greater detail in the body of the report. The state of knowledge in three areas, which have not been re- riewed previously, is also presented in the report. These areas are : Allergy, Public Exposure to Air Pollution from Tobacco Smoke, and the Harmful Constituents of Cigarette Smoke. SUMMARY: CORONARY HEART DISEASE Cigarette smokers have higher death rates from coronary heart disease (CHD) than nonsmokers. This relationship is stronger for men than women. Cigarette smoking markedly increases an individ- ual's susceptibility to earlier death from CHD. Cigarette smoking, hypertension, and elevated serum cholesterol are major risk factors contributing to the development of CHD; cigarette smoking acts both independently and conjointly with these other factors to in- Qeage the risk of developing CHD. Cigarette smoking may con- tribute both to the development of CHD and to the exacerbation of Preexistent CHD; both ni,cotine and carbon monoxide are thought to contribute to these abnormal processes. Cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coronary arteries. Cessation of smoking is associated with a decreased risk of death from CHD. The risk of CHD incurred by pipe and cigar smokers is appreciably less than that incurred by cigarette smokers. Highlights of 1972 Report: Coronary Heart Disease 1. Recent epidemiological studies from several countries confinp! that cigarette smoking is one of the major risk factors con.! tributing to the development of CHD. Avoidance of cigaretb. smoking is of importance in the primary prevention of CHD.' 2. Studies in man and animals have shown a greater myocardial arteriole wall thickness in smokers than nonsmokers. 3. Experimental and epidemiological investigations implicate the elevation of carboxyhemoglobin levels in smokers as a' contributor to the development of CHD and arteriosclerotic peripheral vascular disease. 4. Cigarette smoking is considered to be the major cause of pul. monary heart disease (car pulmonale) in the United States in that it is the most important cause of chronic non-neoplastic bronchopulmonary diseases. Avoidance of cigarette smoking is of importance in the primary prevention of pulmonary heart disease. SUMMARY: CEREBROVASCULAR DISEASE Cigarette smokers have higher death rates from cerebrovascular disease than nonsmokers. SUMMARY: NONSYPHILITIC AORTIC ANEURYSM* Cigarette smokers have higher death rates from nonsyphilitic aortic aneurysm than nonsmokers. SUMMARY: PERIPHERAL VASCULAR DISEASE Cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking appears to aggravate preexistent peripheral vascular disease. o This summary statement is the same as that appearing in previous reports. because new studies adding to the understanding of this area have not ????????? Conseqxntly. the literature in this area is not reviewed and the statement is ?*o? included to complete this summary chapter. 2 SUMMARY: NON-NEOPLASTIC BRONCHOPULMONARY DISEASES Cigarette smoking is the most important cause of chronic obstruc- tive bronchopulmonary disease (COPD) in the United States. Ciga- rette smokers have higher death rates from pulmonary emphysema and chronic bronchitis and more frequently have impaired pul- monary function and pulmonary symptoms than nonsmokers. Ex- cigarette smokers have lower death rates from COPD than do con- tinuing smokers. Cessation of smoking is associated with improved ventilatory function and decreased pulmonary symptom prevalence. For most of the United States population, cigarette smoking is a more important cause of COPD than air pollution or occupational exposure; cigarette smoking may also act conjointly with occupa- tional or environmental exposure to produce greater COPD mar.- bidity and mortality. An infrequent genetic error, homozygous alphal-antitrypsin deficiency, has been commonly associated with the early development of severe, panacinar emphysema. Whether or not cigarette smoking acts together with the J- `mozygous or hetero- zygous deficiency states to increase the risk of developing either panacinar emphysema or the more common forme of COPD has not been adequately studied. Cigarette smoking exerts an adverse effect on the pulmonary clearance mechanism. Respiratory infec- tions are more prevalent and severe among cigarette smokers, par- ticularly among heavy smokers, than among nonsmokers. The risk of developing or dying from COPD among pipe or cigar smokers is probably higher than that among nonsmokers but is clearly less than that among cigarette smokers. Highlights of the 1972 Report: Non-neoplastic Bronchopulmonary Diseases 1. Recent epidemiological and clinical studies from several countries confirm that men and women cigarette smokers have an increased prevalence of respiratory symptoms and have diminished pulmonary function compared to nonsmokers. 