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Stanton A. Gla~tz, PhD William W. Parmley, MD Division of Cardiology University of California San Francisco, CA 94143 The first disease linked definitively to active smoking was lung cancer. It is, therefore, not surprising that the first disease definitively to be caused by passive smoking was also lung cancer (USPHS, 1986). After all, before the adven~ of mass marketed cigarettes, lung cancer was a rare disease. The fac~ that smoking is the major identifiable cause of lung cancer made identifying this link -- for both active and passive smoking -- relatively s~raightforward. This situation contrasts with. hea~ disease, which has many risk factors, so it is not surprising that it took longer for the scientific community to conclude that active smoking caused hear~ disease (USPHS, 1983). Once ~he link between smoking and hear~ disease was established, it became clear that smoking killed more people because of causing or aggravating hear~ disease than did the more widely known lung (and other) cancers. Similarly, smoking is the most important preventable cause of coronary disease. Given this history, it is not surprising that exposure to environmental tobacco smoke (ETS) has now been linked to hea~ disease in nonsmokers. Much of the evidence for this link has appeared since the US Surgeon General (USPHS, 1986) and National Academy of Sciences (NRC, 1986) last reviewed the evidence on the health effects of ETS. The evidence tha~ ETS increases the risk of heart disease comes from several areas of scientific investigation. First, there are now i0 epidemiological studies on the relationship between exposure to envirorunental tobacco smoke in the home and the risk of hear~disease in the nonsmoking spouse of a smoker. All but one of these studies yielded a relative risk greater than 1.0. There is also 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 h~anand animal studies, that exposure to tobacco smoke, including passive smoking, increases aggregation of blood platelets. Such increases in platelet aggregation are an importan~ step in the genesis of atherosclerosis. In addition, increasing platelet aggregation contributes to coronary thrombosis, the 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 arteries. Such c: ~gt an:z~lm~uscr~ T!08872998

injuries are the first step in the development of a~herosclerosis. Thus, expoeure to ETS can contribute to bo~h shor~ term and long term insul~tothe coronary circulation and the hear~. It is no~ surprising that epidemiological studies have identified a modes~ increase in the risk of coronary artery disease in nonsmokers laving with smokers. Effects of Primary Smokin~ Before reviewing the evidence linking ETS with coronaryartery disease, it is woz~h summarizing the evidence linking a~tive smoking with coronaryarterydisease. This evidence was summarized in the 1983 Surgeon General's Report, which was devoted entirely to cardiovascular disease (USPHS, 1983): In 1980, diseases of the circulatory system were responsible for approximately one-half of the total U.S. mortality. CHD WaS the single most immoz~cant cause of death, accounting for approximately 30 percent of all U.S. deaths. Cigarette smoking is one of the three major independent CHD risk favors. The magnitude of the risk associated with cigarette smoking is similar to that associated with the other two major CHD 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 CHD in the United States. Cigarette smoking also acts synergistically with the other major risk factors to greatly increase the risk for CHD. Arteriosclerosis is the predominant underlying cause of cardiovascular disease, and atherosclerosis is the form of arteriosclerosis that most frequently causes clinically significant disease, including CHD, atherothromhic brain infarction, atherosclero~ic aortic disease, and atherom=lerotic peripheral vascular disease. Cigarette smoking contributes both to the development of atherosclerotic lesions and to the clinical manifestations of a~he~osclerotic vascular disease, including sudden death. Although the precise pathophysiologic basis of these clinical manifestations is not understood, it may be related to several deleterious cardiovascular effects of cigarette smoking, including production of an imbalance between myocardial oxygen supply and demand, a decrease in threshold for'ventricular fibrillation, and an increase in platelet aggregation. Nicotine and carbon monoxide are the tobacco smoke constituents most closely associated with these adverse effects; other cigarette smoke constituents such as hydrogen cyanide, oxides of nitrogen, 2 T108872999

