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13 Cardiovascular Disease he impact of cigarette smoking on the U.S. national burden of T cardiovascular disease (CVD) has been well documented. Each year, about 150,000 cardiovascular deaths are attributable to ciga- rette smoking, and of these, about 30,000 are attributable to environmen- tal cigarette smoke exposure among nonsmokers (McGinnis and Foege, 1999, Taylor et al., 1992). The cardiovascular burden of smoking is ampli- fied substantially because smoking significantly increases the risk for many types of cardiovascular morbidity: myocardial infarction (MI), sud- den 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 cessa- tion 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 cardio- vascular-related illnesses. Approximately one in five deaths from cardio- vascular 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 in- formation available, more needs to be known about the mechanisms of smoking-induced CVD injury. This is of particular importance because 470
CARDIOVASCULAR DISEASE 471 one constituent of tobacco smokeânicotineâis 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 smok- ing reduction. This necessitates a detailed consideration of the cardiovas- cular pharmacology of nicotine. The results of the Lung Health Study (Anthonisen et al., 1994) is notable in the consideration of the cardiovas- cular 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 com- plications. Furthermore, it is pertinent to strategies being deployed by tobacco product manufacturers to eliminate selectively discrete constitu- ents of tobacco and cigarettes and then market them as âsafer.â This im- plies a knowledge of the relative contributions of a myriad of tobacco constituents to CVD, which simply does not exist. This chapter summa- rizes 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 re- search. 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 relation- ship 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 dis- ease emerges from integration of data from epidemiological and patho- physiologic 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 coro- nary events. Acute coronary events represent an abrupt transition from stable chronic CAD to one of the major consequences of ischemia: unstable an- gina, myocardial infarction, and sudden cardiac death. Abundant evi- dence 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).
472 CLEARING THE SMOKE Coronary Atherosclerosis Age is a powerful predictor of coronary atherosclerosis, and angio- graphic studies indicate that the relative risk for coronary stenosis associ- ated 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 atheroscle- rosis 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 atheroscle- rotic 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 pro- spective 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 indi- cates 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-
CARDIOVASCULAR DISEASE 473 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 smok- ing rates to CVD outcomes, a dose-response has been observed. Cumula- tive exposures in epidemiological studies are not easy to determine be- cause 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 ciga- rettes 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 dis- ease 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 smok- ing, 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 ânever smokers.â 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 indi- viduals over 60 years of age, a decrease in risk for ischemic heart disease postcessation has been found, though smaller than for younger individu- als (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
474 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 â â â â â â â â () â () â () â 35-39 (0.9) () â â â â â () â () â () â â 40-44 [1.3] 0.6 () â () â (10.4) (1.4) [5.7] ( ) 12.4 â (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 â 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 â 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] â 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) â () 85+ 329.7 265.5 363.3 167.1 308.6 479.4 430.0 333.9 852.3 () () () â â 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: â=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.
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 Never Current Event Smoker Smoker <2 2-4 5-9 10-14 â¥15 Fatal coronary heart disease cases 49 123 7 9 14 4 13 RR b 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) RR c 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 RR b 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) RR c 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 RR b 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) RR c 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. 475 SOURCE: Kawachi et al., 1994. Copyright (1994), American Medical Association.
476 CLEARING THE SMOKE 1.4 1.2 Relative Risk of Total Stroke 1.0 0.8 0.6 0.4 0.2 0 Current <2 2-4 5-9 â¥10 Never Smoker Smoker Years Since Quitting 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 af- fording 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
CARDIOVASCULAR DISEASE 477 disease contributed to the smoking-induced CVD burden. It is now ap- preciated 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 con- sideration. 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 expo- sures are actually being achieved and whether they lead to altered CVD outcomes, without waiting the decades necessary to evaluate the out- comes of smoking these products beginning from initiation of the smok- ing habit. The issues of compensation, nicotine dose-response relation- ships, 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. How- ever, 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 in- creased the ten-year rate of a first CAD event (MI or sudden cardiac death) by 31 per 1,000 persons when neither hypercholesterolemia nor hyper- tension 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 contracep- tive 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.