2. Investigations of high school students have demonstrated that abnormal pulmonary function and pulmonary symptoms are more common in smokers than nonsmokers. 3. Recent occupational studies confirm that cigarette smoking is an important cause of COPD, acting both independently and in combination with occupational exposure. 4. Recent experimental studies confirm that cigarette smoking exerts an adverse effect on pulmonary clearance and macro- phage function. 3 5. Pulmonary macrophages obtained from cigarette smokers ex- hibit characteristic morphologic differences when compared to those obtained from nonsmokers. SUMMARY: CANCER Cigarette smoking is the major cause of lung cancer in men and a significant cause of lung cancer in women. The risk of developing lung cancer in both men and women is directly related to an individ- ual's exposure as measured by the number of cigarettes smoked, duration of smoking, earlier initiation, depth of inhalation, and the amount of "tar" produced by the cigarette. The risk of developing lung cancer diminishes with cessation of smoking. Smokers of pipes or cigars have a lower risk of developing lung cancer than cigarette smokers. Certain occupations are associated with an increased risk of developing lung cancer. In these occupational settings cigarette smoking appears to exert an effect that produces much higher lung cancer rates than those resulting either from the occupational ex- posure alone or from smoking alone. Factors associated with urban living result in an increase in the risk of developing lung cancer; this effect, however, is minor compared to the overriding effect of cigarette smoking. The smoking of cigarettes, pipes, and cigars is a significant factor in the d,evelopment of cancers of the larynx and oral cavity. Pipe smoking is causally related to cancer of the lip. The significant asso- ciation between smoking and the development of cancer of the esophagus is somewhat stronger for cigarettes than for pipes or cigars and the combined exposure to alcohol and cigarettes is asso- ciated with especially high rates of cancer of the esophagus. Ciga- rette smoking is associated with cancer of the urinary bladder in men. There is also an association between cigarette smoking and cancer of the pancreas. Highlights of the 1972 Report: Cancer 1. Preliminary results from a major prospective epidemiological study in Japan demonstrate a strong association between cig- arette smoking and lung cancer. A dose-response relationship was demonstrated for the number of cigarettes smoked. These findings in an Asian population with distinct genetic and cul- tural characteristics confirm the major importance of ciga- rette smoking in the causation of lung cancer, a conclusion which up to now has been based largely on studies of Cauca- sian populations in the United States, Canada, and Europe. 2. 3. 4. 5. 6. 7. Ex-smokers have significantly lower death rates for lung can- cer than continuing smokers. The decline in risk following cessation appears to be rapid both for those who have smoked for long periods of time and for those with a shorter smoking history, with the sharpest reductions taking place after the first two years of cessation. The risk of developing lung cancer appears to be higher for smokers who have chronic bronchitis. Though both conditions are directly related to the amount and duration of smoking, an additional risk for lung cancer appears to exist for ciga- rette smokers with chronic bronchitis which is independent of age and number of cigarettes consumed. Experimental studies on animals have demonstrated that the particulate phase of tobacco smoke contains certain chemical compounds which can act as complete carcinogens, tumor initiators, or tumor promoters. Recently, other compounds have been described that have no independent activity in two- stage carcinogenesis but accelel ate the carcinogenic effects of polynuclear aromatic hydrocarbons in the initiator-promoter system. Additional epidemiological evidence confirms a significant as- sociation between the combined use of cigarettes and alcohol, and cancer of the esophagus. Epidemiological studies have demonstrated a significant asso- ciation between cigarette smoking and cancer of the urinary bladder in both men and women. These studies demonstrate that the risk of developing bladder cancer increases with in- halation and the number of cigarettes smoked. Epidemiological evidence demonstrates a significant associa- tion between cigarette smoking and cancer of the pancreas. SUMMARY: PREGNANCY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birth weight and an increased incidence of prematurity, defined by weight. There is increasing evidence to support the view that women who smoke during pregnancy have a significantly greater risk of an unsuccess- ful pregnancy than those who do not. SUMMARY: GASTROINTESTINAL DISORDERS Cigarette smoking males have an increased prevalence of peptic ulcer disease as compared to nonsmoking males and a greater peptic 5 ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effec- tiveness of standard peptic ulcer treatment and to slow the rate of ulcer healing. Highlights of the 1972 Report: Gastrointestinal Disorders 1. A possible link between cigarette smoking and peptic ulcer has been demonstrated in dogs in which nicotine was found to inhibit pancreatic and hepatic bicarbonate secretion. This could lead to peptic disease by depriving the duodenum of sufficient alkaline secretion to neutralize gastric acidity. 