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CR900213R3 In press Circulation PASSIVE SMOKIr1G AND HEART DISEASE: EPIDEMIOLOGY, PHYSIOLOGY, AND BIOCHEMISTRY Stanton A. Glantz, PhD William W. Parmley, MD Division of Cardiology, Department of Medicine Cardiovascular Research Institute University of California San Francisco, CA 94143 Short title: Passive Smoking and Heart Disease This manuscript is based on a background paper prepared for the U.S. Environmental Protection Agency. It was also presented at the Seventh World Conference on Tobacco and Health, Perth, Australia, April 1-5, 1990, and the World Conference on Lung Health, Boston, MA, May 20-24, 1990. Address for Correspondence and Reprints: Stanton A. Glantz, Ph.D. Professor of Medicine Division of Cardiology ~ Box 0124 M1186 University of California San Francisco, CA 94143-0124 (415) 476-3893 FAX: (415) 476-0424

CR900213R3 ABSTRACT The evidence that environmental tobacco smoke (ETS) increases risk of death from heart disease is similar to that which existed in 1986 when the Surgeon General concluded that ETS caused lung cancer in healthy nonsmokers. Eleven epidemiological studies, done in a variety of locations, reflect a 3096 increase in risk of death from ischemic heart disease or myocardial infarction in nonsmokers living with smokers. The larger studies demonstrate a dose-response effect. The epidemiological studies are complemented by a variety of physiological and biochemical data from human studies which show that ETS adversely affects platelet function and damages arterial andothelium, increasing the risk of heart disease. ETS also exerts adverse effects on exercise capability of healthy people and those with heart disease by reducing the body's ability to deliver and use oxygen. In animal experiments, ETS also depresses cellular respiration at the level of mitochondria. The polycyclic aromatic hydrocarbons in ETS also accelerate, and may initiate, the development of itherosclerotic plaque. Nonsmokers. appear to be more sensitive to ETS than smokers. In terms of cardiovascular disease, it is incorrect to compute "cigarette equivalents" for passive exposure to ETS, then try to extrapolate the effects of this exposure on nonsmokers from the effects of direct smoking on smokers. ETS causes heart disease, and ETS-induced heart disease may account for about ten times as many deaths as ETS-induced lung cancer. ETS is the third leading preventable cause of death, after primary smoking and alcohol. CONDENSED ABSTRACT The evidence that environmental tobacco smoke (ETS) increases risk of death from heart disease is similar to that available when the Surgeon General concluded that ETS caused lung cancer in healthy nonsmokers. ETS increases risk of death from heart disease by 3096 among nonsmokers living with smokers. ETS adversely affects platelet function and damages arterial endothelium. ETS significantly reduces exercise capability of healthy people and those with heart disease, as well as mitochondrial respiration. The polycyclic aromatic hydrocarbons in ETS accelerate the development of atherosclerotic plaque. ETS causes heart disease and is the third leading preventable cause of death, after active smoking and alcohol. c:\Siana\maau.cribuheart.doc

CR900213R3 Key Words artherosclerosis myocardial infarction bentio(a)pyrene passive smoking carbon monoxide platelets environmental tobacco smoke polycyclic aromatic hydrocarbons epidemiology secondhand smoke mitochrondia tobacco smoke pollution