478 CLEARING THE SMOKE The pathophysiological impact of various environmental exposures and risk factor states may be modified by host genetic factors. For ex- ample, a certain polymorphism in coagulation Factor V (Q506) confers resistance to interaction with the endogenous antithrombotic protein acti- vated protein C. Following presentation with an acute coronary syn- drome, 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 seroto- nin 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 poly- morphisms that are of functional significance and relevance to the cardio- vascular 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 to- bacco smoke (ETS; passive smoking) has an adverse effect on cardiovas- cular 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
CARDIOVASCULAR DISEASE 479 coronary atherosclerosis, it has an even greater effect on the process that abruptly converts atherosclerosis to the acute ischemic events of MI, un- stable 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 is- chemic 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 abnor- malities 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 dam- age may result either from a direct toxic effect of nicotine or other compo- nents 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 lipo- protein (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 dys- function. 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, smok- ing produces an increase in very low density lipoprotein (VLDL) and triglycerides and a reduction in high-density lipoprotein (HDL) levels.
480 CLEARING THE SMOKE 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 develop- ment of coronary and other atherosclerotic events in smokers include smoking-induced platelet activation, increased fibrinogen levels, and in- creased blood viscosity. Promotion of Acute Coronary Events In addition to the effect of smoking on the development of atheroscle- rosis, there is a dramatically increased risk of acute ischemic events, in- cluding MI and sudden death. Acute systemic and coronary hemody- namic 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 in- crease, 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 Î±-adrenergic blockade (Winniford et al., 1986). Adrenergic stimulation has been shown to cause exaggerated coronary vasoconstriction in the setting of endothe- lial dysfunction (Vita et al., 1992; Zeiher et al., 1989). Plasma norepineph- rine 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 coro- nary 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 constric- tion 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.
CARDIOVASCULAR DISEASE 481 Inhaled carbon monoxide (CO) in cigarette smoke binds to hemoglo- bin, reducing oxygen delivery to myocardial cells. The carbon monoxide levels found in smokers have been shown to lower anginal threshold (Allred et al., 1989; Aronow, 1981) and increase ventricular fibrillation threshold (Aronow et al., 1979). Carbon monoxide may also have a delete- rious effect on vascular endothelial cells (Thom et al., 1997). Coronary thrombosis plays a major role in acute coronary events, and smoking is associated with several changes in the hemostatic system that lead to a hypercoagulable state. These hemostatic changes include an increase in fibrinogen (De Maat et al., 1996), red cell mass, and blood viscosity; platelet activation with thromboxane A2 release (Benowitz et al., 1993); and impaired release of tissue plasminogen activator from en- dothelial cells (Newby et al., 1999). Most research on the effects of smoking on the cardiovascular system has focused specifically on nicotine and carbon monoxide, but there are more than 4,000 other components in cigarette smoke, some of which may also contribute to smoking-induced vascular disease (Penn and Snyder 1996). Coronary Vasospasm A much less common cause of ischemia than plaque rupture, primary coronary vasospasm usually manifests as variant angina but may also cause MI and sudden cardiac death. Coronary vasospasm is strongly as- sociated with cigarette smoking (Okasha et al., 2000). EXTRACARDIAC VASCULAR DISEASE Smoking markedly accelerates atherosclerosis in the abdominal aorta, and occlusive disease of its branches is increased as well (Reed et al., 1987; PDAY, 1990). Aortic aneurysm, peripheral vascular disease, and renal artery stenosis are increased in smokers. Renovascular hypertension should be strongly suspected in cigarette smokers who have severe hy- pertension. Cigarette smoking is an independent risk factor in the devel- opment of atherosclerosis in the internal pudendal and penile arteries of young men with impotence. Two types of stroke are increased in cigarette smokers (U.S. DHHS, 1989). Smoking is a risk factor for cerebral infarction, and the magnitude of risk increases with greater smoking exposure. This occurs in conjunc- tion with an increase in atherosclerosis of the carotid arteries in smokers. Subarachnoid hemorrhage is markedly increased in cigarette smokers, and in women who take oral contraceptives, this risk if further enhanced.