2. An investigation in human volunteers has suggested that cig- arette smoking decreases the effectiveness of the lower- esophageal sphincter as a barrier against gastro-esophageal reflux. SUMMARY: TOBACCO AMBLYOPIA* Tobacco amblyopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mecha- nisms, particularly in the metabolism of the cyanide component of tobacco smoke. SUMMARY : NON-NEOPLASTIC ORAL DISEASE* Ulceromembranous gingivitis, alveolar bone loss, and stomatitis nicotina are more commonly found among smokers than among nonsmokers. The influence of smoking on periodontal disease and gingivitis probably operates in conjunction with poor oral hygiene. In addition, there is evidence that smoking may be associated with edentulism and delayed socket healing. While further experimental and clinical studies are indicated, it would appear that nonsmokers have an advantage over smokers in terms of their oral health. TOP in.t'o?.ma.tion contained in the fob&g three summary state- ru~nfs: A&q~y, P&lie Exposure to Air Pollution from Tobacco Smoke. awl Harmfzl.1 Constitu.ents of Cigarette Smoke, is new and uppears for the first time. --- * This summary statement is the same as that appearing in previous reports, because new sturliei adding t<, thez understanding of this area have not appeared. Consewentb. the literature in this area is not reviewed and the statement is only included to complete this summa~`~ chapter. b SUMMARY OF THE 1972 REPORT: ALLERGY 1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic in man and animals. 2, (a) Skin sensitizing antibodies specific for tobacco antigens have been found frequently in smokers and nonsmokers. They appear to occur more often in allergic individuals. Precipitating antibodies specific for tobacco antigens have also been found in both smokers and nonsmokers. (b) A delayed type of hypersensitivity to tobacco has been demonstrated in man. (c) Tobacco may exert an adverse effect on protective mech- anisms of the immune system in man and animals. 3. (a) Tobacco smoke can contribute to the discomfort of many individuals. It exerts complex pharmacologic, irritative, and allergic effects, the clinical manifestations of which may be indistinguishable from one another. (b) Exposure to tobacco smoke may produce exacerbation of allergic symptoms in nonsmokers who are suffering from allergies of diverse causes. 4. Little is known about the pathogenesis of tobacco allergy and its possible relationship to other smoking-related diseases. SI'JIMARY OF THE 1972 REPORT: PUBLIC EXPOSURE TO AIR POLLUTION FROM TOBACCO SMOKE 1. An atmosphere contaminated with tobacco smoke can con- tribute to the discomfort of many individuals. 3 LI. The level of carbon monoxide attained in experiments using rooms filled with tobacco smoke has been shown to equal, and at times to exceed, the legal limits for maximum air pollution Permitted for ambient air quality in several localities and can also exceed the occupational Threshold Limit Value for a nor- mal work period presently in effect for the United States as a Rhole. The presence of such levels indicates that the effect of exposure to carbon monoxide may on occasion, depending UPon the length of exposure, be sufficient to be harmful to the health of an exposed person. This would be particularly sig- nificant for people who are already suffering from chronic hronchopulmonary disease and coronary heart disease. ". Other components of tobacco smoke, such as particulate mat- ter and the oxides of nitrogen, have been shown in various 7 concentrations to affect adversely animal pulmonary and' cardiac structure and function. The extent of the contribu. tions of these substances to illness in humans exposed to the concentrations present in an atmosphere contaminated with tobacco smoke is not presently known. SUMMARY OF THE 1972 REPORT: HARMFUL CONSTITUENTS OF CIGARETTE SMOKE A number of substances or classes of substances found in ciga. rette smoke are identified as those which are judged to be con. tributors to the health hazards of smoking. These constituents are further divided into the most likely contributors to these health hazards (carbon monoxide, nicotine, and tobacco "tar"), sub. stances which are probable contributors, and those which are su.s. pected contributors. The recom,mendations for control in this area are to seek progressive reduction of all harmful constituents in cigarette smoke with priority being given first to the most likely contributors named and second to the probable contributors to the health hazards of smoking. These judgments represent the consen. sus of experts based on current knowledge and are subject to modi.. fication and further elaboration as more knowledge becomes available. 