13
Cardiovascular Disease

The impact of cigarette smoking on the U.S. national burden of cardiovascular disease (CVD) has been well documented. Each year, about 150,000 cardiovascular deaths are attributable to cigarette smoking, and of these, about 30,000 are attributable to environmental cigarette smoke exposure among nonsmokers (McGinnis and Foege, 1999, Taylor et al., 1992). The cardiovascular burden of smoking is amplified substantially because smoking significantly increases the risk for many types of cardiovascular morbidity: myocardial infarction (MI), sudden cardiac death, stroke, peripheral vascular disease, and abdominal aortic aneurysms (Green et al., 1993). Importantly, the risk of cardiac ischemic events is substantially and relatively rapidly reversible on cessation of smoking (U.S. DHHS, 1983).

In 1990–1994, an average of 430,700 Americans died each year of smoking-related illness. The largest portion of these deaths were cardiovascular-related illnesses. Approximately one in five deaths from cardiovascular diseases is attributable to smoking. According to the World Health Organization (WHO), 1 year after quitting, the risk of coronary heart disease (CHD) decreases by 50%, and within 15 years, the relative risk of dying from CHD for an ex-smoker approaches that of a long-time nonsmoker.

Despite this well-recognized association between smoking, and CVD, and sudden cardiac death, and the increasing amount of pathogenic information available, more needs to be known about the mechanisms of smoking-induced CVD injury. This is of particular importance because



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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction 13 Cardiovascular Disease The impact of cigarette smoking on the U.S. national burden of cardiovascular disease (CVD) has been well documented. Each year, about 150,000 cardiovascular deaths are attributable to cigarette smoking, and of these, about 30,000 are attributable to environmental cigarette smoke exposure among nonsmokers (McGinnis and Foege, 1999, Taylor et al., 1992). The cardiovascular burden of smoking is amplified substantially because smoking significantly increases the risk for many types of cardiovascular morbidity: myocardial infarction (MI), sudden cardiac death, stroke, peripheral vascular disease, and abdominal aortic aneurysms (Green et al., 1993). Importantly, the risk of cardiac ischemic events is substantially and relatively rapidly reversible on cessation of smoking (U.S. DHHS, 1983). In 1990–1994, an average of 430,700 Americans died each year of smoking-related illness. The largest portion of these deaths were cardiovascular-related illnesses. Approximately one in five deaths from cardiovascular diseases is attributable to smoking. According to the World Health Organization (WHO), 1 year after quitting, the risk of coronary heart disease (CHD) decreases by 50%, and within 15 years, the relative risk of dying from CHD for an ex-smoker approaches that of a long-time nonsmoker. Despite this well-recognized association between smoking, and CVD, and sudden cardiac death, and the increasing amount of pathogenic information available, more needs to be known about the mechanisms of smoking-induced CVD injury. This is of particular importance because

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction one constituent of tobacco smoke—nicotine—is currently used as short-term therapy for smoking cessation, and as discussed elsewhere in this volume, nicotine is being considered for extended use as an aid to smoking reduction. This necessitates a detailed consideration of the cardiovascular pharmacology of nicotine. The results of the Lung Health Study (Anthonisen et al., 1994) is notable in the consideration of the cardiovascular effects of long-term nicotine replacement therapy (NRT) since it was found that long-term use of nicotine gum for the purpose of smoking cessation did not result in an increased incidence of cardiovascular complications. Furthermore, it is pertinent to strategies being deployed by tobacco product manufacturers to eliminate selectively discrete constituents of tobacco and cigarettes and then market them as “safer.” This implies a knowledge of the relative contributions of a myriad of tobacco constituents to CVD, which simply does not exist. This chapter summarizes the current scientific basis of our understanding of smoking and CVD, suggests modern methodologies that might usefully be applied to enhance understanding in this area, and highlights areas for further research. CORONARY HEART DISEASE The incidence of coronary artery disease (CAD), including sudden cardiac death, is more than doubled in cigarette smokers as a group and is increased fourfold in heavy smokers. There is a dose-response relationship between cigarette smoking and CAD, such that the risk increases with the number of cigarettes smoked daily, the extent of inhalation, and the number of years of smoking. Cigarettes that nominally deliver less tar or nicotine have not been shown to confer any protection from ischemic heart disease. The clearest understanding of smoking-induced ischemic heart disease emerges from integration of data from epidemiological and pathophysiologic investigations. In considering the participation of smoking in the etiology of CHD, it is useful to separate the effects of smoking on the development of atherosclerotic stenosis of the coronary arteries from its effects on the process that converts coronary atherosclerosis to acute coronary events. Acute coronary events represent an abrupt transition from stable chronic CAD to one of the major consequences of ischemia: unstable angina, myocardial infarction, and sudden cardiac death. Abundant evidence supports the concept that the rupture of a lipid-rich atherosclerotic plaque with attendant thrombus formation is the initiating event in the development of the vast majority of these ischemic syndromes (Davies and Thomas, 1984; Oates, 1989).

