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CARDIOVASCULAR SYSTEM 257 14 Cardiovascular System The effects of active smoking on exercise tolerance, blood pressure, and the risk of developing cardiovascular disease have been reviewed elsehwere (U.S. Public Health Service, 1983). This chapter discusses studies of ETS exposure to nonsmokers and subsequent possible cardiovascular effects. The constituents that are thought to have the greatest effect on the cardiovascular system are carbon monoxide (CO) and nicotine. The possibility exists that the mechanisms, as well as the magnitude of the effects, for acute and chronic cardiovascular effects may be different for exposure to whole smoke and to ETS. ACUTE CARDIOVASCULAR EFFECTS OF ENVIRONMENTAL TOBACCO SMOKE EXPOSURE Administration of nicotine at level similar to those induced by active cigarette smoking is shortly followed by increases in heart rate and blood pressure (U.S. Public Health Service, 1983). Platelet aggregation has been shown to be increased in in vitro studies. CO rapidly combines with hemoglobin in the blood to form carboxyhemoglobin (COHb), thereby leading to some degree of tissue hypoxia. CO combines with muscle myoglobin, which is followed by some muscle hypoxia. The level of exposure of the nonsmoker to these cigarette smoke constituents, however, is less than that of the active smoker, and the effects are expected to be less. Table 14â1 reviews some of the increases in COHb levels as seen in both experimental and observational studies. The levels of
CARDIOVASCULAR SYSTEM 258 COHb commonly observed in active smokers are higher, ranging between 4 to 6 percent, rarely greater than 12 percent (Schievelbein and Richter, 1984). Because exposure of the nonsmoker is qualitatively different than exposure to smokers, a simple scaling down of effects observed in active smokers does not appear to be fully appropriate. Therefore, the effects of exposure to nicotine, TABLE 14â1 Carbon Monoxide and Carboxyhemoglobin Levels in Nonsmoking Individuals Experimental Studies (Controlled Chambers) Study No. of Cigarettes/h/10m3 No. of Subjects CO, ppma Carboxyhemoglobin Control Change Anderson and Dalhamm, 1973 3.1 â 4.5 0.3 0 Dahms et al., 1981 â 10 15â20 0.6 +0.4 Harke, 1970 3.9 7 30 0.9 +1.2 Huch et al., 1980 2.3 12 â 1.3 +0.5 Hugod et al., 1978 2.5 10 20 0.7 +0.9 Pimm et al., 1978 2.4 10 24 0.5 +0.3 2.4 10 24 0.7 +0.2 Polak, 1977 6.7 15 23 2.0 +0.3 Russell et al., 1973 15.1 12 38 1.6 +1.0 SeppÃ¤nen and Uusitalo, 1977 3.8 28 16 1.6 +0.4 Srch, 1967 50 â 90 2 +3 Observational Studies Study Subjects/Exposure No. of Subjects Nonexposed: Exposed Carboxyhemoglobin, % CO Expired, ppm Foliart et al., 1982 Flight attendants/8 h 6 1.0:0.7 Jarvis et al., 1983 Normal/public house for 2 7 4.7:10.6 h Lightfoot, 1972 Normal/submarine â:1.0 Wald et al., 1981 Participants in health 6,641 screening program Jarvis et al., 1984 Normal/self report 10 0.9:0.8 5.7:5.5 SeppÃ¤nen and Uusitalo, Restaurant for 5 h 47 2.1:2.1 1977 (CO:2.5â15 ppm) Office for 8 h (CO:2.5 15 2.3:2.3 ppm) a Carbon monoxide (CO) measured as a proxy to indicate the concentration of ETS in the chamber.