and carbon disulfide are being studied for possible pathologic cardiovascular effects. Since 1983, evidence has also mounted that the polycyclic aromatic hydrocarbons in cigarette smoke also 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 (USPHS, 1986; NRC, 1986). Emidemiolomical Studies on ETS and Heart Disease Since 1984, the epidemiological evidence linking exposure to ETS with hear~disease has rapidly accumulated. The results of the eleven published studies are summarized in Table 1 and Figure I; four studies present data on men, eight on women, and one on both sexes combined. Despite minor changes in methodology or end points (some used de~hfrom ischemic hear~disease of any origin and some were limited to myocardial infarc~cion), the results of these studies are remarkable consistent. All the studies on men yielded relative risks of death from heart disease exceeding 1 when a nonsmoklng man was married to a woman who smoked, with a median risk of 1.2. All but one of the studies on women (Lee et al, 1986) yielded relative risks exceeding 1, wi~h a median relative risk of 1.4. Several studies also suggested an increase in the risk of nonfatal coronary symptoms (Svendsen et al, 1987; Palmer et al, 1988; Hole et al, 1989). Consistency of an observation across different studies increases the confidence one can have in the belief that an association is causal (Hill, 1984). When interpreting the results of such epidemiological studies, it is always impoz~cant 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 plausibilltyuntil later in tJ1is chapter, when we discuss the effects of ETS on platele~s and the atherogenic agents in ETS. For now, we will concentrate on potential confounding variables. These confounders are paz~cicularly important in a disease like heart disease, because it is known to be caused by multiple risk factors. All of t~e studies controlled for the most important confounding variable, age, and several (Garland et al, 1985; Svedsen et al, 1987; He, 1989~ Hole et al, 1989~ Humble et al, 1990) controlled for known risk factors for coronary artery disease, in particular levels of cholesterol, blood pressure and weight (or body mass or body mass index). 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, in studies that estimated the relative risk both with and without taking these T!08873000

confounding variables into account, found an increase in risk associated with ETS after taking the confounding variables into account (Svendsen et al, 1987, Humble et al, 1990). Against this background, it is interesting to note that the one s~udy that yielded a relative risk below 1 (Lee e~ al, 1986) failed to take into acooun~ any of the potential confounding variables except age and marital s~atus. Lee (1988, 1989, 1990) has suggested that the elevated risk of hear~ (and other) disease with passive smoking could be due to misclassification of nonsmokers who are really smokers. In addition, Wald (1986) has noted that some people who say they live with nonsmokers have detectable levels of the nicotine metabolite nicotine in their blood, indicating that they are actually exposed to ETS, either at work or a~ home. The former type of misclassification will tend to lead roan overestimate ofthe risks associated with ETS and the latter will lead to an underestimate of the risk. Careful analysis of theq~estion of misclassification -- which applies generally to studies of ETS and not just heal disease -- have demonstrated that the observed risks cannot be explained by this technical problem (Wald, 1986; Wells, 1986, 1988, 1990; Kawachi and Pearce, 1989; Reinken, 1989). In particular, both the Surgeon General (USPHS, 1986) and the National Academy of Sciences (NRC, 1986) were presented with the argumen~ ~hat misclassification errors accounted for the link between ETS and lung cancer and concluded that ETS caused lung cancer in healthy nonsmokers. To date, no compelling case has been made that this technical error explains consistent findings linking ETS with hearq: (or lung) disease. Indeed, the net effec~ of these two types of misclassification errors is to lead to an underestimate of the effects of passive smoking. 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. 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 (Helsing et al, 1988 (statistically significant in women, but not men); Hole et al, 1989; Garland et al, 1985 (although not statistically significant); Humble et al, 1990; He, 1989; Hirayama, 1984). The presence of such dose-response effects across multiple studies, done in differen~ locations with different criteria supports the hypothesis that the epidemiology is revealing a real effec~ of ETS on heart disease in nonsmokers. 4 T108873001

