9ceT TABLE A27.—Smoking and thrombosis Author, Whole Partial Recalcified year Number and Experl- blood Pro» thrombo- — plasma Pintelet Platelet Platelet Platelet country, type of mental clotting thrombin — plastin clotting adhesive. count survival turnover Other Comments reference population conditions ? time time lime time Tess Black- 16 adult 12 individuals Plasma burn achizo- smoked 2 atypven etal, phrenic high. time 1959, patienta, & nicotine (+) U.S.A. university atandard (¥5). students, all brand smokers, cigarettes, Mustard = 7 white males Compared Platelet and with vither after clumping Murphy, CVDor periods of time 1963, COrD, all abstinence (-) (—) (-) (—) (-) (+) (+) (4) U.S.A, heavy or continua- decrease increase (£40), smokers 35- tion of 72 years of smoking. axe, Ambrus 20 healthy Deep inhala- Thromboplaatin 2 students and mute non- lion of one yeneration became ill. Mink, smuking nonfiltered (~) (—} (~) (+) (-) time Results 1964, medical cigarette, - increase (-) reflect U.S.A, students <30 dala on 19. (4). years of age, Ashby 27 male 13 controls Increase of etal, medical measured at subjects 1965, students and 2 separate sereater Treland hospital times 14 Chin that (a), staff subjects (+) of controls members, measured inerense ae pe O01, before and after smuking 2 cigarettes in 20 minutes, Let Author, TABLE A2ZT.—Smoking and th runtbusts (cont.) OT ft ee Whole Partial feendeiied year, Number and Experi. blood Peo- thrombi. plasina Platelet Platelet Platelet Platelet country, typeof mental clotting thrombin plastin elotting adhesives out survival turnover Other Comimenty Seference | ovulation eonditingwey time —_.. time ae time ue Gare Nem a ne . Se eee ee ne Sogunt HL observations Smoked 2 thks Mibrivotyaia Wet. tint on male Aveta or (+f) tobacco Joshi, smoker al] 2 btrig or dee rene wrapgecck fey Tbh, revular chewed { {~-) {-) (+) (fe) fabaece tadla tobacen Vetel nut Inereane lowe, (17g), Uyera, guid in? minutes, Engel- ~~ 40 male and 2 ‘ciknretteg Oe es Chandler berg, 20 feninle in 20 {in uttro) 1064, hoxpital pus minutes, thrombosin USA, tients, alt lime (48), smokom 17- + GK yours of decrease tee, Kodra 30 male and 4 cigarettes ~~ —~ ~ ~~ Thrombin and 11 female in) hour. tone Korolku, smokers and (x) (-—) {-+b) (xt) 165, 44 male und dlecvense decrouse deerense Poland 26 fomale (10n), nonsmokery 18-25 years of age, Murchi- 8 males and Z cigarettes t Smoking both son 4 female in 15 lit and unlit and patients minutes, cigarettes Fyfe, with lit or unlit (t) (+) enused a rise 1966, various cigarettes, increase in platelet Scotland diseases, all adhesiveness (239). heavy which the smokers 37- authors 67 years corre|nted of uge. with rine in plasma none esterified fatty neida. 8cl TaBLE A27.—Smoking and thrombosis (cort.) Author, Whole Partial Recalcified year, Number and Experi- blood Pro- thrombo — plasma Platelet Platelet Platelet Platelet country, type of mental clotting thrombin plastin clotting sdhesive. count survival turnover Other Comments reference population conditiona! time time time time ness Glynn 20 male and J cigarettes Platelet Smokers found etal, 17 femole in 30 acrotinin to have a 1966, smokers and minutes, {~) (—) Kreater Cunada 9 male and Platelet tendency for (71). 21 female adenosine plutelet nonsmuokera nucleotide aggregation 17-76 years (~) than none of age, smokers. Engelberg 94 male and 1 cigarette Thrombue No relation and 53 female in 5 minutes. formation found with Futter- patients and time incrvaye in man, medical (+) free fatty 1967, house staff. decrease acidy. ULS.A. (59). Murphy, Literature Platelet 1968, review with adherence to U.S.A, summary of (+) (4) (+) vascular (140). data and increase increase decrease endothelium conclusions. (+) increase Pibrinolyaia {) decrease Thrombua formation time (4+) decrease t t Symbols: + = Definite effect. —=Noeffect, = = Questionable effect, 1 Results, Meusured before and after amoking procedure noted, unicss otherwise stated, conyern specific cougwation teat as TABLE A30.—Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system Author, year country, reference Moyer and Maddock, 20 subjects (including heavy smokers) were studied for the effects of 1940, U.S.A. (154). the following procedures on skin temperature: the inhalation of a lit cigarette, inhalation through an empty paper tube, or the ad- ministration of 1 mg. nicotine intravenously. All subjects responded with decveased cutaneous temperature following the smoking and nicotine procedures, No changes were noted following sham smoking. Mulinos and Shulman, A number of experimental groups, each consisting of 6-17 persons, 1940, U.S.A. (198). were studied for the effects of deep breathing and cigarette smoking on skin temperature and digit or Jimb plethysmography. The au- thors concluded that deep breathing alone could account for the changes in tempevature and blood flow noted upon smoking and noted that denicotinized cigarettes evoked the same or greater vasoconstriction as that noted folluwing the smoking of a standard cigarette. 