CARDIOVASCULAR SYSTEM 259 CO, or ETS need to be separately studied. In addition, consideration needs to be given to persons of different sensitivity or vulnerability. TABLE 14â2 Resting Acute Cardiovascular Effects in Nondiseased Humans of Exposure to Environmental Tobacco Smoke Authors Study Population Conditions Results Measured Variable Before After Luguette et al., 1970 40 children Room: 9 m3 Heart rate 89 97 No. cig.: 6 Blood pressure 116/67 120/72 Time: 15 min Harke and Bleichert, 1972 10 Room: n.g. Heart rate 72Â±8 74Â±12 No. cig.: 150 Blood pressure 123/84 121/84 Time: 20 min Skin temperature (âÂ°C/min) 0 0.0273 Rummel et al., 1975 56 Room: 30 m3 Heart rate 72Â±10 71Â±11 No. cig.: 6â8 Blood pressure 117/71 117/71 Time: 20 min Hurshman et al., 1978 8 Room: n.g. Heart rate 73 79 No. cig.: 2â6 Blood pressure 107/67 114/68 Time: 10 min Pimm et al., 1978 10 males Room: 14.6 m3 Heart rate 84(F) 80(F) 10 females No. cig.: 7 77(M) 70(M) Age=22.3 Time: 2 h Healthy Subjects Table 14â2 lists studies that report on the consequences of exposure of nondiseased individuals to ETS for periods up to 2 hours under experimental, resting conditions. There were no significant changes noted in heart rate or blood pressure in school-aged children or in adult men and women. Two studies evaluated the physiologic responses to exercise with and without exposure to ETS. In the first, Pimm et al. (1978) (see also Table 14â2) had subjects perform a 7-minute progressive exercise test on an electronic bicycle ergometer. During exercise, the women had higher heart rates after exposure to ETS when compared with control conditions (differences of 6.3 beats per minute at 2 minutes and 4.5 beats per minute at 7 minutes, p<0.01). The recovery heart rates were not significantly different. The men, however, showed little difference between test and
CARDIOVASCULAR SYSTEM 260 control conditions (differences of â0.1 beats per minute at 2 minutes and 1.5 beats per minute at 7 minutes). In the second study, Sheppard and colleagues (1979b) tested 11 males and 12 females at two different levels of ETS (i.e., 7 cigarettes over 2 hours, CO= 20 ppm, or 9 cigarettes over 2 hours, CO=31 ppm). Under both exposure conditions, contrary to expectations, both the increment in heart rate and average heart rate were less with ETS exposure. In summary, for normal young adult males and females, no significant acute effects of ETS exposure on heart rate or blood pressure have been reported, either under resting or aerobic conditions. There have been several studies of exposure of normal subjects under resting and aerobic conditions to low levels of CO but higher than those found with ETS exposure (reviewed in Environmental Protection Agency, 1984). No significant effects were found in healthy, exercising subjects during short-term exposure (e.g., Drinkwater et al., 1974; Raven et al., 1974a,b; DeLucia et al., 1983). Angina Patients Angina pectoris is a symptom complex involving feelings of pressure and pain in the chest, which is produced by mild exercise or excitement, presumably because of insufficient oxygen supply to the heart muscle. Under conditions of ETS exposure, the CO levels are increased, thus possibly placing individuals with angina at an increased risk of recurrent episodes. Anderson et al. (1973) and Aronow and his colleagues, in a series of experiments (1973, 1974, 1978, 1981) (Table 14â3), studied angina patients under aerobic conditions with exposures to low levels of CO and to ETS. Ten patients with diagnosed angina pectoris, of whom two were smokers and eight exsmokers, were tested (Aronow et al., 1978). Significant increases in systolic blood pressure and heart rate, and decreases in time to onset of angina, were noted when the subjects were exposed to smoke in either ventilated or unventilated rooms (the actual levels of CO under these conditions were not noted). There were some subjective elements in the evaluation of these patients, and the physician conducting these tests was aware of the test conditions, i.e., smoking or not and ventilated or not. Consequently, the findings of this study, in
CARDIOVASCULAR SYSTEM 261 the absence of a true double-blind approach, require verification by other research workers. TABLE 14â3 Acute Cardiovascular Effects of Exposure to CO or Environmental Tobacco Smoke by Nonsmoking Angina Patients Study Design No. Conditions Results Anderson et al., 1973 Double-blind, Cross- 10a CO: 50 ppm or 100 ppm Mean duration before onset over Time: 4 h for 5 days of pain shortened (50 ppm and 100 ppm); duration of pain longer (100 ppm only) Aronow and Isbell, 1973 Double blind, Cross- 10b CO: 50 ppm Times until onset decreased; over Time: 2 h decrease in BP and heart rate at angina Aronow, 1978 Not blinded 10c No. cig.: 15 Earlier onset of angina; Time: 2 h increased systolic BP and Room: 30.28 m3 heart rate at angina Aronow et al., 1979 Double-blind, Cross- 20 COHb: 4% Impairment in visualization over test Aronow, 1981 Double-blind, Cross- 15 CO: 50 ppm Time until onset decreased; over Time: 1 h decreased systolic BP and COHb: 2% heart rate at angina aIncludes five smokers and five nonsmokers. b