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Coronary Atherosclerosis Age is a powerful predictor of coronary atherosclerosis, and angiographic studies indicate that the relative risk for coronary stenosis associated with having previously smoked is greatest in the youngest age groups, suggesting an acceleration of the process by smoking. Some of the best evidence is provided by a prospective autopsy study performed in Hawaii (Reed et al., 1987) and from the study of autopsies on young men who died violently (PDAY Research Group, 1990). These studies indicate that there is a strong dose-related association of smoking with atherosclerosis of the abdominal aorta, as well as an association with atherosclerosis of the coronary arteries that is significant but less robust. From these two autopsy studies, as well as from an overview of all relevant studies, one gains the impression that the significant increase in fibrous atherosclerotic plaques and atheroma of the coronary arteries is not of sufficient magnitude to account fully for the greater increase in acute coronary events that are linked to cigarette smoking. The finding that the increase in involvement of the coronary arteries with atherosclerosis is of small magnitude is in agreement with the prospective epidemiological evidence that stable angina pectoris is increased modestly, if at all, in cigarette smokers over age 40. In men less than 40 years of age, an increase in stable angina has been detected (twofold), but at 40 years and older the risk is increased only slightly, even after adjusting the incidence of stable angina for the loss of persons at risk owing to acute coronary events (Dawber, 1980). However, excess smoking-attributable mortality rates due to heart disease continue to increase with age and smoking duration, suggesting that smoking continues to be an important independent risk factor in the elderly (Burns, 2000). Acute Coronary Events Prospective epidemiological studies have consistently demonstrated a substantial increase in acute coronary ischemic events in individuals who smoke (U.S. DHHS, 1983). The pernicious effect of cigarette smoking on MI and sudden cardiac death is seen at least to age 70, but the increase in risk for a given individual appears to be greatest during middle age. The largest body of prospectively acquired North American data indicates that middle-aged men who smoke have a tenfold greater risk of sudden cardiac death and a 3.6-fold increased risk of MI (Kannel et al., 1984). The risk for sudden cardiac death is disproportionately greater than that for MI, a finding that is replicated to varying degrees in other studies. Of all the coronary risk factors, cigarette smoking is the strongest predictor of sudden cardiac death. The risk for both of these acute coro-

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction nary events (MI and sudden death) clearly exceeds that for stable angina. Although the incidence of coronary deaths in women during middle age is lower than that in men, cigarette smoking accounts for about half of these deaths. Pipe and cigar smoking are also associated with increased rates of heart attack rates (Nyboe et al., 1991) and coronary mortality, as well as stroke occurrence. In most studies that have explored the relationship of cigarette smoking rates to CVD outcomes, a dose-response has been observed. Cumulative exposures in epidemiological studies are not easy to determine because of interindividual short- and long-term variations in smoking patterns and choices of products. Also, individual inhalation depth and retention may vary in order to titrate the delivery of certain levels of nicotine (Hee et al., 1995). However, population studies employing even a relatively simple measure of exposure, such as cigarettes per day, usually reveal increasing adverse CVD outcomes with increasing numbers of cigarettes consumed. An example is the Cancer Prevention Study (CPS), shown in Table 13–1. Here, although some cells have small numbers of participants, there is a general trend of increased risk of CAD death with increasing baseline cigarette usage, most prominent up to 20 cigarettes per day. Cessation of Smoking Smoking cessation in individuals without known coronary heart disease makes an important contribution to reducing the risk of MI (Cook et al., 1986; Rosenberg et al., 1985, 1990; U.S. DHHS, 1983). The excess risk of MI falls by about 50% within the first two years after cessation of smoking, consistent with a substantial component of the risk of acute ischemic events being reversible. An example of the rate of decline in risk of fatal CAD, total CAD, and nonfatal MI is shown in Table 13–2 from the CPS (Stellman and Garfinkel, 1986). For those who have ceased smoking for 10–14 years, their