Second-Hand Cigarette Smoke as a Risk Factor for Coronary Artery Disease
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Vascular diseases, such as coronary artery (CAD) and cerebrovascular disease are the leading causes of mortality in North American adults, accounting for nearly 50% of all adult deaths [1]. Atherosclerosis is the principal contributor to vascular disease. Once thought to be degenerative in nature and an unavoidable result of aging, atherosclerosis is now believed to be a chronic inflammatory reaction and not a necessary sequale of maturity [2]. Though any artery may be affected by the atherosclerotic process, the aorta the cerebral and coronary arteries are the most at risk. Thus, aortic aneurysms, myocardial infarction, and cerebral infarction (stroke) are the major complications of vascular disease. The classical risk factors involved in the development of vascular disease include: hypertension, diabetes, male gender, obesity, hyperlipidemia, hyperhomocysteinemia, and smoking. The earliest manifestation of atherosclerotic disease is the development of the fatty streak. Paramount to the development of this lesion is the transport of lipoprotein, namely LDL, into the arterial wall. This process is not receptor mediated and is concentration dependent [3,4]. The cells that make up the arterial wall produce and secrete oxidative products that are formed through various metabolic processes of the cell. As these oxidative products are released they consume the intrinsic antioxidants existing within the vascular wall. Because the LDL is localized in the subendothelial space, it is an easy target for oxidative damage [3,4]. As the intrinsic antioxidant concentration decreases, the LDL particles are at risk of being oxidized by the subsequently released reactive oxygen species of the vascular cells. The oxidation of LDL occurs in two stages. First is the oxidation of lipids within the LDL particle with little change to the apoprotein B-100 (apo B) component. This is referred to as minimally modified, or minimally oxidized LDL. The minimally modified LDL particle is in itself chemotactic for circulating monocytes and also has the ability to induce the production and expression of cellular adhesion molecules on the endothelial cell membrane (endothelial activation) [5,6]. The second phase of LDL oxidation occurs when the monocytes attracted by the minimally modified LDL enter the vessel wall and differentiate into macrophages. Macrophages have an enormous oxidative capacity. As the macrophages release their oxidative products, the LDL becomes further oxidized and at this point the apo B component acquires a negative charge [3,4]. This alteration of apo B leads to the loss of recognition by its receptor on the macrophage. Normally, LDL influx into the macrophage is tightly regulated through a receptor mediated feedback mechanism. Because this advanced oxidized LDL can not be endocytosed through its receptor, it enters the macrophage through an additional receptor, the scavenger receptor [3,4]. There is no regulation of the LDL influx through this scavenger receptor and this leads to the massive accumulation of oxidized LDL within the macrophage. When viewed through a microscope these lipid-laden macrophages resemble tiny sponges and are therefore known as foam cells. Foam cells are the distinguishing feature of the fatty streak and represent the visible manifestation of the atherosclerotic lesion. Oxidized LDL and the resulting foam cell have been shown to be mitogenic and migratory stimuli for the vascular smooth muscle cells. At this point in lesion progression, the smooth muscle cells lose their ability to contract and regain their lost ability to divide and begin migrating into the intima. Advanced oxidized LDL is also cytotoxic to both endothelial cells and macrophages. The death of the endothelial cells perpetuates the problem by enhancing the further influx of lipids and adhesion of more monocytes. As the foam cells die they release lipid droplets which are internalized by the migrating smooth muscle cells resulting in the formation of smooth muscle foam cells. Oxidized LDL is also cytotoxic to these smooth muscle foam cells. As all three cell types continue to die as a result of oxidized LDL, they form the center of the atherosclerotic lesion, the necrotic core. As this process continues, the developing lesion grows outward toward the adventitia until a point is reached where it can go no further. The atheroma then begins to expand in the opposite direction and encroaches on the lumen of the vessel, limiting blood flow through the region of the developing lesion. At this point the further influx and proliferation of both monocytes and smooth muscle cells and the production of extensive amounts of extracellular matrix weaken the fibrous cap covering the lesion. Eventually the cap ruptures, leading to the manifestation of the acute coronary event, the heart attack. The acute event is triggered by either the rupture of plaque, which essentially blocks blood flow to the tissue beyond, or exposes the extracellular collagen fibers to which platelets adhere and result in thrombus formation. The thrombus blocks blood flow to the tissue beyond the clot. In addition to the traditional risk factors for the development of coronary artery disease (CAD) such as elevated serum LDL, obesity, smoking, hypertension, male gender, and diabetes, several new risk factors have been identified over the past few years. Hyperhomocysteinemia and