482 CLEARING THE SMOKE OTHER VARIABLES INFLUENCED BY SMOKING Blood Pressure The effect of cigarette smoking on chronic blood pressure levels in uncertain, in part because of concomitant effects of lower body mass in- dex (BMI) and more frequent alcohol consumption among smokers. Some studies have reported lower ambulatory blood pressure levels (Mikkelsen, et al., 1997; Okasha et al., 2000), while others have reported increases (Minami et al., 1999; Mundal et al., 1997). Findings may depend in part on when in the day pressure recordings are made and whether smoking is assessed by self-report or by biochemical verification (Istvan et al., 1999). Smoking in healthy volunteers has been reported to alter the change in blood pressure response to changes in body position (Nardo et al., 1999) and to cause abnormal baroreceptor function (Gerhardt et al., 1999). Of note, maternal smoking has been associated with increased blood pres- sure levels in the children of these pregnancies (Blake et al., 2000). Insulin Resistance The insulin resistance syndrome, as well as insulin resistance per se, has been associated with increased risk of atherosclerotic vascular disease, independent of most other major risk factors and is a risk factor for non- insulin-dependent diabetes mellitus (NIDDM) (Mikhailidis et al., 1998). Increased insulin resistance has been associated with increased intimal- medial thickening in the presence of vasospastic angina (Shinozaki et al., 1997). The syndrome occurs in healthy young men and is sixfold more common in cigarette smokers (Tahtinen et al., 1998). Insulin resistance is also increased among smokers with existing NIDDM (Targher et al., 1997). Smoking cessation improves insulin sensitivity among healthy middle- aged men (Eliasson et al., 1997). Other Lipid or Lipoprotein Measures Lipoprotein (a) (Lp(a)) cholesterol levels are positively and indepen- dently correlated with the risk of coronary events in some but not all prospective studies (Seman et al., 1999). Cigarette smoking does not ap- pear to alter blood Lp(a) levels (Chien et al., 1999; Kamboh et al., 2000). However, smoking appears to alter the ratio of LDL subfractions in the direction associated with increased CVD risk (Griffin et al., 1994). Inflammation There is substantial evidence that inflammation plays a role in the pathogenesis of atherosclerotic lesions in many parts of the arterial tree
CARDIOVASCULAR DISEASE 483 and that elevated blood levels of cytokines such as interleukin-6 (IL-6) and C-reactive protein (CRP) are associated with increased risk of coro- nary events (Ridker et al., 2000; Koenig et al., 1999). Smoking is associated with increased levels of CRP, suggesting that inflammation is one mecha- nism by which smoking promotes the pathogenesis of these lesions. Smok- ing has also been shown to increase local tissue levels of some cytokines in organs other than the vascular tree, such as tumor necrosis factor-alpha (TNF-Î±) in gingival cervicular fluid, but not IL-6 (Bostrom et al., 1999) or IL-8 and ICAM-1 in small respiratory airways (Takizawa et al., 2000). Homocysteine Blood homocysteine levels have been related to an increased risk of coronary heart disease and other atherosclerotic diseases in several stud- ies (Saw, 1999). Cigarette smoking has been shown to be associated with higher blood homocysteine levels, both in the basal state and after a methionine load (Reis et al., 2000; Nygard et al., 1998). In a study in which the dose-response was explored, there was a clear positive correlation between the number of cigarettes smoked and blood homocysteine levels. This raises the possibility that smoking cessation may have its effects in part through this mechanism and that homocysteine level might be devel- oped as a biomarker of smoking exposure. SURROGATE MARKERS The identification and validation of quantitative indices that reflect biochemical mechanisms of cardiovascular injury caused by cigarette smoking would be useful. Such surrogate indices might permit the study of both progression and regression of smoking-related cardiovascular dis- ease and clarify the factors that contribute to interindividual differences in susceptibility to such complications. They might also be useful corre- lates of the relative bioavailability of individual constituents of cigarette smoke and aid in the evaluation of harm reduction strategies, including potentially âsaferâ smoking devices and nicotine replacement therapies. They might also prove of value in assessment of the cardiovascular risk of secondhand smoke. Presently, little information is available relating to the mechanisms of cigarette-induced cardiovascular damage, but the emergence of promising technologies relating to potentially important mechanisms, including platelet activation and oxidative stress, illustrates the potential of the approach. Cigarette smoking causes platelet activation in vivo, as reflected by an accelerated platelet turnover time (Fuster et al., 1981). However, the development of noninvasive approaches to assessment of platelet activa-