Not current smokers. cIncludes eight exsmokers and two current smokers. The effects of rapid angina onset would be expected to be due to increased COHb levels. Anderson et al. (1973) and Aronow et al. (1973, 1981) exposed angina patients to low levels of CO. In these studies, angina pain appeared when COHb levels of patients were measured at 2 and 4%. These studies have been reviewed extensively as part of the Environmental Protection Agency's (1984) activity in establishing air quality criteria for carbon monoxide. The review group found that the results were suggestive for effects at COHb levels above 3%, based on animal and theoretical models. There is concern that elevated levels of CO exposure may affect the electrical stability of the heart in previously compromised heart muscle, thus possibly leading to sudden death. The levels reviewed in Table 14â1 are close to the 3% level. This suggests that there is reason to be concerned with possible effects of exposure. However, a firm quantitative estimate of the risk to nonsmoking persons, under conditions of ETS exposure, cannot be made from the literature at this time.
CARDIOVASCULAR SYSTEM 262 CARDIOVASCULAR DISEASE MORBIDITY AND MORTALITY Possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking were reviewed in the 1983 Report of the Surgeon General. Experimental studies of subcutaneous or intravenous administration of nicotine in rabbits (Schievelbein et al., 1970; Schievelbein and Richter, 1984) and monkeys (Liu et al., 1979) have demonstrated that long-term exposure leads to arteriosclerotic lesions. Exposure to carbon monoxide also leads to atherosclerosis in rabbits, pigeons, and other animals (Astrup and Kjeldsen, 1979). Studies of whole tobacco smoke indicate that total serum cholesterol concentrations are increased and the ratios of the various lipoprotein fractions are changed (McGill, 1979). The contribution of whole tobacco smoke to modifying the lipoprotein fractions is not conclusive. However, there have not been experimental studies of the effects of ETS exposure or administration of ETS extracts. Smoking and Cardiovascular Disease The effects of active smoking on human health are summarized in the Surgeon General's report The Health Consequences of Smoking: Cardiovascular Disease (U.S. Public Health Service, 1983). The principal conclusions are that cigarette smokers experience a 70% greater coronary heart disease (CHD) death rate than do nonsmokers and that smokers of more than two packs per day have 2 to 3 times greater CHD death rates than nonsmokers. The incidence of CHD in smokers is twice that of nonsmokers. Heavy smokers (more than two packs per day) have an almost fourfold increase. The relative risk in smokers for sudden death is greater than that for all deaths from CHD. The relative risk in young smokers is greater than that in older smokers. The relative risk for young women smokers, especially those who use oral contraceptives, is greater than 5. The excess relative risk associated with smoking declines rapidly upon cessation of smoking, in some studies as much as 50% in 1 year. For exsmokers who previously smoked more than one pack per day, the residual excess risk also declines, but never completely disappears. The decline in risk on cessation of smoking cannot be explained by differences in known cardiac risk factors
CARDIOVASCULAR SYSTEM 263 between individuals who continue smoking and individuals who have quit. Smokers who have used only pipes or cigars did not appear to experience a substantially greater CHD risk than nonsmokers. The rapid decline in risk associated with smoking cessation and the greater relative risk for sudden death suggest that active smoking can precipitate cardiac events in individuals with preexisting coronary artery disease. Autopsy evidence of increased arteriosclerosis in smokers, coupled with the fact that risk of exsmokers never returns to the levels found in nonsmokers, suggests that cigarette smoking is also implicated in the development of arteriosclerotic cardiovascular disease (ASCVD). The mechanism by which cigarette smoke may lead to the development of chronic ASCVD, sudden death, or acute myocardial infarction is unknown. There appears, however, to be no threshold in the number of cigarettes smoked below which there is no increase in risk. Data on uptake of cotinine by nonsmokers exposed to ETS indicate that the exposure in nonsmokers chronically exposed to ETS is approximately 1% that of an active smoker (who smokes one pack per day) (see Chapters 8 and 12). If the excess relative risk for CHD mortality or morbidity is a linear, nonthreshold function of dose and, further, if the excess risk of CHD in a one-pack-a-day smoker is twofold, then the relative risk from CHD in nonsmokers exposed to ETS (compared to true nonsmokers) would be approximately 1.02. Such relative risks would be difficult to detect or estimate reliably in nonexperimental studies. Such small increases in relative risk are of the same order of magnitude as what might arise from expected residual confounding due to unmeasured covariates. Nonetheless, because of the large number of cardiovascular deaths each year, these possibilities deserve close attention and further study that could lead to firmer estimates of excess risk. Studies of Environmental Tobacco Smoke Exposure and Mortality from Cardiovascular Disease Garland et al. (1985) have reported that, in a prospective study of the effect of passive smoking, the age- adjusted rates of cardiac disease deaths in nonsmoking women whose husbands were former or current smokers were significantly elevated. It is