dysglycemia (sub-diabetic glucose levels associated with CAD) have recently been implicated as causative agents of heart disease. The first line of defense against reactive oxygen products in the plasma is the water-soluble vitamin C. It is after the depletion of vitamin C that the first reactive oxygen species derived from lipids are seen. The next line in the antioxidant defense mechanism are the lipid-soluble vitamins, such as the tocopherols. As the tocopherols are consumed by the free radicals, the oxidative modification of the polyunsaturated fatty acids (PUFA's) begins. This is followed by the depletion of various other, less abundant antioxidants such as beta-carotene and retinol. The modified LDL is then taken up by the scavenger receptor on the macrophage and becomes atherogenic by having a chemotactic effect on circulating monocytes; an inhibitory effect on macrophage motility; and a cytotoxic effect on cells, such as the macrophage and smooth muscle cells. Several reports in the literature state strong correlations between mortality from ischemic heart disease and plasma levels of both vitamin C and vitamin E. Since only a limited proportion of deaths from CAD can be attributed to the classical risk factors, it is apparent that the development of a clinically significant disease state is related to environmental factors, particularly dietary factors. There have been a number of studies that have shown a decreased risk of mortality from CAD associated with certain diets, for example the Mediterranean diet and the vegetarian diet. This is consistent with the assumption that possible benefits may be expected from dietary consumption of the necessary, or essential, vitamin antioxidants, such as vitamins C and E [7]. A study by Gey et al [7] showed an inverse correlation between the plasma antioxidant status (levels of vitamin C and E) and death from ischemic heart disease. The inverse correlation was particularly strong in relation to plasma vitamin E levels, which seemingly support the oxidative stress hypothesis of atherosclerosis. A study by Jialal et al [8] took 24 healthy, non-smoking volunteers and assessed the susceptibility of their LDL to oxidation before and after taking vitamin C, vitamin E, and beta-carotene for three months. They used two indices of LDL susceptibility to oxidation: malondialdhyde (MDA) and conjugated dienes. They found that supplementation with the antioxidant vitamins significantly reduced the susceptibility of the LDL to oxidation. In vitro studies have also shown that the addition of antioxidant vitamins to LDL exposed to oxidizing agents such as copper, can inhibit the production of conjugated dienes and MDA, suggesting a reduction in LDL oxidation [9]. Further evidence in support of this hypothesis also comes from animal studies where rodents, piglets, and primates were fed meals lacking sufficient amounts of dietary antioxidant vitamins. Atherosclerotic-like lesions developed in these animals [10]. Furthermore, patients with ischemic heart disease have high levels of MDA, a byproduct of the lipid peroxidation process as well as plasma levels of conjugated dienes, an additional byproduct of PUFA oxidation. [11]. It has long been known that smokers are at a higher risk for the development of cardiovascular disease. A possible explanation for this may be that smokers are experiencing a high oxidative stress. Experimental data seems to support this theory. A recent study [12] analysed the relationship between lipid peroxidation and antioxidant status in erthrocytes from 30 adult male cigarette smokers and 30 age matched non-smoking males. They found that the enzymatic antioxidants were decreased in the erthrocytes of the smoking group compared to the non-smoking group. Another study by Zhou et al. [13] involving 1255 smokers and 524 healthy non-smokers investigated the plasma levels of lipoperoxides, nitric oxide, vitamin C, vitamin E, and beta-carotene. In addition the authors also looked at erthrocytic antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. The results showed that when compared to non-smoking group, the average lipoperoxides, nitric oxide, and erythrocyte lipoperoxides were significantly increased, while the average values for vitamin C, vitamin E, beta-carotene, erythrocyte superoxide dismutase, catalase, and gluthione peroxidase were significantly decreased. Through liner regression analysis the authors were able to conclude that with longer smoking duration and greater daily smoking quantity, the plasma values of lipoperoxides, nitric oxide, and erythrocyte lipoperoxides were eleveated, while plasma values for vitamin C, vitamin E, beta-carotene, and erythrocyte superoxide dismutase, catalase, and glutathione peroxidase were decreased. In a group of 73 smokers who stopped smoking completely for six-months, the average plasma values of lipoperoxides, nitric oxide, and erythrocyte lipoperoxides decreased, although they were still significantly higher than those in the matched non-smoking group. Additionally, the average plasma values of vitamin C, vitamin E, beta-carotene, and erythrocyte superoxide dismutase, catalase, and glutathione peroxidase increased, although they were still significantly lower than those in the matched non-smoking group. However, after smoking cessation for one year the plasma levels described above mathced those of the non-smoking group. The authors argue that this finding indicates that the markedly increased oxidative stress in smokers might gradually return to