general CVD risk declines to that of “never smokers.” A similar or even more accelerated risk reduction can be seen for stroke in women, as shown in Figure 13–1 (Kawachi et al., 1993). Even among individuals over 60 years of age, a decrease in risk for ischemic heart disease postcessation has been found, though smaller than for younger individuals (Burns, 2000). For smokers who already have CAD, cessation is also very effective in reducing the incidence of further acute coronary events. Survivors of MI have a greater risk of reinfarction, and survivors of sudden cardiac death have a greater risk of sudden death if they continue to smoke. For individuals who have angina pectoris or a positive exercise test or who have had coronary artery bypass graft surgery, continuing the smoking

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction TABLE 13–1 Age-Specific and Age-Adjusted Death Rates From Coronary Heart Disease, by Number of Cigarettes Currently Smoked   Cigarettes per Day   Never Smoked 1–9 10–19 20 21–39 40 41+ Age M F M F M F M F M F M F M F 30–34 — — — — — — — — ( ) — ( ) — ( ) — 35–39 (0.9) ( ) — — — — — ( ) — ( ) — ( ) — — 40–44 [1.3] 0.6 ( ) — ( ) — (10.4) (1.4) [5.7] ( ) 12.4 — (13.1) ( ) 45–49 2.7 0.4 17.7 [2.1] 14.1 3.3 14.1 2.8 9.9 2.1 19.5 4.6 18.1 — 50–54 5.6 0.8 14.7 3.4 25.1 4.2 21.4 4.0 21.1 6.8 21.9 4.6 20.9 (6.4) 55–59 11.9 2.4 28.0 2.4 31.0 5.7 35.9 9.7 28.4 8.1 31.2 11.3 41.3 14.6 60–64 22.9 6.2 49.4 11.1 57.0 13.5 64.0 19.0 46.1 19.8 59.0 17.3 28.9 ( ) 65–69 40.5 12.6 65.2 22.6 76.9 30.4 82.5 35.4 82.1 29.2 65.6 29.1 78.5 [32.9] 70–74 68.5 25.4 114.1 35.6 110.4 52.6 132.9 49.2 101.0 51.4 114.4 54.8 39.2 — 75–79 123.1 53.0 128.9 72.9 148.7 76.9 176.6 94.4 222.5 103.2 177.9 92.9 [110.0] — 80–84 189.5 97.5 248.5 127.2 279.6 114.2 309.7 149.1 201.9 81.4 315.1 (103.7) — ( ) 85+ 329.7 265.5 363.3 167.1 308.6 479.4 430.0 333.9 852.3 ( ) ( ) ( ) — — Age adjusteda 24.1 11.5 37.0 13.1 38.2 20.3 44.7 20.2 46.9 16.2 37.6 15.9 30.0 13.3 NOTE: —=0 deaths; ( )=1 death; (rate)=2 deaths; [rate]=3 deaths. aAge-adjusted death rates per 10,000 person-years standardized to 1980 U.S. population. SOURCE: Thun et al., 1997. Reprinted with permission from author.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction TABLE 13–2 Time Since Quitting and Age-Adjusted and Multivariate RRs of Fatal Coronary Heart Disease and Nonfatal Myocardial Infarction, Compared with Current Smokers.a   Years Since Quitting Event Never Smoker Current Smoker <2 2–4 5–9 10–14 ≥15 Fatal coronary heart disease   cases 49 123 7 9 14 4 13 RRb 0.24 1.00 0.53 0.68 0.68 0.26 0.31   (0.18–0.33)   (0.25–1.12) (0.35–1.34) (0.39–1.19) (0.10–0.65) (0.18–0.53) RRc 0.23 1.00 1.47 0.58 0.72 0.28 0.32   (0.17–0.33)   (0.42–5.20) (0.23–1.44) (0.36–1.42) (0.09–0.87) (0.16–0.66) Nonfatal myocardial infarction   cases 166 418 36 22 26 13 41 RRb 0.26 1.00 0.85 0.51 0.40 0.26 0.29   (0.22–0.30)   (0.60–1.19) (0.34–0.78) (0.27–0.59) (0.15–0.43) (0.21–0.39) RRc 0.24 1.00 0.81 0.43 0.38 0.26 0.27   (0.20–0.28)   (0.51–1.29) (0.25–0.74) (0.23–0.62) (0.13–0.49) (0.18–0.41) Total coronary heart disease   cases 215 541 43 31 40 17 54 RRb 0.25 1.00 0.77 0.55 0.47 0.26 0.29   (0.22–0.30)   (0.57–1.05) (0.39–0.79) (0.34–0.64) (0.17–0.40 (0.23–0.38) RRc 0.24 1.00 0.75 0.46 0.44 0.26 0.28   (0.20–0.28)   (0.49–1.15) (0.29–0.74) (0.30–0.66) (0.14–0.45) (0.20–0.40) NOTE: RR=relative risk. aMissing for 29 cases, including 6 fatal coronary heart disease and 23 nonfatal myocardial infarction. bAge-adjusted RR. cAdjusted for age in 5-year intervals, during follow-up period (1976–1978, 1978–1980, 1980–1982, 1982–1984, 1984–1986, or 1986–1988), history of hypertension, diabetes, high cholesterol levels, body mass index, past use of oral contraceptives, menopausal status, postmenopausal estrogen therapy, parental history of myocardial infarction before age 60, and daily number of cigarettes consumed. SOURCE: Kawachi et al., 1994. Copyright (1994), American Medical Association.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction FIGURE 13–1 Risk of total stroke by time since quitting. NOTE: Age-adjusted relative risk of total stroke in relation to time since stopping smoking. Current smoker was the reference category. Error bars represent 95% confident intervals. SOURCE: Kawachi et al., 1993. Copyright (1993), American Medical Association. habit confers a worse prognosis. Cessation of smoking after coronary angioplasty or vascular surgery reduces the rate of restenosis by one-third. Thus, there is a major incentive for smoking cessation in this group of patients. When efforts to cease smoking are effective, they probably confer a greater benefit than any pharmacological or surgical intervention aimed at coronary disease. Overall, these observations are encouraging for the motivation to quit. The decline of risk upon smoking cessation can be variable in different risk groups and according to behaviors during cessation, potentially affording insight into interindividual differences in mechanisms relevant to healing smoking-induced cardiovascular injury. An initial interpretation of these data suggested that acute factors, such as hemostatic activation, dominated over more gradual processes, such as occlusive atherosclerotic