50 young male smokers were studied with plethysmography before and after the normal and rapid inhalation of a standard cigarette. The author noted that rapid inhalation was associated with a pro- longed decrease in extremity blood flow while a more natural rate of inhalation was followed by a momentary decrease in flow. The author considered the former reaction to represent the pharmacolo~ gic effect of the smoke and the latter ta represent the physiologic response to deep breathing, as the natural inhalation of an unlit cigarette produced the same transient decrease in flow as did the natural inhalation of the lit cigarette. Sbephberd, 1951, Treland (273). Friedei}, 1953, 52 male and 48 female young smokers and nonsmokers were studied U.S A_ 79). for the effects of smoking on hand blood volume as measured by the use of radioactive iodinated albumin. The inhalation of un- filtered cigarettes was associated with an average decrease in hand blood volume of 19 percent in men and 33 percent in women; while filtered cigarettes showed respective decreases of JL percent and 21 percent. Strombiad, 1959, 11 male and female subjects (smokers and nonsmokers) were studied Sweden (121). for the effect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by venous occlusion plethysmography. Increasing doses of nicotine were asso- ciated with increasing numbers of individuals manifesting vaso- constriction. The vasoconstrictive effects of nicotine were abolished by the prior administration of either hexamethonium or pentojinium. Bamett and Boake 9 male patients with intermittent claudication (7 were heavy smokers) 1960 Australia (18). were studied for the effect of smoking on blood flow to the leg as measured by venous occlusion plethysmography. Smoking an un- filtered cigarette was found not te produce any consistent changes in blood flow to the calf or foot of the affected leg, Freund and Ward, 15 male prison inmates (Jess than 35 years of age} and 14 male 1966. U.S.A. (63). patients with peripheral vascular disease (approximately 65 yeara of age) were studied for the effect of smoking on digital circulation as measured by skin temperature, plethysmography, and radiosodium clearance from the skin. Smoking was found to adversely affect the first and third measures in a significant manner (while plethys- mogvapnic values were variable) only in the healthy prisoners and not at all in the patient group. 100 normal individusls underwent 425 experimental procedures con- cerning the effect of smoking on the pevipheral cireulation. Smok- ing was found to be associsted with a dezrease in extremity skin Roth and Schick, 1360, U.S.A. (161). temperature. 129 TaBLe A30.—Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system (cont.) Author, year, country, reference B males (18-32 years of age) were studied for the effect of intra- venous ‘nicotine on extremity temperature and blood flow. Intra- venous nicotine was found to evoke a decrease in skin temperature while increasing muscle blood flow. The former effect began sooner and lasted longer than the latter. Rottenstein et al., 1960, U.S.A. (162). Allison and Roth, 30 healthy individuals (19-59 years of age) were studied for the effect 1969, U.S.A. (8). of smoking two cigarettes on extremity pulse volumes and skin temperature. Smoking was found to be associated with a 2-6 per- cent decrease in skin temperature and a 45-50 percent decrease in blood pulse volumes to segments of the finger, calf, and toe. 130 Chapter 2 Cardiovascular Diseases Part H 131 CONTENTS Page Coronary Heart Disease(CHD) ........02202.......-....-..... 135 Introduction»... 2... ee 135 Cigarette Smoking as a Major Risk Factor for Coronary Heart Disease 22.2.2... .0000............. 136 Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease .........2.......... 137 Hypertension... 2... 2... eee 137 Coffee Drinking ~. 0.2.0 00000002.......-0222.. 141 Ventricular Premature Beats .................... 142 Carbon Monoxide... 20. ee ee ee. 142 Introduction... 2... ee 142 Sources of Carbon Monoxide Exposure and Human Absorption ....................-.-2..-.. 143 Effects on Healthy Individuals 2.2. ..0002000000........ 148 Effects on Persons With Atherosclerotic Cardiovascular Disease... 0 ee 149 Studies on the Pathogenesis of Cardiovascular Disease. ee 150 Nicotine 2.2... ee ee 151 Acrolein 2... ee ee eee 15l Cerebrovascular Disease... 2... 0. ee 151 Effects of Smoking on the Coagulation System ................... 154 Summary of Recent Cardiovascular Findings ..........22.....0.... 