8 CHAPTER 2 Cardiovascular Diseases Contents Page Coronary Heart Disease Introduction 13 Epidemiological Studies 14 Interaction of Smoking and Other Risk Factors 16 Autopsy Studies 19 Experimental Studies 21 Nicotine and Cigarette Smoke 21 Carbon Monoxide 21 Smoking and Thrombosis 23 Cholesterol Content of Tobacco and Tobacco Smoke 24 Cor Pulmonale (Pulmonary Heart Disease) . . . . . . . . . . . . . 24 Cerebrovascular Disease . . . . . . . , . . . . . . . . . . . . . . . . . . . . . 24 Peripheral Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Oral Contraceptives, Thrombophlebitis, and Smoking . . . . . 26 Highlights of Current Cardiovascular Information . . . . . . . . 27 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 LIST OF TABLES Table L-Incidence (1963-1970) of heart infarct in relation to tobacco consumption in "The Men Born in 1913," Goteborg, Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 2.-Cigarette smoking at entry and subsequent 20-year CHD incidence among Minnesota men . . . . . . . . . . . . . . . . Table 3.-Human autopsy study. Comparison of the thick- ness of myocardial arteriole walls in smokers and non- smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table $.-Average values of carboxyhemoglobin and serum cholesterol in Danish smokers and nonsmokers in control group and group of patients with arteriosclerotic cardio- vascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 15 19 23 11 LIST OF FIGURES Page Figure l.-Canine autopsy study. Comparison of the thick- ness of myocardial arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsmoking dogs . . . . . . . . . . . 20 12 INTRODUCTION In the United States more people die from coronary heart disease (CHD) than from any other disease; furthermore, CHD is the single most important cause of excess death among cigarette smokers (54, 57). The 1971 report, "The Health Consequences of Smoking" (56)) outlined the growing magnitude of this problem and summarized the relationship between smoking and coronary heart disease as follows : 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 physical inactivity) shows that cigarette smoking operates independently of these other factors and can act jointly with certain of them to in- crease the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coronary arteries. 5. The cessation of smoking is associated with 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 catecholamines, causes increased myocardial wall tension, contraction velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. 13 b. Among individuals with coronary atherosclerosis, ciga. rette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient in- crease in coronary blood flow and oxygenation. c. Carboxyhemoglobin, formed from the inhaled carbon monoxide, diminishes the availability of oxygen to the myo- cardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reduc. ing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhe. siveness which might contribute to acute thrombus for- mation. Recent epidemiological, pathological, and experimental studies add to the understanding of the relationship between smoking and CHD. These studies point to cigarette smoking as one of the major risk factors leading to CHD and help clarify some of the biomech- anisms through which this occurs. EPIDEMIOLOGICAL STUDIES A prospective study of 973 men born in 1913 in GGteborg, Sweden, was undertaken in 1963 (51,52). The proportion of myo- cardial infarctions among cigarette smokers was significantly greater than among nonsmokers (P < .05), and the incidence of myocardial infarction rose with increasing cigarette consumption (table 1). Of the 35 individuals who experienced a myocardial in- farction between 1963 and 1970, only two had been nonsmokers; in the whole population of men born in 1913,56 percent were smokers. Although angina pectoris was more common in smokers than nonsmokers, the difference was smaller than for myocardial in- farction and was not statistically significant (52). Paffenbarger, et al. (42) reported on the health experience of 3,263 longshoremen studied over the past 18 years. During this in- terval 1,098 were known to have died, 350 dying from CHD. Long- shoremen who smoked more than 20 cigarettes a day faced a risk of coronary death which was more than twice as great as that of the group made up of both nonsmokers and smokers of less than 20 cigarettes a day (P < .Ol) . Keys, et al. (30) analyzed the 20-year CHD