While all but one of the studies in Table I and Figure 1 yielded relative risks greater than i, the fac~ remains that 3 of the studies in men and 4 of the studies in women had 95% confidence intervals for the relative risk of passive smoking for hea~ disease that fell below 1.0, meaning ~hat the risk was not statistically significantly elevated a~ove 1.0 (with P<.05). It is important to note that the 95% confidence inter~als do not lie symmetrically about 1.0, but rather are skewed towards higher risks. Given the difficulties of obtaining enough patients in epidemiological studies, it is often not possible to obtain sufficient statistical power to detec~ biologically real effects with traditional (95%) levels of statistical confidence (Friedman et el, 1978). To avoid false negative conclusions, Roth~an (1978) suggested examining the confidence interval, as we have done, in concluding the exposure to ETS elevates the risk of hear~ disease (Figure i). One can assess formally how confident one can be in reaching a negative conclusion by computing the power of the study to detec~c an effect of specified size. Table i shows estimates of the power of each of the studies to detect a 20% increase in risk of hear~c disease (i.e., a relative risk of 1.2) with the available samples. The power was computed as described in Muhm and Olshan (1989), 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. The two (Helsing et al, 1988; Hole et el, 1989) that have power above the desirable level of 80% both identified significant increases of hear~: disease risk with ETS exposure. Examining Table i reveals that the greater the power of the study to detec~ an effect, ~he more likely it is to find a significant effect or ETS. Interestingly, the study by Lee (1986) which was the only one with a relative risk below I, also had the lowest power to detect an effect, only 3%. As discussed by Friedman et al (1978), such low powers are common in clinical research, so one should consider not just whether a given study yields statistically significant results, but also the confidence interval as well as the results of several independent studies. It is possible to combine the results of these studies in a formal analysis to derive a global estimate of the relative risk and associated 95% confidence interval. By combining the studies, the sample size and so the power to detect an effect increases. Wells (1988) used the studies by Gillis et al (1984), Lee et al (1985), and Helsing et al (1987) to compute a pooled relative risk of 1.3 (with a 95% confidence interval from I.i to 1.6) for men and the studies by Hirayama (1984), Gillis et al (1984), Garland et al (1985), Helsing et al (1988), Lee et al (1986), and Mar~in et al (1985) to compute a pooled relative risk of 1.2 (with a 95% confidence interval from 1.1 to 1.4) for women. By po61ing the results of these studies, it is possible to increase the power of 5 T!08873002

the tests and so produce estimates of risk that are significantly elevated. It is also significant that the 4 studies published since Wells (1988) completed his computation (Palmer et el, 1988t Humble et al, 1990t He, 1989; Hole et al, 1989) all independently yielded relative risks significantly greater than i, so had these studies been included, they would not have affe~ced Wells' computation, beyond increasing the confidence (i.e., narrowing the 95% confidence inte~al) we can have in the results. Finally, it is worth noting that all these studies are based on the smoking habits of the nonsmoker's~, 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 (Repace and Lowrey, 1985,1987). As a result, these studies will underestimate the risk and attendant public health burden due to ETS-induced hear~ disease. Kawachi et al (1989] have adjusted Wells' (1988) relative risks to account for workplace exposures to ETS and found that the relative risks increase to 2.3 (95% CI 1.4 - 3.4) fo~ men and 1.9 (95% CI 1.4 - 2.5) for women. Thus, any potential confounding of the results due to exposure to ETS outside the home will tend to lead to underestimates rather than overestimates of the effec~c of ETS. Likewise, estimates of public health impac~basedon risks computed from household exposures (Wells, 1988) will be lower than the true public health impact. In addition, Wells (1988) and Kawachi et al (1989) indicate ~hat the number of hear~ disease deaths due to passive smoking is an order of magnitude greater than then number of lung cancer deaths due to passive smoking. Acute Effects of ETS ExDo~ur~ Chronic exposure to ETS exerts carcinogenic effects by increasing the c~mulative risk of a molecule of one of the carcinogens in the ETS damaging the DNA in a cell and initiating or promotingthe carcinogenic process. To date, no one has identified any effects of acute exposure to ETS (or, for that matter, any other carcinogen) on cancer. The situation with hear~ disease is different. In heart disease there are both important chronic changes- (i.e., the development of athercsclerotic 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 ~hrombus and acute myocardial infarction. When the coronary circulation cannot provide enough oxygen to ~he myocardlumto meet the demand, the result is ischemia which can be silent or result in anginal chest pain. Earlier onset of angina or hypotension during exercise is a reflection of more severe hear~ 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 (1987) confirmed earlier work byAronow (1978) Ti08873003