155 Bibliography 2.0... eee eee 156 133 List of Tables Table 1. — Age-standardized blood pressure changes (mm Hg) at followup for continuing cigarette smokers and quitters according to weight changes .......0......0.00.. Table 2. ~ Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quilters 2. ee ee ee Table 3. — Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race ........2..0.... Table 4. — Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by employment status... 2.2.0.2... Table 5. ~ Median percent carboxyhemoglobin (COHb) saturation and 90 percent range for smokers and nonsmokers by location 2.2... ... 2000000000000. eee ee eee Table 6. — Mean percent carboxyhemoglobin (COHb) saturation in cigarette smokers | hour after last cigarette... 2. .000002. Table 7. — Age-standardized death rates and mortality ratios for cerebral vascular lesions for men and women by type of smoking (lifetime history) and age at start of study 2.2... 0. ee eee 134 CORONARY HEART DISEASE (CHD) introduction Coronary Heart Disease (CHD) is the most frequent cause of death in the United States and is the most important single cause of excess mortality among cigarette smokers. The evidence relating smoking to CHD has been reviewed in previous reports on the health consequences of smoking (6/, 62, 63, 64, 65, 66, 67, 68). The following is a bnef summary of the relationships between smoking and CHD presented in these reports. Cigarette smoking, hypertension, and elevated serum cholesterol are the major alterable risk factors for myocardial infarction and death from CHD. Cigarette smoking acts both independently as a risk factor and synergistically with the other CHD risk factors. The magnitude of the risk increases directly with the amount smoked. The excess risk of CHD among smokers has been demonstrated in some Asian, Black, and Caucasian populations and is proportionately greater for younger men, especially those below age 50. Cessation of cigarette smoking results in a reduced mortality rate from CHD compared with the mortality rate for those who continue to smoke. Pipe and cigar smokers have a slightly higher risk of death from CHD than nonsmokers, but they incur a much lower risk than ciga- rette smokers. This has been attributed to the lower levels of inhala- tion that characterize most pipe and cigar smoking. Data from autopsy studies have shown coronary atherosclerosis to be more frequent and more extensive in cigarette smokers than in nonsmokers, and experimental work in humans and animals has suggested several mechanisms by which smoking may influence the’ development of atherosclerosis and CHD. The formation of carboxy- hemoglobin, release of catecholamines, creation of an imbalance between myocardial oxygen supply and demand, and increased platelet adhesiveness leading to thrombus formation have all been demonstrated in smokers and proposed as explanations for the excess CHD mortality and morbidity among smokers. 135 Cigarette Smoking as a Major Risk Factor for Coronary Heart Disease The evidence establishing smoking as a major risk factor in CHD has been reviewed in previous reports (6/, 62. 63, 64, 63, 66. 67, 68). During the last year new epidemiologic data have been published on the relationship between coronary artery disease and smoking. Bengtsson (9, 70) studied the smoking habits of women with myocardial infarction (MI) in Goteborg, Sweden. He found that smoking was significantly more common ina group of 46 women (80 percent smokers), ages 50-54, who had a myocardial infarction than in a control group of 578 healthy nonhospitalized women (37.2 percent smokers). Other investigators examined the effect of cigarette smoking on survival of people with acute myocardial infarction. In a study of 400 patients with documented myocardial infarction who survived to be admitted to a coronary care unit, Helmers (26, 27, 28) found no significant difference between the percentages of smokers and nonsmokers among survivors studied after the first 24 hours, from 2 days until discharge, and from discharge to 3 years. Reynertson and Tzagournis (52), in a 5-year prospective study of 137 patients with documented CHD at age 50 or less, were also unable to find any relationship between CHD mortality rates and smoking habits. Smoking habits after entrance into the study were also considered and again no difference in mortality rates was found. The Coronary Drug Project (/7) found an effect of cigarette smoking on mortality after myocardial infarction. This group studied 2,789 men ages 30-64 years for 3 years after myocardial infarction and found a statistically significant correlation between cigarette smoking determined 3 months after a myocardial infarction and mortality (¢-value of 2.94). None of these