incidence among 279 Minnesota men aged 47 through 57 years who were CHD free at entry into the study. The relationship of cigarette smoking habits at the start of the study to the subsequent incidence of CHD was examined. The originally published table of results was incorrect 14 and the authors have supplied a corrected table which appeared in a later issue of the same journal (table 2). The morbidity ratio for "hard CHD" (CHD deaths plus myocardial infarctions not resulting in death) among those smoking more than 10 cigarettes a TABLE L-Incidence (1963-l 970) of heart infarct in relation to tobacco consumption in "The Men Born in 1913," Giiteborg, Sweden. n = 855 Smoking Heart infarct classification Number Percent Never smoked n ti 207 Stopped smoking n = 168 Cigarette smokers 1-14 cig/day n = 234 15-24 cig/day n= 138 225 cigiday n = 33 Pipe/cigar n = 75 ( 2) 1.0 ( 2) 1.0 (13) 6.0 ( 9) 7.0 ( 4) 12.0 ( 5) 7.0 SOURCE: Tibblin, G.. Wilhelmsen. L. (51). TABLE 2.-Cigarette smoking at entry and subsequent RO-year CHD incidence among Minnesota men.' Number Smoking habit (cigarettes/day) Age of men Item NW`X Stopped 20 47948 53 49,50 51 51,52 69 x1,54 53 -55-57 51 J;-57 277 47-57 277 4:-w 277 47-57 277 47-57 277 ~1-51 277 47-57 277 % with habit 23 % with habit 33 % with habit 33 % with habit 36 % with habit 24 Number of men 83 Hard CHD rate (%) 12.0 Hard CHD rate (SE) -t 3.6 Hard CHD Morbidity Ratio 1.00 All CHD rate (%) "21.7 All CHD rate (SE) k 4.5 All CHD Morbidity Ratio 1.00 19 20 26 30 33 71 15.5 + 4.3 1.29 .83 1.43 1.77 221.1 516.7 k19.5 k26.9 k 4.8 ?I 6.8 2 6.2 r+ 6.1 .97 .77 .90 1.24 9 14 14 8 3: 10.0 * 5.5 19 10 14 13 18 41 17.1 2 5.9 30 23 13 13 i'z 21.2 + 5.7 ' Cigarette smoking habits, by age at start of the XI-year follow-up, ZO-year incidence rates ' per 100 men ) and standard ei-ram (SE) of the rates. `"flrCt.q. .*A,+- "Hard cxD"--CHD death and myoeardial ~iohee. angina peetoris and other CHD diagnoses. "Deaths"-from all ca"ses except SoURCE: Modified from Keys, A., et al. (30). 15 day is similar to that reported from the large prospective studies. However, with the small number of cases in each smoking category, there are no statistically significant differences in the incidence of CHD between the categories, either singly or combined. Retrospective studies of CHD have recently been reported from Czechoslovakia, Sweden, Norway, and India which corroborate earlier studies linking cigarette smoking with excess CHD morbid- ity and mortality. The Prague study (19) included 443 men between the ages of 60 and 64 years. Significantly more (P < .05) individuals with a "probable" myocardial infarction were found among cigarette smokers than among nonsmokers or pipe and cigar smokers. The smoking habits of 120 patients with myocardial infarction who were hospitalized in Goteborg were compared with those of the entire "men born in 1913" population sample (17, 62). A signif- icantly (P < .Ol) greater number of smokers and heavy smokers (more than 15 cigarettes a day) were found in the myocardial in- farction group than in the population sample. The Bergen, Norway, cross sectional study of 2,117 women and 2,472 men documented a relationship between smoking and CHD in men, which was most marked in the 50 to 59 year old age group (16). No effect of smoking on the prevalence of CHD in women was demonstrable in this study, and the effect in men did not appear to be related to the daily number of cigarettes smoked. In New Delhi, 100 "well documented" cases of ischemic heart disease were compared with an equal number of control cases (8). In this study, significantly more (P < .Ol) of the case group smoked cigarettes regularly than the control group (Morbidity Ratio = 2.1). Mulcahy, et al. (40) recently found a positive association between coronary heart disease mortality rate and calculated per capita cig- arette consumption in 21 countries. He interpreted the results as being consistent with the hypothesis that cigarette smoking is a significant risk factor in CHD mortality. Stamler, et al. (50) found that for both men and women the 1964 CHD mortality rates in 17 developed countries were related to aver- age annual per capita cigarette consumption. INTERACTION OF SMOKING AND OTHER RISK FACTORS The Report of the Inter-Society Commission for Heart Disease Resources summarized the evidence indicating that three risk fac- tors (hypercholesterolemia, hypertension, and cigarette smoking) are properly designated major risk factors for premature CHD (28). Other possible risk factors including obesity, physical inac- tivity, diabetes mellitus, elevated resting heart rate, electrocardio- 16 graphic abnormalities, a positive family history of premature CHD, and psychologic and social factors have also been described (54, 55,56). In the study of 973 men born in 1913 in Giiteborg, Sweden, sev- eral coronary risk factors including elevated