demonstrating that exposure to ETS significantly reduced exercise ability in patients with coronary artery disease and ~he rate pressure produ~ (hear~ 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. These effects were present in both smokers and nonsmokers (Khalfen and Klochkov, 1987) and regardless of whether or not the room was ventilated (Aronow, 1978; Khalfen and Kloc21kov, 1987). Exposure to ETS also increased resting hear~ rate and systolic and diastolic blood pressure, and resulted in a lower hear~ rate at the onset of angina (Aronow, 1978). Blood carboxyhe~o~lobin was increased by about 1% after exposure to ETS (Aronow, 1978). Thus, acute exposure to ETS leads to an imbalance between myocardial oxygen supply and demand during exercise in patient~ with coronary artery disease. While ~his discussion has concentrated on ~he carbon monoxide in ETS as ~he 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 hea~ disease. McAq~rray et al (1985) blindly 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 hear~ rate was increased du~ing exposure to ETS, which increased blood carboxyhemoglobin by about i%. Exposure to ETS significantly reduced maximum oxygen uptake (by 0.251/sin and time to exhaustion (by 2.1 sin). Exposure to ETS also increased the perceived level of exertion during exercise, "maximum hear~ rate, and COs 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 ~he 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 subj ec~s, exposure to ETS adversely affects exercise performance. Lamb (1984) has suggested that at maximal exertion levels, up to 90% of the oxygen carrying capacity of the blood may be needed. Probably because of the carbon monoxide, ETS reduces this capacity, so the muscle cannot maintain its high rate of aerobic metabolism u~less cardiac output is further increased; people with hea~ disease and reduced ventricular reserve have difficulty meeting this demand. Moskowitz et al (1990) found evidence ~hat adolescent ~hildren of parents who smoked may suffer from chronic tissue hypoxla such as that observed in anemia, chronic pulmonary disease, cyanotic hear~ disease or high altitude. These children had significantly elevated levels of 2,3-diphosphoglycerate (DPG), which suggests that the body is a~tempting to compensate for hypoxia by increasing DPG level in blood to meet tissue oxygen 7 T108873004

requirements, even after cozTecting for age, weight, height and sex. These changes were dose-dependent; the greater the exposure ~o ETS (m~asured bo~h in terms of parental smoking and serum ~hiocyanate in ~he children), the greater the increase in DPG. In sum, exposure to ETS increases the demands on the hear~ during exercise and reduces the capacity of the hear~ to respond. This in~alance increases the ischemic s~ress of exercise in patients with existing coronary a~ery disease and can acutely precipitate symptoms. There is also evidence that acute exposure to ETS directly affects ~he myocardial muscle at a cellular level. GvozdJ~kova et al (1984) exposed rabbits in a 50 liter child's incubator to the smoke of ~ee burning cigarettes smoked over a 30 minute period and measured several variables related to the metabolism of cardiac mitochondria. (Mitcchondria are the suhcellular elements ~ha~ control cellular respira~iont ~hey conver~ oxygen into usable energy in the form of ATP.) 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 a day for eight weeks. They measured mitochcndrial respiration (QO~) as the consumption of oxygen after adding ADP to a vessel contaihing mitochondrial fragments. Using pyruvate as a substrate, mitochondrial respiration QO2 was reduced significantly compared to control (pure air) for all doses of ETS, even a single exposure (Figure 1), 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 (ADP:O~) with ETS exposure. Gvodjakova et al concluded that pyruvate as a substrata was a sensitive indicator of the toxic action of the ETS on the oxidative process. Later, to fur~er isolate where in the process of mitochondrial respiration, the ETS a~:ed, GvozdJ~k et al (1985, 1987) reported data on succinate, NADH, and cy~ochrome oxidase activity in the mitochcndria in the four groups of rabbits. Figure 2 shows the results of exposure to ETS on the activity of NADH oxidase, succinate oxidase and cy~ochrome oxidase of myocardial mitochond~la. 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. .Cy~ochrome 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 ~hat the deleterious effects of ETS on myocardial mitochcndrial respiration occur at the terminal segment of the mitochondrial respiration process. Prolonged exposure to carbon monoxide has been shown to induce ultrastr~ctural changes in myocardium (KJeldsen et 8 T!08873005