studies (/7, 26, 27, 28, 52) were able to examine the smoking habits of the group of people who die suddenly as a first manifestation of CHD, and therefore may have excluded that group in which there is the highest excess mortality due to cigarette smoking (3/). Additional data from the Swedish twin study of Friberg, et al. (23) have been reported. They found an excess CHD mortality among smokers in dizygotic twins with different degrees of smoking, but no similar excess in monozygotic twins. Although the numbers were [oo small to be significant, the authors suggest that this tends to support the theory that both smoking and CHD are constitutionally 136 determined. These data must be viewed with caution. however, since the difference was demonstrable only in the older age group (born 1901 - 1910). When the younger age group (born 191} - 1925) was considered, no excess CHD mortality was seen in the dizygotic group but a small excess was noted in the monozygotic group (three CHD deaths in the high smoking group and one in the low smoking group). Also the difference in cigarette consumption between the Ingh and low smoking groups was relatively small (seven cigarettes per day). Consequently, data from this study are not sufficient to warrant the conclusion that both smoking and excess CHD mortality are constitutionally determined rather than smoking being a cause-of the excess CHD mortality. Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease Cigarette smoking, elevated serum cholesterol, and elevated blood pressure are generally accepted as the three major modifiable risk factors for CHD. However, there is less agreement concerning other CHD risk factors — obesity, physical inactivity, diabetes mellitus. elevated resting heart rate, psychologic type A behavior, etc. The following studies present recent evidence on the relation- ships between smoking and hypertension, coffee drinking, and ventricular premature beats. Ay pertension Results from several studies have shown that smokers on the average have slightly lower blood pressure than nonsmokers. Some investigators have attributed this finding to the fact that smokers on the average weigh slightly less than nonsmokers. Three current studies (24, 36, 55) discuss this relationship. Gyntelberg and Meyer (24), based on their evaluation of 5,249 men ages 40-59, were of the opinion that lower blood pressure in smokers could not be accounted for by differences in weight, age, or physical fitness. Kesteloot and Van Houte (36), in a study of 42,804 men, performed a multiple regression analysis on age, weight, and height and found that cigarette smokers had lower blood pressure than nonsmokers; however, when they inchided serum cholesterol values in the analysis, the ditference in blood pressure was reduced to approxi- mately | mm Hg. Although this difference was statistically signifi- cant based on the large population, the actual difference in blood pressure was too small to be of clinical importance. 137 Seltzer (55) studied 794 men selected for their initial good health and normal blood pressure (below 140 systolic and 90 diastolic) and followed them for changes in cigarette smoking habits, weight, and blood pressure. During the 5-year period of the study 104 men gave up smoking. For every age group except those over 55, there was a significantly greater weight gain (8 ib) among the “quitters” than among the continuing smokers (3.5 Ib). Blood pressure increased 4 mm Hg systolic and 2.5 mm Hg diastolic in the quitters with no change in systolic and a slight reduction in diastolic (-1.1 mm Hg) in persons who continued to smoke. In order to examine blood pressure changes in relation to weight change, both continuing smokers and quitters were grouped according to their weight changes during the period of study (Table 1). The most significant finding was an increase in the systolic blood pressure (+1.77 mm Hg) among the quitters even in that group with significant weight loss. In contrast, the continuing smokers with significant weight loss had a decline in systolic blood pressure (-3.28 mm Hg). Diastolic blood pressure in quitters showed an increase with weight gain and no change with weight loss, while continuing smokers showed a decrease in diastolic pressure with weight loss and no change with weight gain. The data on subjects whose blood pressure had increased to hypertensive levels (systolic > 150 and diastolic > 95) were evaluated, and it was found that quitters had a much higher frequency of becoming hypertensive than continuing smokers (Table 2). Seltzer, in interpreting these data, suggested that cigarette smoking tends to inhibit blood pressure increases, with only minimal pressure rises occurring even in instances of substantial weight gain. When this inhibiting