clinical examination, while among 204 responding negatively, two were found to have angina by clinical criteria. None of the 11 women who were diagnosed as positive by questionnaire was found to be clinically affected, and of the 136 reporting as negative, three had symptoms of angina pectoris. Other major difficulties associated with these studies include the problems of using prevalence data in the investigation of a disease (CHD) from which a significant number of those affected die shortly after the onset of symptoms, the inclusion of ex-smokers in the smoking population, and the low numbers of heavy cigarette smokers in the Swedish population. In general, the problems of using twin registries to study the etiology of cardiovascular disease with mortality and morbidity ratios in the neighborhood of 2 to 1 are much more difficult than in studying the etiology of bronchopulmonary disease in which the relationships are of the order of magnitude of 4 to 1. More recently, Friberg, et al. (69) reported on mortality data from the Swedish Twin Registry. The authors suggested that part of the increased mortality observed among smokers when com- pared with nonsmokers was not due to smoking per se but to fac- tors associated with smoking. The very small numbers of total deaths presently available (47 deaths among 706 dizygotic pairs and 13 deaths among 246 monozygotic pairs) do not provide a sta- tistically stable base for deriving any conclusions at the present time. Hauge, et al. (81) have recently reported on the influence of smoking on the morbidity and mortality observed in the Danish Twin Register. Among 762 monozygotic and same-sexed dizygotic twin pairs, angina pectoris was found to be significantly more fre- quent in those cotwins with a higher consumption of tobacco than in those with a lower or no consumption. A similar tendency was observed for myocardial infarctions but was not of statistical significance. Seltzer, who has been a proponent of the constitutional hypothe- sis, in a recent review of some of the experimental, clinical, and pathological data relating smoking and CHD, concluded that the evidence from these areas has not "reasonably substantiated" the "hypothesis" of the acute effect of cigarette smoking on the coro- nary circulation, nor has the chronic effect of cigarette smoking on the cardiovascular system been shown to be a "clear" and con- sistent one (170). His views are contrary to those of most re- searchers in this field, Although the data from the twin studies are inconclusive with regard to a role for genetic factors in heart disease, it would be surprising if genetic factors did not play such a role. It is open to 51 question whether findings from twin studies can be used to distin- guish between the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exogenous influence such as cigarette smoking and the hypothesis that genetic factors "cause" both heart disease and smoking. AUTOPSY STUDIES RELATING SMOKING, ATHEROSCLEROSIS, AND SUDDEN CHD DEATH A number of researchers have investigated the cigarette smoking habits and the cardiovascular pathology of those individuals dying suddenly from CHD and of large populations of individuals with and without histories of overt CHD. Spain and Bradess (175) recently analyzed the smoking habits of 189 individuals who died suddenly and unexpectedly, apparently from the first acute clinical episodes of CHD. The authors noted a close correlation of a history of cigarette smoking with this type of sudden death and also with shorter survival times following the acute episode. This association was strongest in those persons under 50 years of age. The authors also observed that those surviving very short pe- riods of time showed a notable lack of intracoronary artery throm- bi at autopsy and that the frequency of thrombi present increased with increasing survival time. They suggested that thrombi found at autopsy may be the result rather than the cause of certain instances of myocardial infarction, particularly of lesions showing subendocardial necrosis. This finding is of significance in the study of the effect of smoking on myocardial metabolism and oxygen supply and demand rather than on thrombus or platelet plug formation. While the autopsy study of Spain and Bradess (175) concerned sudden death among smokers, other autopsy studies from various countries have been directed towards the relationship of cigarette smoking to the presence of atherosclerotic disease in the aorta and coronary arteries. These are concerned with the long-term effects which smoking has on the cardiovascular system and are sum- marized in table 19. The studies of Auerbach, et al. (12)) Avtan- dilov, et al. (13)) Sackett, et al. (165)) and Strong; et al. (182) found that aortic and