CARDIOVASCULAR SYSTEM 264 not certain, however, that the report is correct, because of a possible miscalculation or misuse of the Mantel- Haenszel statistic and some other methodologic problems. Data for the wives of former smokers were grouped with wives of current smokers. If this grouping were made after examining the data, which indicated that the risk was greater among the women whose husbands were former smokers, then this combination would be suspect. The p values based on the Mantel-Haenszel test may be inappropriate in view of the small sample sizes. The authors employ the Cox Proportional Hazard analysis to control for other factors associated with cardiovascular risk, such as age, blood pressure, cholesterol, obesity, years of marriage, etc. They report a relative risk for women married to current or former smokers compared with women married to never-smokers of 2.7 (Garland, 1985, corrected from an earlier report). The p value (<0.10) associated with this estimate is based on the asymptotic assumptions that are implicit in likelihood-based inference from the Cox model. These assumptions may not hold for small sample sizes. In summary, because of the small sample sizes, the significance calculations arising from this study must be looked upon as approximations. Gillis et al. (1984) reported the results of a follow-up study of residents of two urban communities in Scotland. Nonsmokers exposed to cigarette smoke in their homes had a slightly higher rate of myocardial infarction than those unexposed. The sample size was small, so that few of the results were statistically significant, and other risk factors for myocardial infarction were not controlled for. Hirayama (1984) reported the results of a 15-year prospective study of nonsmoking Japanese women classified at start of followup by the smoking status of their husbands. A relative risk from ischemic heart disease of 1.3 was found for nonsmoking women whose husbands smoked more than 19 cigarettes per day compared with nonsmoking women whose husbands did not smoke. A Mantel-Haenszel test for a linear trend was significant at the p<0.01 level. It is unlikely that Hirayama's results can be explained by chance. The potential biases inherent in this study (see Chapter 12) limit the weight that can be placed on these results. The observed relative risk of 1.3 is at the upper limit of the expectations derived from extrapolations from active smokers, unless the uptake of the active component of cigarette smoke to which
CARDIOVASCULAR SYSTEM 265 passive smokers are exposed is of the order of 10% of that of active smokers. Matsukura et al. (1984) have suggested that such high levels of uptake in passive smokers may be seen in Japan. If there were independent evidence that nonsmokers exposed to other people's cigarette smoke do not differ on known risk factors for CHD from unexposed nonsmokers, more reliance could be placed on Hirayama's results. Svendsen et al. (1985) reported on the effect of cigarette smoke exposure to smoking wives among men participating in the Multiple Risk Factor Intervention Trial (MRFIT). MRFIT, which began in the mid-1970s, was a randomized primary prevention trial designed to test the effect of a multifactor intervention program on mortality from coronary heart disease in men with previous cardiac episodes. The men were chosen for participation if they had at least two of three risk factors for heart disease, including smoking, high cholesterol levels, or high blood pressure. The results reported by Svendsen et al. (1985), based on the group of men who never smoked but whose wives may or may not have been smokers, indicate no difference between exposed (i.e., smoking wives) and nonexposed (i.e., nonsmoking wives) of nonsmoking men for blood pressure or serum cholesterol. The MRFIT study demonstrates a roughly twofold increase in the risk of CHD mortality and morbidity among nonsmokers exposed to ETS. The sample size was small, and the results were not statistically significant. Adjustment for other risk factors for CHD did not change the estimates of effect. SUMMARY AND RECOMMENDATIONS What Is Known 1. No statistically significant effects of ETS exposure on heart rate or blood pressure were found in healthy men, women, and school-aged children during resting conditions. During exercise there is no difference in the cardiovascular changes for men and women between conditions of exposure to ETS and control conditions. 2. With respect to chronic cardiovascular morbidity and mortality, although biologically plausible, there is no evidence of statistically significant effects due to ETS exposure, apart from the study by Hirayama in Japan.