effect of cigarette smoking is removed as in the case of the quitters, sharp rises in blood pressure become evident. He cautioned, however, that the development of hypertension in some quitters may have been responsible for decisions to lose weight and that his data do not allow an evaluation of the degree of blood pressure changes according to how recently cigarettes were given up. The results of the ischemic heart disease study by Kahn, et al. (34) raise additional questions about Seltzer’s data. Kahn followed 10,000 Israeli male civil service employees for 5 years to determine what factors were associated with an increased incidence of hypertension. He presented no data concerning persons who stopped smoking, but he did show that the incidence of hypertension increased with age and that the age-adjusted incidence of hyper- tension in smokers was over twice that of nonsmokers (76.9/ 1000 for smokers versus 35.4/1000 for nonsmokers). Seltzer reported no 138 6eT TABLE 1. ~ Age-standardized blood pressure changes (mm Hg)! at followup for continuing cigarette smokers and quitters according to weight changes Weight Change (LB) Significant No Significant Moderate Significant Smoking Class Wt Loss Wt Change Wt Gain Wt Gain tb Ib tb Ih No. 25 to -§ No. -4to+4 No. +5 to +12 No. +13 to +30 Mean systolic BP changes; Continuing smokers 32 ~4.00 84 ~1.$2 7 2.85 24 1.50 Quitters 13 1.77 27 2.22 27 4.04 32 3.69 Mean diastolic BP changes: Continuing smokers 32 -3,28 84 - =2.04 71 0.73 24 ~0.04 Quitters 13 -0.31 27 —1.96 27 4.30 32 3.94 ‘Standardized on basis of age distribution of current cigarette smokers, Source: Seltzer, CC, (55). OovTt TABLE 2, — Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters Blood pressure Continuing cigarette smokers Quitters levels Number Percent Number Percent Systolic blood pressure 150+ 6 2.8 9 87 Systolic blood pressure 160+ 2 0.9 5 4.8 Diastolic blood pressure 95+ 3 14 5 4.8 Source: Seltzer, C.C. (55). data on the incidence of hypertension in nonsmokers, and the age distnbution for his group of smokers (the onginal source of the quitters) is heavily weighted toward younger age groups (with only 33 of 214 men age SO years or over). According to Kahn’s data, this age group would be expected to have a lower incidence of hypertension, and, in fact, Seltzer found only small numbers of men who developed hypertension (eight with diastolic hypertension) (Table 2). Making interpretations based on such small numbers is hazardous; for example, the difference between current smokers and quitters in the incidence of diastolic hypertension could have been produced by only three men quitting smoking because they developed hypertension. Coffee Drinking The Boston Collaborative Drug Study (/2) recently reported a correlation between coffee drinking (> 6 cups per day) and myocardial infarction that persisted after controlling for the effect of cigarette smoking. This was a retrospective study of 276 patients with a hospital discharge diagnosis of myocardial infarction and 1,104 age, sex, and hospital-matched controls discharged with other diagnoses. In addition to the usual limitations of retrospective studies, this study has several characteristics that make interpretation difficult. In controlling for the effect of cigarette smoking, the investigators divided the smokers into those who smoked one pack or less per day and those who smoked more than one pack per day. Because cigarette consumption is highly correlated with coffee consumption (29, 39), it can be expected that within such broad smoking categories those who were heavy coffee drinkers tended to be heavier smokers than those who consumed smaller amounts of coffee. It is also possible that the hospitalized controls represented persons who drank less coffee than the general population because of serious chronic illnesses. These characteristics of the study design do not allow firm conclusions to be made concerning the extent to which the relationship between coffee drinking and myocardial infarction is independent of the relationship of both variables to cigarette smoking. The question of the independent nature of this relationship is also dealt with in a prospective study by Klatsky, et al. (39) of 464 patients with myocardial infarction who previously had had multi- phasic health checkups. Both ordinary controls and CHD risk factor-matched controls were drawn from 250,000 people who had undergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee drinking and myocardial infarction when risk-matched controls were used. 141 The Framingham Study (18) recently published data on coffee drinking based on a {2-year followup of 5,209 men and women ages 30-62. An increased risk cf death from all causes was demonstrated in coffee drinkers, but this