normal but only after a long period of smoking cessation. In conclusion, they add that in the bodies of smokers a series of free radical chain reactions were gravely elevated, the dynamic balance between oxidation and antioxidation were seriously disrupted, and oxidative stress was clearly exacerbated, which is closely related to many disorders and diseases in smokers. They argue for the need and urgency for the complete cessation of smoking. A study by Bui et al. [14] investigated the role of vitamin C intake and concentrations in the body fluids of smokers and non-smokers. They compared the ascorbic acid levels in plasma, leukocytes, bronchoalveolar lavage fluid, and alveolar macrophages from a group of smokers and non-smokers. They found a higher level of vitamin C in the bronchoalveolar lavage fluid and alveolar macrophages of smokers compared to non-smokers. This may reflect a defensive mechanism against free radicals derived from cigarette smoke. Smokers in this study were observed to have a higher daily intake of vitamin C, 116 +/-68 mg/d versus 107+/-59 mg/d for non-smokers. Another study by Brown, et al. [15] investigated not only the role of vitamin C, but vitamin E as well in relation to lipid peroxidation in smokers and non-smokers. Male smokers (n=50) from a Scottish population with habitually low vitamin C and vitamin E intakes consistently had lower plasma ascorbic acid concentrations and a greater susceptibility to hydrogen peroxide-stimulated erythrocyte peroxidation in vitro than non-smokers from the same population. Erythrocyte vitamin E concentrations increased in a dose-dependent manner during 20 weeks of supplementation with increasing concentrations of alpha-tocopherol 70, 140, 560, 1050 mg/d. In smokers each dose was associated with a significant decrease in susceptibility of erythrocytes to peroxidation. However, erythrocytes of non-smokers receiving the 1050 mg/d supplement had an increased susceptibility to peroxidation, probably due to the pro-oxidant effect of high vitamin E levels. The cardiovascular effects of cigarette smoking are well established. Evidence is accumulating suggesting an increased oxidative stress in smokers which may account for the detrimental effects of smoking on the vascular system. Research is extending into the non-smoking population in order to examine the effects of environmental exposure to tobacco smoke on the incidence of heart disease. A study by Ayaori et al. [16] attempted to clarify the effects of active and passive smoking on the plasma vitamin C levels, the redox status of vitamin C as measured by the ratio of dehydroascorbic acid to total ascorbic acid, and the levels of thiobarbituric reactive substance (TBARS), and the levels of lipid peroxides in smokers, non-smokers, and non-smokers regularly exposed to environmental cigarette smoke (passive smokers). The study population consisted of 149 healthy males (75 active smokers defined as consumption of >15 cigarettes/day for more than 5 years; 36 passive smokers defined as more than 10 hr/week exposure to environmental cigarette smoke; and 38 non-smokers defined as no exposure to environmental cigarette smoke. There were no significant differences in vitamin C, redox status of vitamin C, TBARS, and lipidperoxides between the three groups at the outset of the study. Plasma levels of ascorbic acid reduced vitamin C were significantly lower in active smokers compared to the other two groups. The redox status of vitamin C was signficantly higher in the active and passive smoking groups than in the non-smoking groups. The results suggest that passive smoking affects the redox status of plasma ascorbic acid suggesting an increased oxidative stress. Additional support for the increased oxidative stress in non-smokers exposed to environmental smoke comes from a study by Robinson et al. [17]. Here a sample of 1579 California adults completed a 1-day time diary of a full days activities in which they reported whether any smoker was present during each activity. Sixty-one respondents reported at least some environmental exposure to cigarette smoke for an average of 5 hours a day. Heaviest smokers reported at least four times as much exposure as non-smokers, this is most likely due to the fact that smokers lead life-styles that expose them to a far higher levels of environmental tobacco smoke exposure. Additional biochemical data comes from a study by Husgafvel-Pursiainen [18] where biochemical analysis of restaurant personnel was used to evaluate exposure to environmental tobacco smoke as compared to active smokers and non-exposed non-smokers. All of the measured parameters, carboxyhemaglobin, thiocyanate, and cotinine in plasma, continine and mutagenicity in urine, total white blood cell count, and sister chromatid exchange frequency in cultured lymphocytes were significantly elevated in the active smoker group compared to the non-smoking-non-exposed group. Work related passive exposure was seen most clearly in the cotinine values, both from plasma and from urine, but significant increases were also seen in the thiocyanate levels and total leucocyte count. The authors argue that due to this increased oxidative stress and the assocation of oxidative stress and tobacco smoke exposure to disease, that environmental tobacco smoke may be an occupational health hazzard. More recently Tribble et al. [19] demonstrated reduced plasma ascorbic acid levels in non-smokers regularly exposed to environmental tobacco smoke. In this study the ascorbic acid