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction disease contributed to the smoking-induced CVD burden. It is now appreciated that anatomic atherosclerosis may also restructure toward more normal vessels at rates comparable to the clinical and epidemiological findings, bringing vascular factors relevant to plaque stability into consideration. In summary, the kinetics of declining CVD risk after smoking cessation do not serve to discriminate easily between hemostatic and other vascular factors as mediators of smoking-induced disease. However, the pattern of decline in CVD risk after quitting suggests that CVD may offer a particular advantage in assessing tobacco-related harm reduction over a reasonable time. That is, patterns of change in morbidity and mortality rates after changes from a conventional to a risk reduction tobacco product may help reveal whether lower toxic exposures are actually being achieved and whether they lead to altered CVD outcomes, without waiting the decades necessary to evaluate the outcomes of smoking these products beginning from initiation of the smoking habit. The issues of compensation, nicotine dose-response relationships, and aspects of nicotine-related cardiovascular risk are discussed in Chapter 9. Smoking and Other Cardiac Risk Factors Cigarette smoking, hypercholesterolemia, and hypertension have been the most extensively studied risk factors for CAD. The risk of CAD imposed by cigarette smoking is magnified by the presence of several other factors that cause coronary heart disease. Cigarette smoking alone imposes a risk for CHD that is independent of other risk factors. However, smoking in conjunction with another risk factor increases the actual rate of coronary heart disease events to a greater extent than smoking alone, and these risk factors may work additively or geometrically. In one large study (The Pooling Project Research Group, 1978), smoking increased the ten-year rate of a first CAD event (MI or sudden cardiac death) by 31 per 1,000 persons when neither hypercholesterolemia nor hypertension was present. In conjunction with either hypercholesterolemia or hypertension, cigarette smoking increased the rate by 49 per 1,000 persons, and when both hypercholesterolemia and hypertension were present, the superimposition of smoking increased the rate by 97 per 1,000 persons. In women, there is a tenfold increase in the risk of MI among oral contraceptive users who smoke. Therefore, hypercholesterolemia, hypertension, and oral contraceptive use provide an incentive to not smoke or to cease smoking that exceeds the abundant benefit of avoiding this addiction in the rest of the population. Further, control of elevated cholesterol and high blood pressure reduces the risk of CAD (Brown, 2000; Mormando, 2000; The sixth report, 1997), as does smoking cessation.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction The pathophysiological impact of various environmental exposures and risk factor states may be modified by host genetic factors. For example, a certain polymorphism in coagulation Factor V (Q506) confers resistance to interaction with the endogenous antithrombotic protein activated protein C. Following presentation with an acute coronary syndrome, smokers with this polymorphism have an increased risk of MI and death compared to smokers with a normal genotype, extending to at least two years after the initial event (Holm et al., 1999). Another example is the interaction between smoking and the guanosine-adenosine at the G455A polymorphism in the b-fibrinogen gene. This polymorphism is associated with higher levels of circulating fibrinogen, which in turn have been associated with increased risk of CAD (Humphries et al., 1999). This association is more pronounced in smokers (Green et al., 1993; Humphries et al., 1999). Similarly, polymorphisms in the coagulation factor VII gene have been associated with reductions in risk of CAD (Donati et al., 2000). Cigarette smoking interacts to a variable degree with genes related to other aspects of cardiovascular risk, including antioxidant enzymes such as paraoxonase (Sen-Banerjee et al., 2000), apoliprotein B (Glisic et al., 1995), DNA repair genes (Abdel-Rahman and El-Zein, 2000), and proteins that regulate the availability of cardiotoxic autacoids such as the serotonin transporter (Arinami et al., 1999). Finally, the cardiovascular hazards of tobacco may be modulated by the presence of functionally important polymorphisms in enzymes that detoxify harmful constituents of tobacco smoke (Li et al., 2000). Clearly, emerging information about genetic polymorphisms that are of functional significance and relevance to the cardiovascular system will afford an increasing opportunity to understand and predict the effect of smoking on CVD risk at the individual level. Environmental Tobacco Smoke There is considerable evidence that exposure to environmental tobacco smoke (ETS; passive smoking) has an adverse effect on cardiovascular health (Kawachi et al., 1997a). Pooled results of epidemiological studies indicates a 20% excess coronary heart disease death rate among nonsmoking spouses of smokers (Steenland et al., 1996). As many as 40,000 deaths from MI each year may be the result of passive smoking. The mechanisms linking ETS exposure and cardiovascular disease are probably similar to those for active smoking. Pathophysiology A review of the mechanisms linking cigarette smoking and coronary heart disease must consider the fact that whereas smoking accelerates

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction coronary atherosclerosis, it has an even greater effect on the process that abruptly converts atherosclerosis to the acute ischemic events of MI, unstable angina, and sudden cardiac death. The effect of chronic smoking on the initiation of acute ischemic events appears to be largely reversible, given the substantial and rapid reduction in the incidence of acute ischemic events after smoking cessation. Although there is likely overlap between the mechanisms by which smoking accelerates atherosclerosis and promotes acute ischemic events, it is useful to consider these adverse effects of smoking separately. Acceleration of Atherosclerosis As for other risk factors, vascular endothelial dysfunction likely plays a central role in the promotion of atherosclerosis in chronic smokers (FitzGerald et al., 1988; Heitzer et al., 1996a). Extensive endothelial abnormalities are present in the umbilical arteries of infants born to smoking mothers, and lesions of endothelial cells, subendothelial damage, and platelet adhesion have been described in vessels of experimental animals exposed to cigarette smoke. Increased in vivo prostacyclin biosynthesis and functional abnormalities of vascular endothelium also result from cigarette smoking. Impaired endothelium-dependent vasodilatation in both forearm and coronary vascular beds has been demonstrated even in young smokers (Campisi et al., 1998; Heitzer et al., 1996b; Zeiher et al., 1991). These functional abnormalities may be due to smoking-induced inhibition of nitric oxide (NO) release (Campisi et al., 1999; Kugiyama et al., 1996) or to acceleration of NO breakdown. Structural endothelial damage may result either from a direct toxic effect of nicotine or other components of cigarette smoke on endothelial cells or from smoking-induced oxidative stress (Heitzer et al., 1996a, b). Smokers have reduced levels of antioxidant vitamins and increased levels of oxidized low-density lipoprotein (LDL), a potent inhibitor of endothelial function (Heitzer et al., 1996b; Morrow et al., 1995). Smoking-induced acute and chronic systemic hemodynamic changes may also contribute to vascular endothelial dysfunction. For example, some but not all studies suggest that smoking a single cigarette causes an acute rise in systemic blood pressure and heart rate, and chronic smoking results in a persistent elevation in daytime blood pressure. The effect of chronic smoking on blood pressure is more complex as outlined later. Smoking is associated with lipid abnormalities that may contribute to the development of atherosclerosis (Duthie et al., 1993; Craig et al., 1989). In addition to increased levels of oxidized low-density lipoprotein, smoking produces an increase in very low density lipoprotein (VLDL) and triglycerides and a reduction in high-density lipoprotein (HDL) levels.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Smoking has been shown to increase monocyte adhesion to endothelial cells, an important early event in atherosclerosis (Adams et al., 1997; Weber et al., 1996). Additional factors that may contribute to the development of coronary and other atherosclerotic events in smokers include smoking-induced platelet activation, increased fibrinogen levels, and increased blood viscosity. Promotion of Acute Coronary Events In addition to the effect of smoking on the development of atherosclerosis, there is a dramatically increased risk of acute ischemic events, including MI and sudden death. Acute systemic and coronary hemodynamic effects of smoking are likely to play an important