relationship was accounted for by the associ- ation between coffee consumption and cigarette smoking. No association between coffee drinking and myocardial infarction OT between coffee drinking and the development of CHD, stroke, or intermittent claudication was demonstrated. Heyden, et al. (29) also found no relationship between excessive coffee consumption (> 5 cups per day) and atherosclerotic vascular disease. Ventricular Premature Beats Ventricular premature beats have been shown to be a risk factor for sudden death from CHD. Vedin, et al. (69), ina study of 793 men in Goteborg, Sweden, examined the frequency of rhythm and conduction disturbances at rest and during exercise. They found no statistically significant correlation between cigarette smoking habits and the presence of supraventricular or ventricular premature beats at rest or during exercise. CARBON MONOXIDE Introduction Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemo- globin levels below 15S to 20 percent were thought to have little effect on humans. Currently there is considerable interest in determining the effect of chronic exposure to low levels of carbon monoxide (65, 66, 67, 68). Carbon monoxide is present in concentrations of | to5 percent of the gaseous phase of cigarette smoke (J, 45). The concentration varies with temperature of combustion as well as with factors which control the oxygen supply such as the porosity of the paper and packing of the tobacco. The amount of carbon monoxide produced increases as the cigarette burns down. Carboxyhemoglobin levels in smokers vary from 2 to 15 percent depending on the amount smoked, degree of inhalation, and the time elapsed since smoking the last cigarette. Carbon monoxide, which has 230 times the affinity of oxygen for hemogtobin, impairs oxygen transportation in at least two ways: 142 First, it competes with oxygen for hemoglobin binding sites. Second. it increases the affinity of the remaining hemoglobin for oxygen. thereby requiring a larger gradient in Po2 between the blood and tissue to deliver a given amount of oxygen; this increased gradient is usually produced by a lowering of the tissue Po2. Carbon monoxide also binds to other heme-containing pig- ments, most notably myoglobin, for which it has even a greater affinity than for hemoglobin under conditions of low Po2. The significance of this binding is unclear, but may be important in tissues, such as the heart muscle, which have both high oxygen requirements and large amounts of myoglobin. Sources of Carbon Monoxide Exposure and Human Absorption Several researchers (13, 32, 35, 57, 60, 70) have estimated the relative contribution of cigarette smoking and air pollution to the human carbon monoxide burden as measured by carboxyhemoglobin levels (COHb). Kahn, et al. (35), in a study of 16,649 blood donors. determined that smoking was the most important contributing factor, followed by industrial work exposure. Nonsmoking industrial workers had COHb levels of 1.38 percent, and nonsmokers without industrial exposure had levels of .78 percent. Cigarette smokers, on the other hand, had very high levels. Smokers with industrial exposure had levels of 5.01 percent, while smokers without industrial exposure had levels of 4.44 percent (Tables 3 and 4). Stewart, et al. (57) found similar results in a nationwide survey of blood donors and noted marked vanation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However, in all areas, smokers still had COHb levels two to three times higher than nonsmokers and had increasing COHb levels with increasing level of cigarette consumption (Table 6). Similar findings were reported by Torbati, et al (60) in a study of 500 male Israeli blood donors. Nonsmoking workers exposed to automobile exhaust — London taxi drivers (32) and garage and service station operators (/3) — have higher baseline levels of carboxyhemoglobin than nonsmokers of the general population. But even in these high exposure occupations smokers have markedly higher COHb levels (8.1 and 10.8 percent) than nonsmokers (6.3 and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed to an average of 63 ppm CO with peak exposure levels as high as 217 ppm CO: cigarette smokers still maintained much higher COHb levels (5.01 percent) than nonsmokers (2.93 percent) (8). 