coronary atherosclerosis were more common and more severe among smokers than among nonsmokers. Auerbach, et al. (12) noted that this relationship persisted when the cases were matched for both age and cause of death or when the follow- ing cases were excluded; men with a history of diabetes; men who had died of any type of heart disease; and men whose hearts weighed 400 grams or more. Sackett, et al. (165) found that the 52 (Figures in parentheses are number ut individuals in that smoking category)' [SM = smokers NS = nonsmokers] Author. Year. countru, reference Autopsy population Data collection Cigarettes per dny Conclusions Comments Wilens 989 consecutive Routine clinical Severity of am-tic sclerosis The authors conclude that Smoking data unavailable and Plair, male autopsies records of Above average Average Below average in 60 percent of cases. the for 120 cases. 1962, at New York previous and NS . . . 9.9(161) 60.2 29.8 degree of sclerosis at Each aorta specimen given U.S.A. City VA present <20 . 19.1(162) 63.2 17.8 autopsy was e"mme"- an "atherosclerotic age" (214). hospitals. admissions. 20-30 .,,,..... 26.4(288) 62.5 11.1 surate with age of patient. by comparison with a >30 .t25.1(199) 61.3 t13.6 regardless of smoking standard. If "athero- habits. In the remaining sclerotic age" was found 40 percent there is evi- to be 10 years more than dence that cigarette real age. the aorta was smoking may be ass"- said to show above- ciated with an above- average sclerosis. average degree of aortic tp40 . . . . ..0.6(144) 18.1 36.4 45.9 smoking. This relation- have overt CHD ship persisted even at death. when cases were matched for age and cause of death. 1 unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the cn w exclusion of either occasional. miscellaneous, mixed, or ex-smokers. TABLE 19.-Autopsy studies of atherosclerosis (cont.) (figures in parentheses are number of individuals in that smoking category)' [SM = smokers NS = nonsmokers] !E Author, year, Autopsy Data cou"trY. population collection Cigarettes per day Conclusions CO"l"l.3h reference Avtandilov. 269 male and Not specified, Comparative size of mean area of alhe+osclerotic ~&WUI The author concludes that Causes of death 96-athero- 1966, 141 female hut there were: in inner coat of eosmkwu a+teriea. the worst changes were sclerotic, lO%accidental. RUSB~IS autopsies. 130 SM and Right ~o?`onaw artery Left cosona~~ artery found in the left and POP-various diseases. (16). 220 NS. SM NS SM NS right coronary arteries tT-test for sjgnificance 30-3s Q5.5(30) 1.3(32) t6.3 2.2 with less severe changes of difference between 40-4s t23.6 (34) 11.6(27) t1e.e 4.4 in circumflex artery means is significant 60-59 ..t36.3(39) 14.8(39) 127.9 9.9 and aorta. at P25 cigarettes/day .12 (9) 31(14) 26(25) 39(20) The authors conclude that: This report concerns o"Iy "Atherosclerotic in- ages 26-64. volvement of aorta and No data on statistical coronary arteries is significance provided. greatest in heavy smokers and least in nonsmokers." NS . Negro 4(14) 3 (3) 16(11) 17(14) l-24 cigarettes/day 3(39) ll(31) 14(30) 28(22) >25 cigarettes/day .17(10) 14(17) 29(12) 16(11) `Unless Otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional. miscellaneous, mixed, or a-smokers. severity of aortic atherosclerosis, as measured both by intensity and duration, increased with increasing use of cigarettes and that this dose-relationship persisted when the patients were matched for the consumption of alcohol. On the other hand, Viel, et al. (ZOO) concluded from their study of accidental deaths in Chile that "no relationship between atherosclerotic lesions and the use of tobacco was discernible." Examination of the data (provided in graph form only) indicates that heavy smokers showed consistently higher percentages of diseased areas than nonsmokers, but appar- ently these differences were not statistically significant when sub- jected to an analysis of variance. Thus, in addition to the acute effects which smoking exerts on cardiovascular physiology, cigarette smoking is associated with a significant increase in atherosclerosis. EXPERIMENTAL STUDIES CONCERNING THE RELATIONSHIP OF CORONARY HEART DISEASE AND SMOKING Several areas of interest in cardiovascular pathophysiology have been investigated in the search for the mechanisms by which ciga- rette smoking contributes to cardiovascular disease, particularly coronary artery disease. Previous Public Health Service Reviews (191, 192, 193, 198) have described in detail and commented on the results of experiments by many teams of researchers. Central to the discussion which follows is a concept of cardiac physiology which provides a framework for analysis and under- standing of the varied research. That concept concerns the dynamic balance between