CR900213 R3 The first disease linked definitively to active smoking was lung cancer. It is, therefore, not surprising that the first disease identified as caused by passive smoking was also lung cancer'. Before the advent of mass marketed cigarettes, lung cancer was a rare disease. Since smoking is the primary cause of lung cancer, identication of this link - for both active2 and passive smoking' - was relatively straightforward. This situation contrasts with heart disease, which has many risk factors. It is not surprising that it took longer for the scientific community to conclude that active smoking caused heart disease. Once the link between smoking and heart disease was established, it became clear that smoking killed more people by causing or aggravating heart disease than did the lung cancer. In fact, smoking is the most important preventable cause of coronary disease. Exposure to environmental tobacco smoke (ETS) has now been linked to heart disease in nonsmokersxa. Much of the evidence for this link has appeared since the US Surgeon General' and National Academy of. Sciences7 reviewed the evidence on the health effects of ETS in 1986. Based on the information available then, both reports concluded that the evidence linking ETS and heart disease was equivocal and that more research was necessary before any definitive statements could be made. These conclusions were reasonable in 1986. In the four years since these reports were written, considerable information on both the epidemiology and biological mechanisms by which ETS causes heart disease has accumulated. Most of the results presented here were published after the 1986 Surgeon General and National Academy of Science reports. There are now eleven epidemiological studies on the relationship between exposure to environmental tobacco smoke in the home and the risk of heart disease in the nonsmoking spouse of a smoker. All but one of these studies yielded relative risks or odds ratios greater than 1.0. There are several lines of biological evidence which make this association plausible. There is evidence that exposure to ETS reduces exercise tolerance of both healthy individuals as well as people with existing coronary artery disease. Such reduced exercise capability is one of the landmarks of acute compromises to the coronary circulation. There is good evidence, from both human and animal studies, that exposure to tobacco smoke, including passive smoking, increases aggregation of blood platelets. Such increases in platelet aggregation are an important step in the genesis of atherosclerosis. In addition, increasing platelet aggregation contributes to risk of coronary thrombosis, i cause of acute myocardial infarction. Finally, carcinogenic agents in ETS, including benzo(a)pyrene have been shown to produce injuries to the endothelial cells which line ¢ajlaMZ\aarnuacrikaheut.doc I

CR900213R3 arteries. Such injuries are the first step in the development of atherosclerosis. Thus, exposure to ETS can contribute to both short term and long term insults to the coronary circulation and the heart. It is not surprising, therefore, that epidemiological studies have identified an increase in the risk of coronary artery disease in nonsmokers living with smokers. Effects of Primary Smokina Before reviewing the evidence linking ETS with coronary artery disease, it is worth summarizing the evidence linking active smoking with coronary artery disease. This evidence was summarized in the 1983 Surgeon General's Report, which was devoted entirely to cardiovascular disease; it concluded that cigarette smoking is one of the three major independent heart disease risk factors. It also concluded that the magnitude of the risk associated with cigarette smoking is similar to that associated with the other two major heart disease risk factors, hypertension and hypercholesterolemia; however, because cigarette smoking is present in a larger percentage of the U.S. population than either hypertension or hypercholesterolemia, cigarette smoking ranks as the largest preventable cause of heart disease in the United States. Since 1983, evidence has also mounted that the polycyclic aromatic hydrocarbons in cigarette smoke can injure the arterial endothelium and initiate the atherosclerotic process. All the compounds implicated as damaging to the cardiovascular system of smokers have been identified in ETS'.'. Epidemiological Studies on ETS and Heart Disease Since 1984, the epidemiological evidence linking exposure to ETS with heart disease has rapidly accumulated. The results of the eleven published studies'''= are summarized in Table 1 and Figure 1; four studies present data on men, nine on women, and one on both sexes combined. Despite minor differences in methodology or end points (some used death from ischemic heart disease of any origin and some were limited to death from myocardial infarction), the results of these studies are remarkablly consistent. All the studies on men yielded relative risks of death from heart disease exceeding 1.0 when a nonsmoking man was married to a woman who smoked, with a median risk of 1.2. All but one of the studies on women' yielded relative risks exceeding 1, with a median relative risk of 1.4. Several studies'a"•"a0 have also suggested an increase in the risk of nonfatal coronary cA;lantzl=nuscrikt.heart.doc 2