143 9oT TABLE 3. — Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race Total Sample Nonsmokers Smokers! No. X +S No. X +Sz No. X + Sx Total Sample 16,649 2.30 £0.02 10,157 0.85 +0.01 6,492 4.58 £0.03 Male 10,542 2.66 40.03 5,888 1.00 £0.01 4,654 4.76 + 0.04 Female 6,107 1.68 + 0.03 4,269 0.64 +00) 1,838 4.10 + 0.06 White 15,167 2.28 £0.02 9,474 0.85 £0.01 5,693 4.66 40.04 Male 9,669 2.65 £0.03 5,508 1.00 40.01 4,161 4.83+0.04 Female 5,498 1.63+0.03 3,966 0.64 +001 1,532 4.19 + 0.06 Black 1,429 2.59 + 0.06 641 0.86 + 0.03 788 4.00 t 0.08 Male 829 2.91 £0.10 347 1.07 £0.05 482 4.244 0.10 Female 600 2.15 £0.09 294 0.62 +0.04 306 3.63 40.12 1 smokers are defined as those who smoked on the day of giving blood. NOTE. — X = mean percent; Sy* standard error of mean percent. Source: Kahn, A., et al. (35). TABLE 4, ~ Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by employment status Nonsmokers Smokers! No. Xs: No, X tS Persons employed 8.478 0.89 + 0.0) 5,962 V6OUb OUI Chissed ats industrial workers! 1,523 1.38 + 0.04 1,738 5.01 t 0.06 Classed as workers other than industrial 6,955 0.78+0.01 4,224 4.44 + O04 Persons not employed 1,678 0.63 + 0.02 531 4247041 cvT Nodustrial workers are employed in either durable or nondurable goods manufacturing (craftsmen, Operatives, or laborers). Smokers are defined us those who smoked on the day of giving blood. NOTE. ~ X= mean percent; Sz 5 Standard error of nivan Percent, Source: Kahn, A., et al. (35). 97T TABLE 5. — Median percent carboxyhemoglobin (COHb) saturation and 90 percent range for smokers and nonsmokers by location Cigarette Smokers | Nonsmokers - Location | Median Range | Median Range Anchorage 4.7 0.9 - 9.5 1.5 0.6 -- 3.2 Chicago 5.8. 2.0 - 9.9 17 10-32 Denver 5.5 2.0 - 9.8 2.0 0.9 -3.7 Detroit 5.6 1.6 - 10.4 1.6 0.7 - 2.7 Honolulu 49 : 1.6 - 9.0 1.4 0.7 = 2.5 Houston 3.2 1.0 -7.8 1.2 0.6 - 3.5 Los Angeles 6.2 2.0 - 10.3 1.8 1.0 ~ 3.0 Miami $.0 12+ 9.7 1.2 0.4 ~ 3.0 Milwaukee 4.2 1.0 - 8.9 1.2 0.5 - 2.5 New Orleans 5.5 2.0 - 9.6 1.6 1.0 - 3.0 New York 4.8 12-91 4,2 0.6 - 2.5 Phoenix 4.1 0.9 - 8.7 1.2 0.8 - 2.8 St. Louis 5.) "17-922 1.4 0.9 - 2.1 Salt Lake City S.1 15-9.5 1.2 0.6 + 2.5 San Francisco 5.4 1.6 - 9.8 1.8 O8 - 2.7 Seattle 5.7 1.7 - 9.6 1.5 Q.8 - 2.7 Vermont, New Hampshire 4.8 1.4 - 9.0 1.2 0.8 = 2.1 Washington, DC 4.9 12-84 ‘ 1.2 0.6 ~ 2.5 | VT Source: Stewart, R.D., et al. (57). L4T TA BLE 6, ~ Mean percent carboxyhem oglobin (COND) saturation in cigarette smokers | hour after last cigarette Packs of Cigarettes Smoked Per day Location Nonsmoker <¥% Yael 1 I% 2 Milwaukee 1.3 3,0 4,2 5.3 6.2 4,7 New Hampshire, Vermont 1.4 3.3 4.4 5.7 6.7 5.3 New York City 1.4 3.1 4.3 4.7 5.8 6.3 Washington, DC 1.4 3.8 4.6 5.2 5.8 6.6 Los Angeles 2.0 4.0 5.2 6.0 7.4 7.5 Chicago 2.0 4.8 5.4 6.3 7 7 Source: Stewart, R.D., et al . (57), Studies on the CO burden of each cigarette have determined the body burden of CO per cigarette to be 7.10-8.66 ml (49). and the increase in COHb Jevel produced by smoking one cigarette to be .94 to 1.6 percent after 12 hours of abstinence (40, 53). The half-life for the washout of CO in healthy college smokers (40) was calculated to be from 3 to 5 hours. Effects on Healthy Individuals Several studies have been published on the effects of carbon monoxide on healthy individuals. Small doses of CO (COrb levels 2.4-5.4 percent) were found to have no effect on heart rate (56). Raven, et al. (5/), ina study of young men exposed during exercise on a treadmill to 50 ppm CO (COHDb levels 2.5 percent in nonsmokers and 4.1 in smokers), found no decrease in maximum aerobic capacity when the subjects were tested at 25°C. Ina similar experiment conducted at 35°C by the same researchers (20), there was a decrease in maximum aerobic capacity in nonsmokers exposed to 50 ppm CO, but not in smokers despite an increase in the carboxyhemoglobin levels of 1.5 percent in both groups. They postulated a possible physiologic adaptation of smokers to carbon monoxide. Ekblom and Huot (22) studied five young men who inhaled CO to reach given COHb tevels. They reported that as COHb levels increased, there was a decrease in maximal oxygen uptake and lower heart rates at maximal treadmill exercise. Sagone, et al. (54), in a study of 9 cigarette smokers and 18 nonsmokers ages 20-32, showed significantly higher values for COHb, red cell mass, hemoglobin, and hematocrit in the smokers. Levels of 2,3 DPG were unaltered while oxyhemoglobin affinity P50 and ATP levels were significantly lower in the smokers. The three smokers with highest red cell mass had normal arterial blood gases and one smoker had very high values of red cell mass which returned to normal after he stopped smoking. The authors interpret these data.as evidence of tissue hypoxia. Millar and Gregory (43), in a study of both fresh heparinized blood and ACD-stored blood from a blood bank, showed a reduction in the oxygen carrying capacity of up to 10 percent in the blood of cigarette smokes, this reduction persisted for the full 21-day storage life of blood bank blood. Cole, et al. (16), in a study of pregnant women, found COHb levels in the fetus to be 1.8 times 4s great as those in the 148 simultaneously measured blood of the mother. Fetal blood was exposed to carbon monoxide in