myocardial oxygen need and supply. CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE The inhalation of tobacco smoke or the parenteral administra- tion of nicotine has been found by many researchers to be asso- ciated with a number of specific acute cardiovascular responses. These responses have been observed in human as well as animal subjects, including increased heart rate, blood pressure, cardiac output, stroke volume, velocity of contraction, myocardial contrac- tile force, myocardial oxygen consumption, arrhythmia formation, and electrocardiographic or ballistocardiographic changes (tables A20 to A22). The effect of these responses on coronary blood flow will be discussed in a following section. That the acute effects observed following the inhalation of ciga- rette smoke are due primarily to the nicotine present in the smoke may be seen in the results of a number of experiments. In humans, Irving and Yamamota (89) and Von Ahn (202) duplicated the 56 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, Burn and Rand (35) 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 (12.5)) 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, ,211) (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 cornsilk 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 (112) 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 to catecholamine release. 57 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. (16), 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 had 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 probably predispose the myocardium to the initiation of arrhythmias. CORONARY BLOODFLOW 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 Blesa (160)) Travell, et al. (189)) and West et al. (208)) working with normal animals, and Bargeron, et al. (27)) 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 block the response to nico- tine by pretreatment with pentolinium. The direct action of catecholamines on the coronary arteries may not, however, be solely responsible for the increase in CBF 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 tracheostomized dogs, found that without blood pressure and cardiac output changes CBF did not increase following either the inhalation of cigarette smoke or the administration of nicotine 58 intravenously, although CBF did increase following such changes. Recent work by Leb, et al. (126) has utilized Rb@ as a radioactive marker in order to distinguish capillary flow from overall total 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 normals. Regan, et al. (154) 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 he capable of increasing their coronary flow in the face of the in- creased demands of a myocardium stimulated by nicotine or ciga- rette 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 PO, values incom- patible with proper tissue oxygenation. CARDIOVASCULAR EFFECTS OF CARBON MONOXIDE Carbon monoxide (CO) is a colorless and odorless gas, 10~ levels of which have significant effects on human and animal physi- ology which are just now beginning to be understood. According to Wynder and Hoffmann (215)) 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 59 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. mately 4 percent CO in cigarette smoke will produce alveolar levels of around 0.04 percent which, equilibrated with hemoglobin, result in carboxyhemoglobin (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 levels of 6.8 percent and that smokers of lesser amounts had intermediak levels. Occupational exposure accounted for the mean nonsmokers' level being over 1.0 percent, an unusual 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 inhaling smokers 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- sive review by the United States Public Health `Service National Air Pollution Control Administration (194). Apart from its effects on respiratory and circulatory function, CO has been found to affect certain central nervous system functions adversely. These effects 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 greater than its affinity for oxygen, and thus CO can easily dis- place oxygen from hemoglobin. Second, CO shifts the oxyhemo- globin dissociation curve. By increasing the avidity with which oxygen is 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 to approximately 40 percent saturation. Here the shift can sub- stantially decrease the oxygen tension supplying the tissues. Third, and of more recent note, is the possible interference by CO with the homeostatic mechanism by which 2, S-diphosphogly- cerate (2, 3-DPG) controls the affinity of hemoglobin for oxygen. Bunn and Jandl (3$) have recently reviewed the various experi- 60 ments 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, 143), 