484 CLEARING THE SMOKE tion facilitates repeated investigation of the effects of smoking on platelet function. Platelets are extremely susceptible to platelet activation ex vivo during blood sampling, and this has constrained the usefulness of circu- lating biomarkers of platelet activation, such as circulating platelet aggre- gates and Î²-thromboglobulin or, indeed, of more contemporary ap- proaches such as P selectin expression on platelets ex vivo. Studies of the platelet aggregation response ex vivo have also proven uninformative. Platelets activated by cigarette smoke in vivo might be less available for harvesting for such ex vivo studies. Indeed, platelet responses to adenos- ine 5Â´-diphosphate (ADP) were reportedly diminished ex vivo in smokers in one large-scale epidemiological study (Meade et al., 1985). By contrast, urinary excretion of the 2,3-dinor and 11-hydro metabolites of thrombox- ane have proven to be noninvasive indices of platelet activation in vivo (FitzGerald et al., 1983). Thus, phasic increases in excretion of these me- tabolites occur during the ischemic episodes of unstable angina and in patients undergoing therapeutic thrombolysis (Fitzgerald et al., 1988; Lewis et al., 1983), two situations in which the functional importance of thromboxane dependent platelet activation is implied by the therapeutic efficacy of aspirin (Intravenous streptokinase, 1987; Lewis et al., 1983). Excretion of thromboxane metabolites is increased in apparently healthy individuals who smoke and decreases on short-term cessation (Nowak et al., 1987). This observation has been confirmed, both in a large population study and in a case-control study of monozygotic twins dis- cordant for the smoking habit (Lassila et al., 1988; Wennmalm et al., 1991). Interestingly, excretion of the major metabolite of prostacyclin, 2,3-dinor- 6-keto-PGF1Î± (prostaglandin F1Î±) (Brash et al., 1983), is also elevated in chronic cigarette smokers. Prostacyclin, like thromboxane, is a product of cyclooxygenase (COX) catalyzed metabolism of arachidonic acid. While prostacyclin is the major product of COX in endothelial cells, thrombox- ane is the principal product of the same enzyme in platelets. Platelets express exclusively COX-1, and the suppression of thromboxane biosyn- thesis by low-dose aspirin (Nowak et al., 1987) implies that this is the major source of its formation in smokers (Lassila et al., 1988). However, COX-2 in the vessel wall or in infiltrating cells, such as monocyte or macrophages, represents a second theoretical source of thromboxane for- mation. Indeed, COX-2 seems the likely source of prostacyclin formation (Wennmalm et al., 1991; Brash et al., 1983; McAdam et al., 1999), although the effects of selective inhibitors of COX-2 on the formation of either eicosanoid in cigarette smokers remains to be reported. Although ciga- rette smoke reduces the capacity of endothelial cells to form prostacyclin in vitro (Reinders et al., 1986), the capacity of cells to form this and other eicosanoids greatly exceeds actual biosynthetic rates in vivo (FitzGerald et al., 1983). The increment in prostacyclin biosynthesis coincident with
CARDIOVASCULAR DISEASE 485 that of thromboxane is consistent with the capacity of thromboxane ana- logues to evoke its formation by endothelial cells in vitro (Nicholson et al., 1984) and its role as a homeostatic response to accelerated platelet vessel wall interactions in vivo (FitzGerald et al., 1984). Deletion of the prostacyclin receptor increases the response to thrombotic stimuli (Murata et al., 1997). While an abundant literature supports the use of these indi- ces of platelet-vascular interactions, they could be usefully related to other, more functional surrogates of the cardiovascular response to smoking, such as impaired endothelial function (Raitakari et al., 2000) and non- invasive assessment of atherosclerosis progression, using ultrasonogra- phy or electron beam computerized tomography (EBCT) (OâMalley et al., 2000; Raggi et al., 2000). Such surrogates could represent an intermediate link between the noninvasively acquired biochemical indices and true functional outcomes of smoking, such as myocardial infarction and