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).

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 coronary 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.

TABLE 13–1

Age-Specific and Age-Adjusted Death Rates From Coronary Heart Disease, by Number of Cigarettes Currently Smoked.

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).

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.

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.

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 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 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.

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 hypertension. Cigarette smoking is an independent risk factor in the development 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 conjunction 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.

OTHER VARIABLES INFLUENCED BY SMOKING

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 disease and clarify the factors that contribute to interindividual differences in susceptibility to such complications. They might also be useful correlates of the relative bioavailability of individual constituents of cigarette smoke and aid in the evaluation of harm reduction strategies, including potentially “safer” 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 activation 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 circulating biomarkers of platelet activation, such as circulating platelet aggregates and β-thromboglobulin or, indeed, of more contemporary approaches 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 adenosine 5′-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 thromboxane have proven to be noninvasive indices of platelet activation in vivo (FitzGerald et al., 1983). Thus, phasic increases in excretion of these metabolites 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 discordant 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-PGF_1α (prostaglandin F_1α) (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, thromboxane is the principal product of the same enzyme in platelets. Platelets express exclusively COX-1, and the suppression of thromboxane biosynthesis 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 formation. 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 cigarette 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 that of thromboxane is consistent with the capacity of thromboxane analogues 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 indices 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 noninvasive assessment of atherosclerosis progression, using ultrasonography or electron beam computerized tomography (EBCT) (O'Malley 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 sudden 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 biomarkers. 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 Morrow, 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-dependent manner in cigarette smokers (Reilly et al., 1996). Some evidence exists suggesting their elevation by secondhand smoke and in the children 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 incidental 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, 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 relevance 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 expensive 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 methodologies, 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 from many studies such as the CPS-2 (Thun et al., 1997) and Harvard Nurses' Health Studies (Kawachi et al., 1997b). In both instances, there is a relationship between the number of cigarettes smoked and the incidence 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.

TABLE 13–3

Number of Cigarettes Smoked Daily and Age-Adjusted and Multivariate RRs of Fatal Coronary Heart Disease and Nonfatal Myocardial Infarction, Compared with Never Smokers.

TABLE 13–4

Age-Adjusted RRs of Stroke (Fatal and Nonfatal Combined), by Daily Number of Cigarettes Consumed Among Current Smokers.

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 encouraging smokers to quit completely. Second, the shallow dose-response relationship, with the impression of a plateau, accords with similar observations 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 represent 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 unmeasured, constituents of cigarette smoke. The relative contribution of distinct constituents of cigarette smoke to smoking-related cardiovascular morbidity and mortality is unknown. In this regard, the available information is incomplete regarding any differences between the dose-response relationship of filter or low-tar versus high-tar or unfiltered cigarettes.

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

1.

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 unstable 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.

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 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.

3.

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.

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 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.

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 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 variation in such genes and its relevance to smoking-induced cardiovascular disease risk.

6.

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.

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