el, 1974; Thom~en and KJeldsen, 1974; Lough, 1978), and may account for ~he effects of ETS exposure on adverse mitochondrial func1:ion. Thus, acute exposure to ETS not only increases the demand and compromises the supply of oxygen to the hear~ as a whole, but also reduces the myocardi~m's ability to use this oxygen to create ATP to provide energy to suppor~ the heart's pumping activity. Given these effe~cs on the supply and demand for oxygen, and the effec"cs of ETS on platelets discussed below, it is not surprising that men with a high risk of heart disease enrolled in the MRFIT study had a greater relative risk of death from hear~ disease due ~o being married to a woman who smoked, than otherwise healthy men mazTied ~o nonsmokers (2.1 vs. 1.2, see Table i). Effects on Pla~elets The action of ETS to increase platelet aggregation is another way in which ETS can acutely increase the risk of a coronary event. When blood platelets aggregate inappropriately and form a thromhus (blood cio~), this clot can form in a fissured plaque in the coronary circulation and precipitate a myocardial infarction. Platelets are important for the normal body process of hemostasis, to prevent blood loss after an injury. Hemostasis depends on complex interactions among the dynamics of blood flow, components of ~he vessel wall, blood platelets and plasma proteins. A thrombus can be considered as an inappropriate form of hemostasis and is composed of a mass of cellular material held together by a fibrous network. Definitive evidence has confirmed that platelets play a major role in t-hrombus formation and embolization, especially in the arterial system. In addition, increasing evidence has shown that platelet deposition and throm~us formation can contribute to the growth and progression of a~herosclerotic plaques (Fuster and Chesebro, 1981; Ross, 1986). An arterial throm~us appears to develop in three phases: platelet adhesion, platelet aggregation, and activating of clotting mechanisms. Passive smoking increases platelet aggregation and so increases the likelihood of throm~us formation and myocardial infarction. Table 2 summarizes the results of three studies (Davis e~ al, 1985, 1986, 1989) on the effects of cigarette smoke on platslet aggregation a~d damage to the arterial endothellum (lining). (We will discuss the effects on the endothelium below.) Davis et al (1989) also measured pla~elet aggregation ratio and endothelial cell counts in nonsmokers before and after being exposed to 20 minutes of ETS while sitting in a hospital atrium. Mean values before and after passive smoking were 0.87 and 0.78 (P-.002) for platelet aggregation ratio and 2.8 and 3.7 (P~.002) for counts of anuclear endothelial cell carcasses in venous blood. These changes are in between the effects observed after nonsmokers smoked ~wo tobacco cigarettes and the effects observed after smoking two non- tobacco cigarettes (Davis et al, 1985) and similar to the values observed in nonsmokers who smoked two cigarettes while trying not c: ~gLan:z~mm~scr~ ~p~ T!08873006

CO inhale (Davis et al, 1986). These effects were not correlated with the level of nicotine in the blood of ~he experimental subjects in any of these or other (Davis e~ el, 1985, 1987), related studies on how drugs modify platelet aggregation and endothelial cell counts. In paz~cicular, the effects observed in nonsmokers smoking without inhaling were similar to the effects on smokers smoking two cigarettes, despite the fact that the plasma nicotine levels in the nonsmokers were a factor of 5 smaller than those observed in the smokers (Davis et el, 1986). In contrast, other work in the same laboratory comparing smoking with snuff use revealed similar changes under both conditions (Davis et el, 1990). This result, combined with the finding that smoking non-tobacco cigarettes (Davis et el, 1985) failed to produce changes in platelet function as large as observed with tobacco cigarettes, suggests that nicotine is an impoz~ant active agent. Since non- tobacco cigarettes also affected platelet aggregation somewhat, however, it is possible that carbon monoxide or other combustion products are also influencing the platelets. Sinzinger and Kefalides (1982) measured platelet sensitivity to antiaggregatory prostaglandins (E~, and D2) before, during and after 15 minutes of exposure to ETSI~ healthy nonsmokers and smokers (Table 3). Passive smoking reduced platelet sensitivity to the antiaggregatory prostaglandins I2 and ~ significantly (P<.01) by a factor of about 2 by the end of 15 mlnutes exposure to ETS among nonsmokers. This effect persisted at 20 minutes after end of exposure, and was gone by 40 minutes. Platelet response prostaglandinD2changed modestly in a similar pattern, but did not reach statistical significance. Among smokers, the control level of platelet aggregation was higher (P<.01) and the prostaglandins had no significant effects on platelet aggregation over time during or following exposure to ETS. Thus, nonsmokers' platelets seem much more sensitive to a single exposure to ETS than do smokers' platelets, with platelet sensitivity ~o diasggregating prostaglandins having similar effects in nonsmokers acutely exposed to ETS as it does on the chronic levels of platelet aggregation observed chronically in smokers. Fuz~her evidence from the same laboratory that passive smoking increases platelet aggregation comes from work by Bur~huber at al (1986), who had smokers and nonsmokers smoke two cigarettes and also ex~oseda different group of smokers and nonsmokers to ETS in • an 18 m~ room in which 30 cigarettes had been smoked just before exposing the nonsmokers. They measured the sensitivity of platele~s to the disaggre~ating substance prostaglandin I~ (PGI2), which is released by endotheliumand inhibits platelet aggr-egati6n. (PGI2 is also called prostacyclin.) Figure 3 shows the results of this experiment. In smokers, neither smoking nor passive smoking affected t21e sensitivity of the platelets to the disaggregating effect of prostaglandin I2. The sensitivity of platelets in smokers was also significantly lower than nonsmokers. In contrast, platelets were more sensitive to prostaglandin Iz in nonsmokers, 10 T108873007