CR900213R3 symptoms. Consistency of an observation across different studies increases the confidence one can have that an association is causal. Several authors also observed a dose-response relationship between increasing amounts of smoking by the spouse and the risk of heart disease in the nonsmoking spouse'"13•`5'", which in most cases was statistically significant. The presence of such dose-response effects across multiple studies, done in different locations with different criteria, supports the hypothesis that ETS causes heart disease in nonsmokers. While all but one of the studies in Table 1 and Figure 1 yielded relative risks greater than 1.0, the fact remains that 3 of the studies in men and 5 of the studies in women had 95 96 confidence intervals for the relative risk of passive smoking for heart disease that included 1.0, meaning that the risk was not statistically significantly elevated above 1.0 (with P <.05). It is important to note that the 95 96 confidence intervals do not lie symmetrically about 1.0, but rather are skewed towards higher risks. Exn*+,ining the confidence intervals leads to the conclusion that exposure to ETS elevates the risk of heart disease (Figure 1). It is also possible to combine the results of these studies in a formal analysis to derive a global estimate of the relative risk and associated 95 96 confidence interval. By combining the studies, the sample size and so the power to detect an effect increases. Wells' used several of the studies in Table 1''''"' to compute a pooled relative risk of 1.3 (95% confidence interval 1.1 to 1.6) for men and and 1.2 (95 96 confidence interval 1.1 to 1.4) for women. A similar analysis using all the studies in Table 1 yields a relative risk of 1.3 (with a 95 96 confidence interval from 1.1 to 1.6). When interpreting the results of such epidemiological studies, it is always important to consider biological plausibility and potential confounding variables which could explain the results. Aside from noting that the compounds in mainstream smoke that have been implicated in heart disease are in ETS, we will defer the discussion of biological plausibility until we discuss the effects of ETS on platelets and the atherogenic agents in ETS. For now, we will concentrate on potential confounding variables, such as the possible confounding effect of a correlation of spouses' poor health behaviors (e.g., diet high in animal fat). These confounders are particularly important in a disease like heart disease, because it is known to be caused by multiple risk factors. All the studies controlled for the most important confounding variable, age, and several"'`" controlled for known risk factors for coronary artery disease, in particular levels of serum or plasma cholesterol, blood pressure and body mass. Most of the studies also included one or more measures of socioeconomic status, such as the nature of the housing or amount of education. Indeed, studies that estimated the relative risk both with and c:4lantzlmanu.criletaheart.doc 3

CR900213R3 without taking these confounding variables into account found an increase in risk associated with ETS after taking the confounding variables into account'a's. Lee='" has suggested that the elevated risk of heart (and other) disease with passive smoking could be due to misclassification of nonsmokers who are really smokers. In addition, Wale has noted that some people who say they live with nonsmokers have detectable levels of the nicotine metabolite cotinine in their blood, indicating that they are actually exposed to ETS, either at work or at home. The former type of misclassification would tend to lead to an overesdmate of the risks associated with ETS and the latter would lead to an underestimate of the risk. Careful analysis of the question of misclassification - which applies generally to studies of ETS - have demonstrated that the observed risks cannot be explained by this problems-2`a. There is always the possibility that there is some other confounding variable relating to cultural factors, such as the nature of housing or employment or the nature of time spent outside the home. The fact that results from all over the world in widely varying cultural settings - including several regions in the United States, the United. Kingdom, Japan, and China - argues against this concern. One can assess formally how confident one can be in reaching a negative conclusion by computing the power of the study to detect an effect of specified siuP. Table 1 shows estimates of the power of each of the studies to detect a 20% increase in risk of heart disease (i.e., a relative risk of 1.2) with the available samples. The power was computed as described in Muhm and Olshan30, using a two-sided test for the relative risk with a Type I risk of 5% (i.e., requiring the 95% confidence interval for the relative risk to exclude 1.0 before concluding a statistically significant elevation in risk in an individual study). Most of the studies have low to moderate power. All fourl','4,'5," that have power above 4096 identified significant increases of heart disease risk with ETS exposure. Examining Table 1 reveals that the greater the power of the study to detect an effect, the more likely it was to find a significant adverse effect of ETS. Finally, it is worth noting that all these studies are based on the smoking habits of the nonsmoker's sQousc, and so exposure to ETS at home. Household exposures to ETS at home are generally much smaller than exposures at work, where the density of smokers is generally higher"X. As a result, these studies generally underestimate the risk and attendant public health burden due to ETS-induced heart disease. Kawachi at alm have adjusted Wells's relative risks to account for workplace exposures to ETS and found that the relative risks increase to 2.3 (95 96 Cl 1.4 - 3.4) for men and 1.9 (95% Cl 1.4 - 2.5) for women. Thus, any potential confounding of the results due to e:ijlaatzlmanuacciktaheart.doc 4