vitro, and fetal hemoglobin was found to have a shift of the oxvhemoglobin disassociation curve to the left as occurs with adult hemoglobin. The higher fetal COHb levels were attributed to the lower fetal Poz and a resultant decrease in the ability of oxygen to compete for the fetal hemoglobin. It was felt by the authors that the high COHb levels may be responsible for the lower birth weight of infants born to mothers who smoke. Effects on Persons with Atherosclerotic Cardiovascular Disease Aronow and Isbell (5) and Anderson, et al. (/) have shown a decrease in the mean duration of exercise before the onset of pain in patients with angina pectoris exposed to low levels of carbon monoxide (50 and 100 ppm). Carboxyhemoglobin levels were significantly elevated (2.9 percent after 50 ppm; 4.5 percent after 100 ppm) and the systolic blood pressure, heart rate, and product of systolic blood pressure times heart rate (a measure of cardiac work) were all significantly lower at onset of angina pectoris. In a continuation of this work, Aronow, et al. (2, 3) studied eight patients during two separate cardiac catheterizations, one during which each patient smoked three cigarettes and one during which each patient inhaled carbon monoxide until the maximal coronary sinus COHb level equalled that produced by smoking during the first catheterization. All eight had angiographically demonstrated CHD (> 75 percent obstruction of at least one coronary artery). Smoking increased the systolic and diastolic blood pressure, heart rate. left ventricular end-diastolic pressure (LVEDP), and coronary sinus, arterial, and venous CO levels. No changes were noted in left ventricular contractility (dp/dt), aortic systolic ejection period, or cardiac index, and decreases were found in stroke index and coronary sinus, arterial, and venous Po. When carbon monoxide was inhaled, increased LVEDP and coronary sinus, arterial, and venous CO levels were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and decreases in left ventricular dp/dt, stroke index, cardiac index and coronary sinus. arterial, and venous Poz were found. These data suggest that carbon monoxide has a negative inotropic effect on myocardial tissue resulting in the decrease in contractility (dp/dt) and stroke index. When the positive effect of nicotine on contrac- tility and heart rate is added by cigarette smoking, the net effect is increased cardiac work for the same cardiac output. In the heart with 149 coronary artery disease there is a greatly restricted capacity to increase blood flow in response to this increase in cardiac work. The result is early cardiac decompensation manifested by elevation in LVEDP and angina pectoris. Aronow, et al. have also shown decreased exercise time prior to onset of angina pectoris in persons exercised after riding for 90 minutes on the Los Angeles Freeway (4). In a related study, they demonstrated a decrease in exercise time before claudication in a group of patients with intermittent claudication who were exposed to 50 ppm CO (6). Studies on the Pathogenesis of Cardiovascular Disease In a review of some of their work on carbon monoxide, Astrup and Kjeldsen (7) noted that in cholesterol-fed rabbits exposed to 170 ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to 340 ppm for 2 weeks, the cholesterol content of the aorta was 2.5 times higher than that of cholesterol-fed, air breathing controls. Groups of cholesterol-fed rabbits intermittently exposed to carbon monoxide for 12 or 4 hours per day produced three- to fivefold increases in the cholesterol content of their aortas. Cholesterol-fed rabbits made hypoxic at 10 and 16 percent oxygen had 3 to 3.5 times the aortic cholesterol content, while those exposed to 26 and 28 percent oxygen had a considerable decrease in cholesterol accumulation. Theodore, et al. (98) studied the aortas of monkeys, baboons, dogs, rats, and mice fed a normal diet but exposed to very high levels of CO (COHb levels 33 percent) and found no atheromatous changes in their aortas. Further work by Astrup and Kieldsen (38) revealed that in rab- bits fed normal diets but exposed to 180 ppm carbon monoxide for 2 . weeks, there were local areas in their hearts of partial or total necrosis © of myofibrils; in the arteries there was endothelial swelling, formation of subendothelial edema, and degeneration of the myocytes. When the aortas of these rabbits were examined (37), the luminal coats showed pronounced changes characterized by severe edematous reaction with extensive swelling and formation of subendothelial blisters and plaques. The authors postulate that carbon monoxide increases endothelial permeability to albumin which results in formation of edema leading to changes indistinguishable from early atherosclerosis. 150