role in the development of these ischemic events. After smoking a single cigarette, systemic arterial pressure, heart rate, and myocardial contractility increase, resulting in a rise in myocardial oxygen demand (Cryer et al., 1976; Nicod et al., 1984). Simultaneously, in patients with atherosclerosis, smoking causes acute vasoconstriction of both conduit and resistance coronary vessels, with a decrease in coronary blood flow (Czernin et al., 1995; Nicod et al., 1984; Quillen et al., 1993). Even in the absence of a hemodynamically significant stenosis, coronary flow may fall by more than 20% despite a significant increase in myocardial oxygen demand. In some individuals, smoking causes intense focal vasoconstriction or spasm that can lead to myocardial ischemia (Moauad et al., 1986). These acute hemodynamic effects of smoking in the coronary bed are most likely adrenergically mediated, since they can be prevented by α-adrenergic blockade (Winniford et al., 1986). Adrenergic stimulation has been shown to cause exaggerated coronary vasoconstriction in the setting of endothelial dysfunction (Vita et al., 1992; Zeiher et al., 1989). Plasma norepinephrine and epinephrine levels rise acutely after smoking (Cryer et al., 1976); this catecholamine release may lower arrhythmia threshold and increase the risk of sudden death. In addition to lowering anginal threshold, repeated episodes of coronary vasoconstriction and elevations of systemic arterial pressure may increase hemodynamic stresses at the site of an atherosclerotic plaque. An increase in shear stress at the site of a vulnerable plaque is considered a potentially important cause of plaque rupture. Smoking has also been shown to exacerbate the cardiovascular effects of cocaine (Moliterno et al., 1994). Both the epicardial coronary constriction and the increase in myocardial oxygen demand caused by cocaine are potentiated by concomitant smoking, perhaps increasing the risk of MI and sudden death attributed to cocaine use.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction TABLE 13–4 Age-Adjusted RRs of Stroke (Fatal and Nonfatal Combined), by Daily Number of Cigarettes Consumed Among Current Smokersa   Cigarettes Smoked per Day Among Current Smokers Event Never Smoker Former Smoker Current Smoker 1–14 15–24 25–34 ≥35 Total stroke cases 126 114 208 40 92 38 34 RRb 1.00 1.34 2,58 1.79 2.84 2.70 4.23   (1.04–1.73) (2.08–3.19) (1.26–2.54) (2.19–3.67) (1.91–3.84) (2.99–6.00) RRc 1.00 1.35 2.73 2.02 3.34 3.08 4.48   (0.98–1.85) (2.18–3.41) (1.29–3.14) (2.38–4.70) (1.94–4.87) (2.78–7.23) Subarachnoid hemorrhage cases 19 25 64 13 21 17 11 RRb 1.00 2.01 4.96 3.68 4.05 7.31 8.28   (1.12–3.61) (3.13–7.87) (1.91–7.11) (2.30–7.14) (4.15–12.85) (4.45–15.42) RRc 1.00 2.26 4.85 4.28 4.02 7.95 10.22   (1.16–4.42) (2.90–8.11) (1.88–9.77) (1.90–8.54) (3.50–18.07) (4.03–25.94) Ischemic stroke cases 85 70 120 23 58 19 18 RRb 1.00 1.20 2.25 1.54 2.69 2.06 3.43   (0.88–1.65) (1.72–2.95) (0.98–2.44) (1.95–3.72) (1.27–3.36) (2.13–5.51) RRc 1.00 1.27 2.53 1.83 3.57 2.73 3.97   (0.85–1.89 (1.91–3.35) (1.04–3.23) (2.36–5.42) (1.49–5.03) (2.09–7.53) Cerebral hemorrhage cases 19 16 18 4 10   RRb 1.00 1.27 1.46 1.18 2.01 1.18     (0.66–2.44) (0.77–2.78) (0.40–3.46) (0.94–4.28) (0.41–3.46) RRc 1.00 1.24 1.24 1.68 2.53 1.41   (0.64–2.42) (0.64–2.42) (0.34–5.28) (0.71–6.05) (0.39–5.05) NOTE: RR=relative risk. aNumber unknown for four cases, including two subarachnoid hemorrhage and two ischemic stroke. bAge-adjusted RR. cAdjusted for age in five-year intervals, during follow-up period (1976–1978, 1978–1980, 1980–1982, 1982–1984, 1984–1986, or 1986–1988), history of hypertension, diabetes, high cholesterol levels, body mass index, past use of oral contraceptives, postmenopausal estrogen therapy, and age at starting smoking. dThese two categories were combined due to small numbers. SOURCE: Kawachi et al., 1993. Copyright (1993), American Medical Association.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction there is evidence that the increase in biomarkers of oxidant stress, platelet activation, and inflammation (Benowitz et al., 1993), all of potential mechanistic relevance to tobacco-related cardiovascular injury, rapidly falls toward the normal range on quitting cigarettes. The offset kinetics of more functional surrogates, such as endothelial dysfunction, remain to be determined in smokers. In summary, the data from quitters encourage the prospect that a graded reduction in cardiovascular risk and in biomarkers of this risk may accompany a reduction in the number of cigarettes smoked in pursuit of a harm reduction strategy. It is possible, indeed likely, that individuals and perhaps populations, differ in their susceptibility to tobacco-induced cardiovascular risk and, indeed, in their