CR900213R3 exposure to ETS outside the home will tend to produce underestimates rather than overestimates of the effect of ETS. Likewise, estimates of public health impact based on risks computed from household exposures' will be lower than the true public health impact. In addition, Wellss and Kawachi et al-" indicate that the number of heart disease deaths due to passive smoking is an order of magnitude greater than then number of lung cancer deaths due to passive smoking. Even though the relative risks for heart disease and lung cancer caused by ETS are similar (about 1.3 for both diseases), the attributable deaths for heart disease is greater since heart diease is much more common than lung cancer. Of 53,000 annual deaths in the U.S. attributed to passive smokings, 37,000 are attributed to heart disease, compared with 3,700 for lung cancer (Figure 2). These epidemiological studies demonstrate a connection between ETS exposure and death from heart disease. We now turn our attention to possible physiological and biochemical mechanisms which could explain these observations. Acute Effects of ETS Exposure Chronic exposure to ETS exerts carcinogenic effects by increasing the cumulative risk of a molecule of one of the carcinogens in the ETS damaging a cell and initiating or promoting the carcinogenic process. The situation with heart disease is different. In heart disease there are both important chronic changes (i.e., the development of atherosclerotic lesions) and acute changes. The latter include an increase in myocardial oxygen demand which may outstrip the oxygen supply and produce ischemia, and increased platelet aggregation which can lead to coronary thrombosis and acute myocardial infarction. When the coronary circulation cannot provide enough oxygen to the myocardium to meet the demand, the result is ischemia which can be silent or result in aaginal chest pain. Earlier onset of angina or hypotension during exercise is a reflection of more severe heart disease. Oxygen supply can be reduced by atherosclerotic narrowing or vasoconstriction of the coronaries or by reducing the oxygen carrying capacity of the blood by forming carboxyhemoglobin. Khalfen and Klochkov" confirmed earlier work by Aronow" demonstrating that exposure to ETS significantly reduced exercise ability in patients with coronary artery disease and the rate pressure product (heart rate times systolic blood pressure). In both studies, patients were exposed to realistic levels of ETS by simply sitting in a waiting room while someone was smoking. '1'hese effects were present in both smokers and nonsmokers" and regardless of whether or not the room was ventilated"-'s. Exposure to ETS also increased resting c:4laatzlmuw.crikUheait.doc 5