serum cholesterol, ele- vated serum triglyceride, low physical activity at work, and smok- ing were found to be related to an increased risk for the development of coronary heart disease during the subsequent years of the study. Failure to find a relationship between hypertension and an in- creased risk of CHD may have been due to the fact that all patients with hypertension in 1963 have been under treatment since that time. Tibblin and Wilhelmsen (52) found that as a patient accumulated more risk factors his chance of developing CHD became substan- tially greater. Werkij (61) reported from the same Gijteborg study that patients who were smokers, had sedentary jobs, and had both elevated cholesterol and triglycerides experienced a 4-year incidence of new coronary events of about 20 percent; the 4-year incidence among those who exhibited only one or two risk factors was much lower, ranging from 0 to 3 percent. ECG changes and angina1 pain were included in the definition of new coronary events. Paffenbarger, et al. (42) evaluated coronary risk factors in the study of 3,263 longshoremen. They found that, with the exception of diagnosed heart disease, smoking was the most important factor Predictive of high risk for coronary mortality. Keys, et al. (30) in the study of 279 Minnesota men, concluded that a positive cold pressor test, elevated serum cholesterol, and elevated systolic blood pressure had major predictive power for CHD death or infarction; in their analysis smoking seemed less important. Stamler (49) has analyzed the data on 13 deaths occurring dur- ing the first years of the Chicago Coronary Prevention Evaluation Program, which originally consisted of 519 coronary-prone male volunteers aged 40 to 59 who were free from clinical CHD. Eleven of the 13 decedents had three or more coronary risk factors at entry into the program, and at least 8 were cigarette smokers at the time of death. Forty-three men, who were cigarette smokers at entry into the Coronary Prevention Evaluation Program, gave up smok- ing and have remained active in the program. There have been no deaths from cardiovascular causes in this group. Stamler (49) commented : "Even though the number of decedents was small, these data strongly suggest that continued cigarette smoking is as- sociated with very high risk of premature death for very coronary- Prone men, and that other preventive measures are by themselves of limited value for them as long as they fail to give up cigarette smoking." 17 As described in the 1971 report, "The Health Consequences of ! Smoking" (56), some studies have indicated that smokers show increased levels of serum lipids while others have not. Such contra. dictory results are also present in recent studies from Germany, Poland, and Sweden (21, 39, 53). After a patient suffers a myocardial infarction, he frequently gives up smoking (17,26). Only fragmentary data are available on what effect the cessation of cigarette smoking might have on the likelihood of a recurrent myocardial infarction (9,34, 43). Ninety- two survivors of a first myocardial infarction were studied over a S-year period by Par&s Chavero, et al. (43). During this time, 37 pati,ents continued smoking, and 12 of them (32 percent) experi- enced a second myocardial infarction. The 51 patients who did not smoke during this 3-year period included 39 ex-smokers and 12 pa- tients who had never smoked. Eight of the nonsmokers (16 percent) experienced a second myocardial infarction. The smoking habits of four of the patients were not known. Although the continuing smokers experienced a greater rate of recurrent myocardial infarc. tion than the nonsmokers, the difference was not statistically sig- nificant (P = .07). The role of genetic factors in the development of CHD and the difficulties associated with the use of twin studies were discussed in the 1971 report, "The Health Consequences of Smoking" (56). Mailed questionnaires were used to establish the diagnosis of angina pectoris in a study by Lundman, et al. of twin pairs discordant with respect to smoking habits and in a study by Liljefors of twins with CHD. Lundman, et al. (36) recently investigated 69 male twins with the diagnosis of angina pectoris established by questionnaire. Only 22 percent of these diagnoses could be verified by clinical examina- tion. In a study of CHD, Liljefors (35) studied 91 pairs of twins from the Swedish Twin Registry of 1967. The twins ranged in age from 42 to 67 years, and 51 pairs were monozygotic. Smoking habits were not significantly different in pairs discordant for the probable presence of CHD. However, Liljefors noted that ". . . in many pairs the smoking habits were similar and that the material included few pairs discordant with respect to smoking, so that it does not pro- vide a suitable basis for conclusions as to the causal importance of smoking for CHD." As observed in the 1971 report, "The Health Consequences of Smoking" (56)) it would be surprising if genetic factors did not play a role in heart disease; however, it is open to question whether findings from twin studies can be used to dis- tinguish between ". . . the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exo- genous influence such as cigarette smoking and the hypothesis that genetic factors `cause' both heart disease and smoking." 