sud- den death. Another mechanism that has been widely implicated in cigarette- induced tissue injury is oxidative stress. Free-radical-catalyzed damage has been suggested to be of relevance to both atherogenesis and tumor progression and, as such, may well be relevant to the harm caused by cigarette smoking. Indeed, cigarette smoke contains abundant radicals, and smoking is known to cause activation of platelets and neutrophils, which may in turn increase radical generation (Pryor, 1997; Shinagawa et al., 1998; Yamaguchi et al., 2000). Until recently, the study of oxidative damage in vivo has been constrained by the specificity of available bio- markers. However, the discovery of isoprostanes (iPs), free-radical- catalyzed products of arachidonic acid (Lawson et al., 1999; Roberts and Morrow, 2000), has transformed this situation. These products are formed initially in situ in the phospholipid domain of cell membranes, where they may be immunolocalized or quantitated directly (Roberts and Mor- row, 2000). Following phospholipase-dependent cleavage, iPs circulate and are excreted in urine. Urinary iPs reflect the oxidant stress attendant on inflammation (McAdam et al., 2000) and are increased in a dose-de- pendent manner in cigarette smokers (Reilly et al., 1996). Some evidence exists suggesting their elevation by secondhand smoke and in the chil- dren of smokers (Sinzinger et al., 2000). Elevated urinary iPs in smokers appear to fall rapidly on quitting (McAdam et al., 2000; Morrow et al., 1995; Reilly et al., 1996; Sinzinger et al., 2000). It is possible that iPs may be of functional relevance to smoking-induced cardiovascular injury besides serving as a marker of the process. Thus, individual iPs may act as inci- dental ligands both at membrane receptors for prostanoids (Kunapuli et al., 1998; Morrow et al., 1995) and at peroxisomal proliferator activated receptors (PPARs) (Audoly et al., 2000). Thus, certain iPs activate platelets via thromboxane receptors in smokers (McNamara et al., 1999) and may,
486 CLEARING THE SMOKE in turn, lead to generation of thromboxane itself, creating a vicious cycle (Davi et al., 1999). In this setting, effective antioxidants might suppress both iP generation and thromboxane biosynthesis. Cigarette smokers are susceptible to depletion of endogenous vitamin C, and supplementation of smokers with vitamin C depresses elevated iPs (Valkonen and Kuusi, 2000). By contrast, their endogenous levels of vitamin E are replete, and exogenous vitamin E does not suppress elevated iPs in smokers (Reilly et al., 1996). Other noninvasive indices of lipid peroxidation, such as 4- hydroxynonenal (Benedetti et al., 1980), and of radical-induced protein (Pennathur et al., 1999) and DNA (Marnett, 2000) damage have begun to emerge in clinical investigation. No information is available on relative effects of these distinct targets for radical-induced damage or their rel- evance to smoking-induced cardiovascular injury. In summary, the examples of urinary thromboxane, prostacyclin, and isoprostanes illustrate the potential value of developing and validating quantitative, noninvasive biochemical indices of the mechanisms of smoking-induced cardiovascular damage and tissue injury in general. Initially, the methodology involved (e.g., mass spectrometry) is often ex- pensive and labor intensive. However, once the proof of principle for such approaches has been established, effort can be rationally devoted to the development of simpler, more widely applicable, but validated meth- odologies, such as enzyme immunoassays. The power of this approach, which can also be applied to animal models (Pratico et al., 1998; Heinecke, 1999), will be greatly enhanced by its integration with surrogate markers of functional impairment and, ultimately, with actual clinical events in the assessment of the cardiovascular risks of smoking. Potential surrogate markers to be used in animal models developed to detect potentially adverse effects of smoking and of the use of potential reduced-exposure products (PREPs) on arteries throughout the body and in the lungs and heart include measurements of platelet activation, blood pressure and heart rate, and oxidative stress. Other surrogate markers that may be utilized in clinical studies include measurements of oxidative stress, measurements of platelet activation, elements of the coagulation system, lipids and lipoproteins, pulmonary function studies, studies of endothelial function, myocardial stress perfusion studies, and periodic evaluation by ultrasound of the carotid, abdominal aortic, and lower- extremity arteries. CONCLUSIONS Dose-Response Relationship Highly informative information on the existence of a dose-response relationship between cigarette exposure and cardiovascular risk comes