CR900213 R3 heart rate and systolic and diastolic blood pressure, and resulted in a lower heart rate at the onset of angina's. Blood carboxyhemoglobin was increased by about 196 after exposure to ETS'3. Thus, acute exposure to ETS leads to an imbalance between myocardial oxygen supply and demand during exercise in patients with coronary artery disease. While this discussion has concentrated on the carbon monoxide in ETS as the active agent, it is possible that some other component of the ETS is causing or contributing to this effect. The effects of ETS on cardiac performance are, in fact, severe enough to affect exercise performance in young healthy subjects with no evidence of heart disease. McMurray et al" exposed young healthy women to pure air and air contaminated with ETS while they exercised on a treadmill. The results were similar to those observed in patients with coronary artery disease. Resting heart rate was increased during exposure to ETS, which increased blood carboxyhemoglobin by about 196. Exposure to ETS significantly reduced maximum oxygen uptake (by 0.251/min and time to exhaustion (by 2.1 min). Exposure to ETS also increased the perceived level of exertion during exercise, maximum heart rate, and CO2 output. It also significantly increased levels of lactate in venous blood (from a mean of 5.5 mM during control period to 6.8 mM after exposure to ETS). This greater lactate at a lower oxygen consumption during the passive smoking trials indicates a greater reliance on anaerobic metabolism. The combined effect of the reduced oxygen carrying capacity and increased lactate resulted in a reduction in maximal aerobic power and the duration of exercise. Thus, even in healthy subjects, exposure to ETS adversely affects exercise performance. Lamb" has suggested that at maximal exertion levels, up to 90% of the oxygen carrying capacity of the blood may be needed. Probably because of carbon monoxide, ETS reduces this capacity, so the muscle cannot maintain its high rate of aerobic metabolism unless cardiac output is further increased; people with heart disease and reduced ventricular reserve have difficulty meeting this demand. In sum, exposure to ETS increases the demands on the heart during exercise and reduces the capacity of the heart to respond. This imbalance increases the ischemic stress of exercise in patients with existing coronary artery disease and can acutely precipitate symptoms. Moskowitz et al" found evidence that adolescent children of parents who smoked may suffer from chronic tissue hypoxia such as that observed in anemia, chronic pulmonary disease, cyanotic heart disease or high altitude. These children had significantly elevated levels of 2,3-diphosphoglycerate (DPG), even after correcting for age, weight, height and sex. 2,3-DPG acts as a physiologic modulator of hemoglobin oxygen affinity. It binds to specific amino acid sites and increases the P., (lowers the oxygen affinity), thus making more oxygen available to c:1=lamzlmanu.crikuheact.doc 6

CR900213R3 peripheral tissues. This observatiion suggests that the body is attempting to compensate for hypoxia by increasing DPG level in blood to meet tissue oxygen requirements, The changes were dose-dependent; the greater the exposure to ETS (measured both in terms of parental smoking and serum thiocyanate in the children), the greater the increase in DPG. There is also evidence that acute exposure to ETS directly affects respiration of the myocardium at a cellular level. GvotdjQkovli et al" exposed rabbits in a 50 liter child's incubator to the smoke of three burning cigarettes smoked over a 30 minute period and measured several variables related to the metabolism of cardiac mitochondria. They had three groups of rabbits: one group exposed to a single dose of ETS, one group exposed to 30 min of ETS twice daily for two weeks, and one group exposed to 30 minutes of ETS twice daily for eight weeks. They measured mitochondrial respiration as the consumption of oxygen after adding ADP to a vessel containing mitochondrial fragments. Using pyruvate as a substrate, mitochondrial respiration was reduced significantly compared to control (pure air) for all doses of ETS, by even a single exposure; to about half the control value. The oxidative phosphorylation rate was also reduced significantly at all exposures by about one-third. There were no significant changes in the coefficient of oxidative phosphorylation with ETS exposure. Gvozdjikovi et al" concluded that pyruvate as a substrate was a sensitive indicator of the toxic action of the ETS on the oxidative process. Later, to further isolate where in the process of mitochondrial respiration, the ETS acted, GvozdjQk et al'0." reported data on succinate, NADH, and cytochrome oxidase activity in the mitochondria in the four groups of rabbits. Exposure to ETS affects the activity of NADH oxidase, succinate oxidase and cytochrome oxidase of myocardial mitochondria. The activity of the first two oxidases exhibited no changes compared with the control group - neither after a single exposure to ETS or following exposures up to 2 weeks. Cytochrome oxidase activity decreased both after a single exposure to ETS and over time, with increasing effects as the duration of exposure to ETS is extended. The observation that cytochrome oxidase and not NADH or succinate oxidase activity was affected by ETS suggests that the deleterious effects of ETS on myocardial mitochondrial respiration occur at the terminal segment of the mitochondrial respiration process. Prolonged exposure to carbon monoxide has been shown to induce ultrastructural changes in myocardium4z'' and may account for the adverse effects of ETS exposure on mitochondrial function. c:\gtuuz\m.nuactAeuheaR.doc 7