CARDIOVASCULAR SYSTEM 266 What Scientific Information Is Missing 1. Experimental studies with animal models need to be performed with ETS to determine whether the cardiovascular changes seen following exposure to whole smoke also occur following exposure to ETS. 2. Existing studies have not provided evidence of serious harm in people with heart disease. With regard to angina onset, the findings are uncertain and need to be repeated. REFERENCES Anderson, G., and T.Dalhamn. Health risks due to passive smoking (in Swedish). LÃ¤kartidningen 70:2833â2836, 1973. Anderson, E.W., R.J.Andelman, J.M.Strauch, N.J.Fortuin, and J.H. Knelson. Effect of low-level carbon monoxide exposure on onset and duration of angina pectoris. Ann. Intern. Med. 79:46â50, 1973. Aronow, W.S. Effect of passive smoking on angina pectoris. N. Engl. J. Med. 299:21â24, 1978. Aronow, W.S. Aggravation of angina pectoris by two percent carboxyhemoglobin. Am. Heart. J. 101:154â157, 1981. Aronow, W.S., and M.W.Isbell. Carbon monoxide effect on exercise-induced angina pectoris. Ann. Intern. Med. 79:392â395, 1973. Aronow, W.S., J.Cassidy, J.S.Vangrow, H.March, J.C.Kern, J.R.Goldsmith, M.Khemka, J.Pagano and M.Vawter. Effect of cigarette smosking and breathing carbon monoxide on cardiovascular hemodynamics on anginal patients. Circulation 50:340â347, 1974. Aronow, W.S., R.Charter, and G.Seacat. Effect of 4% carboxyhemoglobin on human performance in cardiac patients. Prev. Med. 8:562â566, 1979. Astrup, P., and K.Kjeldsen. Model studies linking carbon monoxide and/or nicotine to arteriosclerosis and cardiovascular disease. Prev. Med. 8:295â302, 1979. Bridge, D.P., and M.Corn. Contribution to the assessment of nonsmokers to air pollution from cigarette and cigar smoke in occupied spaces. Environ. Res. 5:192â209, 1972. Dahms, T.E. J.F.Bolin, and R.G.Slavin. Passive smoking: Effects on bronchial asthma. Chest 80:530â534, 1981. DeLucia, A.J., J.H.Whitaker, and L.R.Byrant. Effects of combined exposure to ozone and carbon monoxide (CO) in humans, pp. 145â159. In S.D.Lee, M.G.Mustafa, and M.A.Mehlman, Eds. Advances in Modern Environmental Toxicology, Vol. V. International Symposium on the Biomedical Effects of Ozone and Related Photochemical Oxidants. Princeton, New Jersey: Princeton Scientific Publishers, 1983. Drinkwater, B.L., P.B.Raven, S.M.Horvath, J.A.Gliner, R.O.Ruhling, and N.W.Bolduan, and S.Taguchi. Air pollution, exercise and heat stress. Arch. Environ. Health 28:277â282, 1974.
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