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. (1 4,15) observed unexpectedly that exposure of individuals to CO sufficient to raise their levels of COHb to between 5 and 10 percent was associated with a signifi- cant fall in arterial PO,. Greater fall in venous p0, was noted, but this was considered secondary to increased tissue extraction. In a recent article, Brody 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 OZ 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- tomatic 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 COHb. Accord- ing to the investigators this implied that the same work was being done at a greater metabolic cost. These same authors (221, 1.22) had previously noted similar findings among smokers and observed 61 that cessation of smoking was associated with a significant im- provement 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 4 pa- tients suffering from CHD (proven arteriographically) . The induc- 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, and lactate and pyruvate extraction ratios. The induction of simi- lar COHb 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 could not extract O? from HbO, which was under the influence of CO, coronary sinus oxygen tension decreased to a point which could inactivate certain oxida- tive 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 (215), the amount present ranges from 11 to 32 micrograms HCN per puff. It is known that a significant amount of this material is d.etoxified 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 the other factors mentioned above which tend to decrease the oxygen supply available and increase the need for oxygen on the part of the myocardium. 62 EFFECTS OF SMOKING ON THE FORMATION OF ATHEROSCLEROTIC LESIONS A number of autopsy studies have demonstrated a significant association between cigarette smoking and 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 certain 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 (75) or definite atheromatous lesions (46, 75, 80, 130, 178). Studies by Choi (42) and by Wenzel, et al. (207) did not demonstrate this synergism between cholesterol and nicotine. The other major cigarette smoke component under discussion m 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. (IO) 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. (114) 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 `I-month period than when exposed only to room air. Recent 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 (212)) who considers the filtration theory to be an inadequate hypothesis for 63 TABLE 24.-Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia Author. ye*=. country, reference Number and type of animal Procedure Results Astrup 24 female Regular diet plus 2 percent The experimental group exposed to carbon monoxide showed increased macro- and et al., albino rabbits. cholesterol: microscopic aortic atheromatosis over that show" by control animals. Micro- 1967 I. (12) control. scopic examination revealed intimal lipoid deposition limited in penetration by Denmark II. (12) continual exposure to the internal elastic membrane. Coronary vessels were found to show similar (f0). carbon monoxide: changes. Carboryhemoglobin. (COHb) levels averaged 16-19 percent during the 0.017 percent for 8 weeks. first 8 weeks and 33 percent during the final 2 weeks. 0.035 percent for 2 weeks. - Kjeldsen 24 castrated male Regular diet plus 2 percent The experimental group exposed to hypoxia showed increased macroscopic aortic et al., albino rabbits. cholesterol: atheromatosis over that shown by control animals. Microscopic examination re- 1968, I. (12) control. waled more intimal and subintimal lipid deposition in the aortas of the exposed Denmark II, (12) continual exposure. rabbits than in those of the nonexposed. The total amount of cholesterol de- (117). to hypoxia: posited in the aortas of the experimental group was three times higher than in 10 percent-O2 for 6 weeks. those of the control group. 9 percent O2 for 2 weeks. Kjeldsen 24 castrated male Regular diet plus 2 percent Macroscopically, the experimental group showed significantly fewer atheromatous et al., albino rabbits. cholesterol: changes. Microscopically, the experimental group showed significantly less aortic 1969. I. (12) control. intimal lipid deposition. Denmark II. (12) exposure to 28 percent (114). 0% for 10 weeks. Webster 22 female squirrel Diet containing 0.5 percent The experunental group exposed to carbon monoxide showed a greater mea" per- et al., monkeys. cholesterol and 25 percent fat: centage of coronary arteries with atherosclerotic lesions and more lumen occlu- 1970. I. (10) control. sion among the affected arteries. There were significantly more CO-treated U.S.A. IL (12) experimentaUyexposed to monkeys than control monkeys having 35 percent or more apparent atbero- (204). 