18 AUTOPSY STUDIES In previously reported autopsy studies, Auerbach, et al. found that aortic and coronary atherosclerosis in man were more common and severe among smokers than among nonsmokers (5). They have now extended their investigations to the myocardial arterioles of men and beagle dogs (6). In a study of 1,184 men, they found that the thickness of myocardial arteriole walls was greater, on the average, in smokers than nonsmokers (table 3). The thickness in- creased with the number of cigarettes smoked per day and with age. The thickness was less, on the average, among cigar and pipe smokers than among cigarette smokers, but it was greater than in men who had never smoked regularly. TABLE S.-Human autopsy study. Comparison of the thickness of myocardial arteriole wa2Z.s in smokers and nonsmokers.' Age (Year) Smoking Number of Me" Percent of Men :Grade XGrade XGrade SGrade $Grade :Grade Total 0 1 2. 3 Total 0 1 2.3 < 45 None 22 2 19 1 100.0 9.1 85.4 4.5 Cigar, pipe 4- 13 100.0 - t25.0 y75.0 Cig. 1-19 50 1 31 18 100.0 2.0 62.0 36.0 Cig. 20-39 85 4 35 46 100.0 4.7 41.2 54.1 Cig. 240 29 - 10 19 100.0 - 34.5 65.5 45-59 None 15 1 12 2 100.0 6.7 80.0 13.3 Cigar, pipe 13 - 8 5 100.0 - 61.5 38.5 Cig. 1-19 33 - 17 16 100.0 - 51.5 48.5 Cig. 20-39 99 - 35 64 100.0 - 35.4 64.6 Cig. 240 50 - 11 39 100.0 - 22.0 78.0 GO-69 None 56 4 36 16 100.0 7.1 64.3 28.6 Cigar, pipe 35 - 22 13 100.0 - 62.9 37.1 Cig. 1-19 92 - 44 48 100.0 - 47.8 52.2 Cig. 20-39 193 - 58 135 100.0 - 30.1 69.9 Cig. 240 87 - 21 66 100.0 - 24.1 75.9 2 70 None 32 2 18 12 100.0 6.3 56.2 37.5 Cigar,pipe 40 - 19 21 100.0 - 47.5 52.5 Cig. 1-19 30 - 12 18 100.0 - 40.0 60.0 Cig. 20-39 46 - 12 34 100.0 - 26.1 73.9 Cig. 240 g- 3 6 100.0 - $33.3 t66.7 ' 1" the right ventricular ~111 of 1.020 me" bu age and smoking habits. ' P=="tages based on less than ten cakes. * Four Point Scale for the Thickness of bfyocardial Arteriole Walls: @-normsi thickness; l-slight thickness; 2-moderate thickness; 3-great thickness. SoURCE: Auerbacb. 0.. et al. (6). 19 In one experiment, beagle dogs inhaled cigarette smoke daily through tracheostomae. Twenty-eight dogs that died between days 57 and 875 formed one group; 32 dogs that were killed after 875 days formed another group. Eight control dogs were not exposed. Beagle myocardial arteriole walls were found to be thicker in smok- ing than nonsmoking dogs, in dogs smoking many cigarettes than in dogs smoking fewer cigarettes, and in dogs smoking nonfilter cig- arettes than in dogs smoking filter-tip cigarettes (figure 1). Also, the thickness of arteriole walls increased with the duration of smoking. Group N No smoking 8 Dogs . . i :: . . . . . . . . . . . . . . . . . . Group L Nonfilter Cigarettes (% as many cigarettes) 10 Doas . . . . . . Group F . . . . Filter-Tip : Cigarettes . 10 Dogs A----l- Group H Nonfilter Cigarettes 12 Dogs I I Grade of 0 1 Thickness :: . . .ii ::: : :: :ii . . . . . . ..* . . . . . . . . . . . . . . . . . . . . . ::: . . . . . . . . . 2 Each dot represents one section. The three d.ots on a line represent the three sections from a particular dog. FIGURE L-Canine autopsy study. Comparison of the thickness of myocardial arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsmoking dogs. SOURCE: Auerbach, O., et al. (6). 20 EXPERIMENTAL STUDIES NICOTINE AND CIGARETTE SMOKE Schievelbein, et al. (47) investigated the effect of oral nicotine administration over a 20-month period on lipid metabolism in 35 rabbits. Even though lipoprotein lipase levels and calcium content of the aorta were significantly greater in the group given nicotine than in the control group, the histological changes of arteriosclero- sis were found with equal frequency in both groups. The authors concluded that the epidemiological correlations between CHD and cigarette smoking could not be explained by the pharmacologic ef- fect of nicotine alone. A study of the interaction of chronic nicotine administration and acute hypoxia in 280 rats was performed by Wenzel and Richards (60). Pretreatment of the rats with nicotine increased the mortality during hypoxia, but the difference was not statistically significant. Pretreatment with the nicotine also was associated with marked variability of regression of hypoxic heart lesions. The interaction of nicotine pretreatment and the hypoxic insult produced variable effects on myocardial enzymes. Aronow (1) recently studied the effect of cigarette smoking on the A wave of the