potential benefit from a harm reduction strategy. Data from quitting studies indicate a considerable variance in the rate of offset of risk, which declines with time. No data are available to address such issues across ethnic groups or gender. Acquisition of such information and research on the environmental and genetic factors that condition interindividual variability in exposure-risk relationships are necessary. Utility in a Preclinical Setting Studies in cell culture and model systems can afford much needed information on tobacco-related cardiovascular risk. These might include a profiling of gene expression and translation in cardiovascular tissues in response to cigarette smoke, constituents of smoke, and potential risk reduction substituents. These might identify proteins of potential functional relevance to the transduction of cardiovascular risk. Such studies might be coupled with gene inactivation and overexpression studies to address the role of these proteins in vivo. Similarly, studies of exposure to cigarette smoke or to discrete constituents of smoke might be deployed to investigate effects on atherosclerosis progression, susceptibility to vascular injury, thrombotic stimuli, graft rejection, cardiovascular development, or endothelial dysfunction in model systems such as mice. Studies of cardiovascular genomics and ultimately proteomics can also be extended to model systems to investigate gene expression and translation in response to exposure to tobacco-related products in vivo. These observations may, in turn, be related to the pattern of gene expression and translation in cardiovascular tissues obtained from cigarette smokers. Biomarkers of Tobacco-Related Disease The predominant mechanisms by which cigarette smoking induces cardiovascular injury is unknown. However, small studies in smokers of potentially relevant biomarkers of platelet and vascular activation, lipid

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction peroxidation, and inflammation afford evidence of a dose-response relationship and a decline on quitting. There is even evidence of a signal in individuals exposed to ETS in the case of some of these markers. More mechanism-based clinical studies are required to confirm and expand these findings. Where possible, these should be related to surrogate measurements of cardiovascular function, such as hemodynamics, flow-mediated endothelial function and estimates of plaque progression by ultrasound or EBCT. Furthermore, biomarker studies can usefully be integrated into many studies in model systems (see above) as well as studies of clinical outcome (discussed below) to afford their ultimate validation. Clinical Assessment of Tobacco-Related Disease The time course of offset of myocardial infarction and stroke in people who stop smoking suggests that cardiovascular disease represents a tractable scenario in which one might evaluate harm reduction strategies. Clearly, assessment of the impact of such events can occur in a fairly reasonable time compared to that which is possible for cancer or lung disease. RESEARCH AGENDA Determine whether physiological and biochemical measures that are altered by tobacco products may be used as indicators of disease risk and as a means to distinguish various forms of tobacco use in a broad range of exposures (doses), including: activation of platelet function; endothelial function; endothelial thickening and plaque formation; blood pressure and heart rate alterations; vascular aneurysm formation; vascular thrombosis (arterial and venous); cardiac electrophysiology, including ventricular and atrial ectopy, heart rate variability, and variations in conduction times, especially QT intervals; and other risk factors for cardiovascular disease including lipid and carbohydrate abnormalities, homocysteine, folic acid and antioxidant vitamins, markers of inflammation, and immune function. Based on current evidence, oxidative stress seems likely to play an important role in mediating the cardiovascular effects of smoking. Determining reliable biomarkers of oxidative stress and the interaction of un