CARDIOVASCULAR DISEASE 487 from many studies such as the CPS-2 (Thun et al., 1997) and Harvard Nursesâ Health Studies (Kawachi et al., 1997b). In both instances, there is a relationship between the number of cigarettes smoked and the inci- dence of cardiovascular events. This is illustrated for the incidence of myocardial infarction (Table 13-3) and stroke (Table 13-4). In both cases, the most striking difference is between nonsmokers and individuals who smoke the least number of cigarettes recorded. The relationship becomes somewhat less pronounced as the number of cigarettes smoked per day increases. Interestingly, ex-smokers tend to occupy a space intermediate between nonsmokers and those with the lowest daily smoking frequency. This dose-response curve prompts several considerations. First, there is no persuasive evidence of a threshold below which a cardiovascular risk does not exist. This observation affirms the primary objective of en- couraging smokers to quit completely. Second, the shallow dose-response relationship, with the impression of a plateau, accords with similar obser- vations relating the number of cigarettes smoked and measurements of systemic bioavailability, such as nicotine and cotinine. The same is true of the relationship with CO (Gori and Lynch, 1985). Although this may rep- resent saturation kinetics of nicotine or CO, the most likely explanation is compensation for lower numbers of cigarettes smoked. Thus, the smoker titrates nicotine delivery toward a range of convergence that is reflected by the measurement of nicotine delivery, which in turn, may reflect dose- dependent convergence of the delivery of additional toxic, but unmea- sured, constituents of cigarette smoke. The relative contribution of dis- tinct constituents of cigarette smoke to smoking-related cardiovascular morbidity and mortality is unknown. In this regard, the available infor- mation is incomplete regarding any differences between the dose- response relationship of filter or low-tar versus high-tar or unfiltered cigarettes. Feasibility of Harm Reduction in Therapy There are no data that are directly informative on the issue of harm reduction. Thus, although a dose-response relationship exists for cardio- vascular and cerebrovascular events, we do not know if reducing the number of cigarettes smoked results in a quantitative reduction in the risk of these events. However, the intuitively appealing prospect that this is indeed the case is supported by evidence from individuals who quit smok- ing. Thus, quitting results in a time-dependent reduction in the incidence of myocardial infarction (Table 13-2) and stroke. The latter is most nicely illustrated by data relating to subarachnoid hemorrhage, which was sig- nificantly elevated in women smokers in the Nursesâ Health Study (Fig- ure 13-1). In addition to evidence from such unequivocal clinical events,
TABLE 13-3 Number of Cigarettes Smoked Daily and Age-Adjusted and Multivariate RRs of Fatal Coronary 488 Heart Disease and Nonfatal Myocardial Infarction, Compared with Never Smokersa Never Former Cigarettes Smoked per Day Among Current Smokers Event Smoker Smoker 1-4 8-14 15-24 25-34 35-44 â¥45 Fatal coronary heart disease cases 49 53 4 18 53 28 14 4 RR b 1.00 1.63 1.87 2.78 4.29 5.36 5.56 10.00 (1.11-2.40) (0.69-5.09) (1.66-4.67) (3.00-6.15) (3.53-8.14) (3.26-9.50) (4.35-22.97) RR c 1.00 1.62 <ââââ2.85ââââ> 4.85 6.96 <ââââ7.84ââââ> (1.09-2.40) (1.53-5,32) (3.01-7.81) 3.90-12.43 (3.71-16.57) Nonfatal myocardial infarction cases 166 161 15 56 189 95 54 7 RR b 1.00 1.47 1.97 2.46 4.21 4.87 5.58 4.64 (1.19-1.83) (1.17-3.30) (1.83-3.29) (3.48-5.11) (3.87-6.13) (4.24-7.35) (2.34-9.21) RR c 1.00 1.44 <ââââ2.45ââââ> 4.77 5.21 <ââââ5.32ââââ> (1.16-1.79) (1.69-3.56) (3.64â6.26) (3.73-7.28) (3.61-7.86) Total coronary heart disease cases 215 214 19 74 242 123 68 11 RR b 1.00 5.51 1.94 2.53 4.22 4.97 5.57 5.74 (1.25-1.82) (1.23-3.08) (1.96-3.26) (3.56-5.00) (4.06-6.08) (4.36-7.11) (3.36-9.81) RR c 1.00 1.48 <ââââ2.53ââââ> 4.79 5.49 <ââââ5.49ââââ> (1.22-1.79) (1.84-3.50) (3.78-6.08) (4.10-7.35) (3.87-7.77) NOTE: RR=relative risk. aDaily number smoked was missing for four cases, including two cases of fatal coronary heart disease and two cases of nonfatal myocardial infarction. 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, menopausal status, postmenopausal estrogen therapy, and age at starting smoking. SOURCE: Kawachi et al., 1994. Copyright (1994), American Medical Association.