200-300 p.p.m. carbon monoxide sclerotic stenosis among the affected arteries. Aortic atherosclerosis was appar- for 20 hours per week for 7 ently not aggravated by exposure to CO. COHb levels at the end of each exposure months. period averaged 16-26 percent during the flnal 24 weeks of the experiment. 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 mitochondrial enzymes whose hydrogen donor is NADH. Substances which slow or impair the reoxidation of this compound tend to increase mito- 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, particularly in view of the fact that cyanide is also a respiratory chain inhibitor and thus may also adversely affect arterial wall fat metabolism. THE EFFECT OF SMOKING ON SERUM LIPID LEVELS In the discussion concerning the epidemiological aspects of CHD, 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 A25 and A25a. The table is divided into a section concern- ing 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 responsible 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 listed in table A26. Among rabbits fed increased amounts of cholesterol, 65 the authors observed significant increases in cholesterol and tri. glyceride concentrations in those exposed to CO versus those maintained in a normal atmosphere. THE 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 ar- 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 thrombus 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 vitro but few about the effect of smoking on platelet behavior in vivo. 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 INVESTIGATION 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- tions 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- viously (192,192), and the reader is referred to those discussions. CEREBROVASCULAR DISEASE The term cerebrovascular disease (CVD) refers to a number of different 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 listed as dying from CVD as the underlying cause (196). Epidemiological studies indicate that cigarette smoking is asso- 66 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- tinkel (76). The data from their study, as presented in table 28, 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 (123)) 20 habitual smokers re- 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 (132) studied the effect of smoking on the cerebral circulation of 12 moderate/heavy cigarette smokers as measured indirectly using an ultrasonic D,oppler 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 60 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- larly its extracranial portion) is likely 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 inc.rease the risk of dying from this disease, perhaps by promoting the atherosclerotic proc- ess 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. 67 TABLE B.-Deaths from eerebrovascular disease Telated to smoking (Mortality ratios--actual number of deaths shown in parentheses)' [SM = smokers NS = nonsmokers] PROSPECTIVE STUDIES Number of Author, Follow- deaths due Ye*=* Number and Data UP to CVD as years underlying Cigarettes per day PJt; country, type of collection cigars reference population CB"W Age variation Comments Hsmmond 137.783 white Questionnaire 355 1,050 NS .l.OO (164) t (PZO 1.46 (83) Doll and Hill, 1964, Great Britain (50). Approximately Questionnaire 41,000 male and follow- British up of death physicians. certificate. KlXlIlCl et al.. 1965 U.S.A. (96). 5,127 males Medical and females examination 30-59 year?, and follow- of age. UP. 605 NS . ..l.OO All SM ..I.06 All cigarette 1.12 1-14 . . . ..l.lO 15-24 . .I.09 >25 . 1.26 13 NS .I.00 (6) Data apply only Heavy SM to males 3&59 (>20) .3.23 (8) ye*rs Of me at entry. Data apply only to cerebral infarction. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories arc due to the exclusion of either occasional, miscellaneous, mixed. or ex-smokers. TABLE 28.-Deaths fmm cerebrovascular disease wzltcted to srrrokiag (cont.) (Mortality ratios-actual number of deaths shown in parentheses) [ SM = smokers NS = nonsmokers] PROSPECTIVE STUDIES Number of Author. deaths due Pipes Year. Number and Data Follow- underlying Cigarettes per day and Age variation Comments country, type of collection UP years to CVD as cigars reference population Ca"Be Kahn. U.S. male Questionnaire 1966. veterans and follow- U.S.A. 2,266.674 ~1, of death (93). person certificate. year*. Hammond 358,534 males Questionnaire and 445,875 and follow- Garfinkel. females 40-79 UP of death Sly! 2.008 NS _.. .l.OO (614) All SM current .1.30(1.394) NS current cigarettes .1.52 (692) NS 1-9 1.51 (98) SM lo-20 1.42 (326) 21-39 . . . .1.70 (216) >39 . 