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction stable oxygen intermediates with lipids, proteins, and DNA should receive high priority. Since inflammation is a proximate cause of oxidative stress, further work on biomarkers of inflammation such as C-reactive protein, cytokines, and acute-phase proteins and the effects of tobacco exposure appears to be an important research direction. Similarly, further assessment of the effects of various tobacco products on biomarkers of hemostatic activation and platelet function should be fruitful in understanding and predicting atherogenesis. Develop studies to determine whether new biomarkers, such as products of lipid peroxidation and corresponding adducts to DNA, and products of arachidonic acid metabolism can serve as intermediate indicators (risk factors) of cardiovascular disease risk related to different tobacco products, and tobacco-related PREPs in particular. Through well-designed clinical trials, determine the ability of antioxidant or related therapies to counter the tobacco-related perturbations due to oxidative stress that are likely to be caused by both conventional and new tobacco products. Develop long-term observational studies in individuals exposed to conventional and modified tobacco products primarily and secondarily (i.e., passive smoking), better to identify actual risks for cardiovascular disease, including dose-response characteristics. Included should be evaluations of the variables described in items 1 and 2, subsequent cardiovascular disease development, and potential differences in different tobacco or smoking products. Further apply modern in vitro and other model systems, and ex vivo in humans, to assist in elucidating the comparative toxicology or adverse effects of cigarette smoke and PREPs. Such studies might include the use of gene array and proteomic technologies to study differential gene expression and translation; the use of chronic exposures to investigate effects on atherosclerosis progression, response to thrombotic and arrhythmogenic stimuli, and cardiovascular disease development; and studies of the effects of cigarette smoke and its constituents on the function and integrity of cardiovascular cells in vitro, including platelets, leukocytes, endothelial cells, vascular smooth muscle cells, and myocytes. Apply modern genomic and proteomic analyses to elucidate the array of genes of potential relevance to cardiovascular hazards differentially induced by exposure to conventional tobacco products and PREPs. Utilize such techniques as transgenic and knockout model systems to elucidate the relevance of single genes to vascular injury induced by cigarette smoke and its discrete constituents, including nicotine. Assess the possibility of allelic varia

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction tion in such genes and its relevance to smoking-induced cardiovascular disease risk. Continue to elucidate further aspects of the vascular biology of nicotine in view of its effects on flow-mediated vasodilation and the particular susceptibility of young smokers to prolonged exposure to nicotine products. Further careful evaluation of the dose-related effects of nicotine on platelet, leukocyte, hemostatic, and endothelial function and subsequent vascular injury, thrombogenesis, and atherogenesis is indicated. REFERENCES Abdel-Rahman SZ, El-Zein RA. 2000. The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett 159(1):63–71. Adams MR, Jessup W, Celermajer DS. 1997. Cigarette smoking is associated with increased human monocyte adhesion to endothelial cells: reversibility with oral L-arginine but not vitamin C. J Am Coll Cardiol 29 (491). Allred EN, Bleecker ER, Chaitman BR, et al. 1989. Short-term effects of carbon monoxide exposure on the exercise performance of subjects with coronary artery disease. N Engl J Med 321:1426. Anthonisen NR, Connett JE, Kiley JP, et al. 1994. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 272(19):1497–1505. Arinami T, Ohtsuki T, Yamakawa-Kobayashi K, et al. 1999. A synergistic effect of serotonin transporter gene polymorphism and smoking in association with CHD. Thromb Haemost 81(6):853–856. Aronow WS. 1981. Aggravation of angina pectoris by two percent carboxyhemoglobin. Am Heart J 101:154. Aronow WS, Stemmer EA, Zweig S. 1979. Carbon monoxide and ventricular fibrillation threshold in normal dogs. Arch Environ Health 34:184. Audoly LP, Rocca B, Fabre JE, et al. 2000. Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo. Circulation 101(24):2833–2840. Benedetti A, Comporti M, Esterbauer H. 1980. Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids. Biochim Biophys Acta 620(2):281–296. Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. 1993. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol 22(4):1159–1167. Blake KV, Gurrin LC, Evans SF, et al. 2000. Maternal cigarette smoking during pregnancy, low birth weight and subsequent blood pressure in early childhood. Early Hum Dev 57(2):137–147. Bostrom L, Linder LE, Bergstrom J. 1999. Smoking and cervicular fluid levels of IL-6 and TNF-alpha in periodontal disease. J Clin Periodontol 26(6):352–357. Brash AR, Jackson EK, Saggese CA, Lawson JA, Oates JA, FitzGerald GA. 1983. Metabolic disposition of prostacyclin in humans. J Pharmacol Exp Ther 226(1):78–87. Brown WV. 2000. Cholesterol lowering in atherosclerosis. American Journal of Cardiology 86(4B):29H–32H.

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