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 Never Former Current Event Smoker Smoker Smoker 1-14 15-24 25-34 â¥35 Total stroke cases 126 114 208 40 92 38 34 RR b 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) RR c 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 RR b 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) RR c 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 RR b 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) RR c 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 <ââââ4dââââ> RR b 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) RR c 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. 489
490 CLEARING THE SMOKE 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 suscepti- bility to tobacco-induced cardiovascular risk and, indeed, in their poten- tial 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 variabil- ity 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 func- tional 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 vas- cular injury, thrombotic stimuli, graft rejection, cardiovascular develop- ment, or endothelial dysfunction in model systems such as mice. Studies of cardiovascular genomics and ultimately proteomics can also be ex- tended to model systems to investigate gene expression and translation in response to exposure to tobacco-related products in vivo. These observa- tions may, in turn, be related to the pattern of gene expression and trans- lation 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
CARDIOVASCULAR DISEASE 491 peroxidation, and inflammation afford evidence of a dose-response rela- tionship 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 mea- surements 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 inte- grated 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 trac- table 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 1. Determine whether physiological and biochemical measures that are altered by tobacco products may be used as indicators of dis- ease risk and as a means to distinguish various forms of tobacco use in a broad range of exposures (doses), including: â¢ activation of platelet function; â¢ endothelial function; â¢ endothelial thickening and plaque formation; â¢ blood pressure and heart rate alterations; â¢ vascular aneurysm formation; â¢ vascular thrombosis (arterial and venous); â¢ cardiac electrophysiology, including ventricular and atrial ectopy, heart rate variability, and variations in conduction times, especially QT intervals; and â¢ other risk factors for cardiovascular disease including lipid and carbohydrate abnormalities, homocysteine, folic acid and anti- oxidant vitamins, markers of inflammation, and immune func- tion. Based on current evidence, oxidative stress seems likely to play an important role in mediating the cardiovascular effects of smoking. Deter- mining reliable biomarkers of oxidative stress and the interaction of un-
492 CLEARING THE SMOKE stable oxygen intermediates with lipids, proteins, and DNA should re- ceive 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 under- standing and predicting atherogenesis. 2. 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 interme- diate indicators (risk factors) of cardiovascular disease risk related to different tobacco products, and tobacco-related PREPs in par- ticular. 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. 3. Develop long-term observational studies in individuals exposed to conventional and modified tobacco products primarily and sec- ondarily (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 po- tential differences in different tobacco or smoking products. 4. 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 ex- posures to investigate effects on atherosclerosis progression, re- sponse to thrombotic and arrhythmogenic stimuli, and cardiovas- cular disease development; and studies of the effects of cigarette smoke and its constituents on the function and integrity of cardio- vascular cells in vitro, including platelets, leukocytes, endothelial cells, vascular smooth muscle cells, and myocytes. 5. 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 prod- ucts and PREPs. Utilize such techniques as transgenic and knock- out model systems to elucidate the relevance of single genes to vascular injury induced by cigarette smoke and its discrete con- stituents, including nicotine. Assess the possibility of allelic varia-
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