1.59 (37) 6 4,099 Pipes .1.06 (82) .1.00(614) Cigare .1.00(614) . .1.08(136) Current tBased on onlg regular M&8 6-9 deaths. riaarettc JO-49 50-59 60-69 70-79 1969, years of age certificate. NCTer U.S.A. at entry. smoked 1.00 (76). l-9 .2.79 10-19 .I.14 20 39 .2.21 >40 .1.64 Never smoked 1.00 l-9 .1.50 lo-19 .2.60 1.00 1.00 1.95 1.30 1.48 t1.44 2.03 1.62' 2.40 1.72 FC7lllllC8 1.00 1.00 1.26 1.26 2.70 2.16 1.00 0.95 0.92 1.22 0.68 1.00 0.83 0.57 20-39 .2.90 2.67 1.83 1.28 >4n .t5.70 t3.52 - - * Unless otherwise specified, disparities between the total number of deaths and the aurn of the individual smoking categories are due to the exclusion of % either occasional. misceIIaneous. mixed, or ex-smokers. TABLE %.-Deaths from ccrc4wvrcsczclnr disease related to smoking (cont.) (Mortality ratios--actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. PROSPECTIVE STUDIES Paffen- 3,263 male Initial multi- 16 67 NSand barger. longshoremen phasic <20 __. 1.00 (42) et al. 35-64 years screening >20 _. ._ .1.15 (26) 1970 of age in and follow- U.S.A. 1951. UI, of death (144). crrtificnte. RETROSPECTIVE STUDY Prlff`Z"- >50,000 male Initial college bsrger University entrance and students medics1 CY- Williams followed up nminations 1967 to 50 ye*rs. with follow- U.S.A. up of death (145). certificate. Controls- surviving classmates age-matched. Death Rates Cases (1.58) Controls (615) SM 45.0 31.3(P10 per day 20.9 11.2 (p39 ,.,............. 7.26 (17) Hammond 358,534 males and 445,875 females Garfinkel. 40-79 years of 1969, nge at entry. U.S.A. (76). Weir and 68,153 California DU"". male workers 1970, 35-64 years of U.S.A. age at entry. (20.5). Questionnaire and follow-up of death certificate. Questionnaire and follow-up uf death certificate. 6 337 NS ........... .l.OO l-9 .2.62 10-19 ......... ,335 20-39 ......... ,454 >40 ........... .R.OO 5-8 51 NS ,. _. ,. ,. .l.OO SM include All _. .2.64 a-smokers. k-10 _. _. .2.44 NS include pipe -c20 __ __ .2.88 and cigar 230 _. ,. . .2.64 smokers. Data apply only to males 50-69 years of age. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual categories are due to the exclusion of either occasional, miscellaneous. mixed. or ex-smokers. 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 factor 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. (92) reviewed the records of and contacted 478 male patients with arteriosclerosis obliterans (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 implicated 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 all cases. The author also noted obesity, high blood pressure, and elevated serum cholesterol 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 had been hospitalized for injuries. The in- vestigators reported that certain risk factors, including hyper- cholesterolemia, hypertension, and cigarette smoking, were signifi- 72 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. (213) compared 277 male patients with arterial occlusion of the limbs as demonstrated by aortography or oscillog- 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. EXPERIMENTALEVIDENCE 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 Stromblad (181) on blockade of this response with automatic sys- tem blockers indicates that the reactivity of these vessels is sec- 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) is 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 from peripheral arterioscle- rosis. McKusick, et al. (128) consider it to be a distinct entity 73 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 physical 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 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 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 74 velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient increase in coro- nary blood flow and oxygenation, c. Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the availability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. CEREBROVASCULAR DISEASE 1. Data from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cerebro- vascular disease. 2. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conclusions concerning pathogenesis. However, some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction, NON-SYPHILITIC AORTIC 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 vascular disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. Cigarette smoking has been observed to alter peripheral blood flow and peripheral vascular resistance. CARDIOVASCULAR REFERENCES (1) ACHESON, I?. M., JESSOP, W. J. E. Tobacco smoking and serum lipids in old men. British Medical Journal 2: llOS-1111, October 28, 1961. (2) ADLER, I., HESSEI, 0. Intl,avenous injections of nicotine and their ef- fects uljon the aorta of rabbits. Joul,nal of Medical Research 15: 229-Xl, 1906. 75