apexcardiogram in 20 men with CHD. The A wave reflects the left ventricular filling wave associated with the impact of blood upon the ventricular wall during left atria1 contraction. He found that the mean maximum increase in A wave ratio after smoking was 34 percent for high-nicotine cigarettes, 13 percent for the low-nicotine cigarettes, and 6 percent for the non-nicotine ciga- rettes. He ascribed these changes to increased myocardial ischemia produced by cigarette smoking, which was reflected by a larger A wave ratio in the apexcardiogram. While nicotine appears to have produced most of these changes, the observation that a 6 percent increase occurred in the absence of nicotine suggests the possibility that carbon monoxide plays a role in this effect. CARBON MONOXIDE Because cigarette smoke contains from 2.7 to 6 percent carbon monoxide (CO), significantly higher carboxyhemoglobin ( COHb) levels are found in smokers than nonsmokers (j3,20,24,63). COHb levels in nonsmokers are usually less than 1 percent, while those in smokers average around 4 percent and may exceed 15 percent (4, 20, 56). Heavy smokers and those who inhale show the highest carboxyhemogldbin levels (20). Haebisch (24) found that a smoker with a daily consumption of 35 to 40 cigarettes easily attains and maintains for hours an alveolar 21 CO concentration of 50 p.p.m., which reaches or exceeds legally- established ambient air quality standards (14,18, 23, 24). Cohen, et al. (23) and Aronow, et al. (2) have shown that there is no significant difference in mean expired air carbon monoxide levels after patients have smoked tobacco or lettuce leaf cigarettes. Although pipe and cigar smokers in the United States are reported to have lower exposure to CO than cigarette smokers (20) , CO in- toxication has been reported in cigar smokers (25). CO exerts its adverse effects on the cardiovascular system of smokers through one or more of the following mechanisms : (a) re- duction of the amount of hemoglobin available for oxygen trans- port ; (b) shift of the oxygen-hemoglobin dissociation curve to the left with consequent interference in oxygen release at the tissue level ; and (c) induction of arterial hypoxemia. CO may interfere with the homeostatic mechanism by which 2,3-DPG controls the affinity of hemoglobin for oxygen (56). CO has also been implicated in experimental atherogenesis in animals (56). Ayres, et al. (7) recently studied 41 patients during diagnostic cardiac catheterization, at which time they inhaled either 5 percent or .l percent CO. Arterial and mixed venous oxygen tensions were decreased by administration of either concentration. In patients with CHD, coronary artery 0, extraction decreased 7.9 percent after inhalation of .1 percent CO and 30.5 percent after inhalation of 5 percent CO. Some of the patients with CHD experienced changes in lactate and pyruvate metabolism indicative of inadequate myocar- dial oxygenation. The higher level of CO inhalation in this experi- ment is comparable to that experienced intermittently by cigarette smokers. Brewer and his colleagues (11) investigated cigarette smoking as a cause of hypoxemia in residents of Leadville, Colorado, at an altitude of 3,100 meters. The arterial p0, of 8 smokers was signif- icantly lower (P < .05) than that of 12 nonsmokers, but this was reversible upon cessation of smoking. They concluded that the ad- verse effect of cigarette smoking on 0, transport may be especially pronounced at high altitude and may restrict an individual's ability to adapt to reduced 0, tensions (11,12). Kjeldsen (31, 32) examined 993 industrial workers, about one- half of whom were tobacco workers. Fifty-nine cases of arterio- sclerosis were documented by such clinical symptoms as angina pectoris and intermittent claudication or by a previous history of myocardial infarction. While 20.9 percent of the 934 "control" in- dividuals were nonsmokers, only 2 (3.4 percent) of the 59 patients with arteriosclerosis were nonsmokers. A significantly higher per- centage of diseased workers were heavy smokers and inhaled the smoke. 22 The diseased smokers had significantly higher carboxyhemoglobin and serum cholesterol levels than either smoking or nonsmoking control patients. This was true after standardizing for differences in levels of smoking between controls and diseased patients. As ex- pected, there was a gradient in carboxyhemoglobin levels from lower levels in light smokers to higher levels in heavy smokers (table 4). TABLE 4.-Average values of carboxyhemoglobin and serum choles- terol in Danish smokers and nonsmokers in control group and group of patients with arteriosclerotic cardiovascular disease. Smoking category Carboxyhemoglobin Serum cholesterol (saturation percentage) ba/lOO ml) controls patients signifi- controls patients signifi- M?S.D. M%S.D. canee MIS.D. MfS.D. cance Smokers 4223.1 7.043.7 p