levels and vitamin C intake were measured in non-smokers regularly exposed to environmental tobacco smoke as compared to active smokers and non-exposed-non-smokers, to determine whether passive smokers also exhibit altered ascorbic acid levels suggestive of oxidant exposure. Plasma levels of ascorbic acid in passive smokers were intermediate between those of active smokers and non-exposed-non-smokers, despite similar vitamin C intakes. Hypovitaminosis C was observed in 245 of the active smokers and 12% of passive smokers but not in the non-exposed-non-smokers. Reduced plasma vitamin C concentrations were associated with low vitamin C intakes within the smoking population only. The authors concluded that chronic smoke exposure, particularly in association with low vitamin C intake, may reduce ascorbic acid pools in both active and passive smokers. It is established that oxidative stress increases the risk of cardiovascular disease and that smoking increases oxidative stress. How then does this oxidative stress in passive smokers affect the atherogenic process? Two studies demonstarate this. The predominant theory in the development of atherosclerosis involves oxidative stress-induced endothelial dysfunction. Passive smoking has been shown to impair endothelial function in young, healthy adults. A study by Celermajer et al. [20] studied 78 healthy subjects aged 15 to 30: 26 control subjects who had never smoked nor had exposure to environmental tobacco smoke, 26 subjects who had never smoked but had regular exposure to tobacco smoke, and 26 active smokers. Dopler ultrasound was used to asses flow-mediated endothelial function and nitric oxide endothelial-independent vasoreactivity. They found that flow-mediated endothelial-dependent vasodilatation was significantly impaired in both active and passive smokers compared to controls. In the passive smokers there was an inverse relation between the intensity of exposure to tobacco smoke and flow-mediated dilatation. Endothelial-independent dilatation as measured by nitric oxide was similar in all three groups. They concluded that passive smoking is associated with dose-related impairment of endothelial-dependent dilatation in healthy young adults, suggesting early arterial damage. Further evidence for the oxidative stress-induced endothelial dysfunction comes from a study by Neunteufl et at [21]. Here the investigators measured the effects of vitamin E on chronic and acute endothelial dysfunction in active smokers. Here 22 healthy male smokers were randomly assigned to either 600 IU of vitamin E/day or placebo for four weeks; and 11 age-matched healthy male non-smokers were used as controls. Flow mediated vasodilatation and endothelial-independent nitric oxide induced vasodilatation was measured in all groups using Dopler ultrasound. Smoking was stopped 2 hours before the ultrasound examinations. At baseline, flow-mediated dilatation was abnormal in both vitamin E and placebo active smoking groups. Flow mediated vasodilatation results remained similar after the four week treatment peroid in both groups but declined after smoking a cigarette in subjects taking placebo compared to those receiving vitamin E. The transient attenuation of flow-mediated dilatation was related to the improvement in antioxidant status as measured my TBARS. Nitroglycerin-induced dilatation did not differ between the groups at baseline or after therapy. The authors conclude that oral supplementation of vitamin E can attenuate transient impairment of endothelial function after heavy smoking due to an improvement in the antioxidant status but can not restore chronic endotheial dysfunction within four weeks. Additional studies, such as one carried out by Moffatt et al. [22], offer other possible mechanisms for the development of cardiovascular disease in smokers. In this study the influence of worksite tobacco smoke on serum lipoprotein profiles in healthy female non-smoker was investigated. High-density lipoprotein (HDL) subfractions, apolipoprotein A-I, and apolipoprotein B were all measured in premenopausal women aged 21-50, free from factors known to influence HDL, who were not taking oral contraceptives, were moderate consumers of alcohol, caffeine, and dietary fat. The women were divided into two groups: (1) non-smokers who had never smoked cigarettes and were generally free from environmental tobacco smoke (non-smokers), and (2) non-smokers who had never smoked but were subjected to concentrated doses of environmental tobacco smoke (passive smokers). A third group consisted of current smokers who had a minimum of 20 cigarettes/day for at least the past five consecutive years served as a smoking control (smokers). The participants were recruited from local taverns and restaurants where they were employed. The results showed that HDL-C, HDL2, and apo A-I were significantly depressed in the passive smokers and active smokers as compared to non-smokers. It was concluded that excessive exposure to environmental tobacco smoke in female workers can have deleterious effects similar to effects observed in active smokers. It is postulated that these effects increase risk of coronary artery disease. Other studies have focused on the effects of smoking on the accumulation of inflammatory cells. One such study by Weber et al. [23] investigated the effects of vitamin C on the adhesion of monocytes. Monocyte adhesion to unstimulated human umbilical vein endotheial cells was measured in both smokers (1-2 packs/day) and non-smokers. Plasma vitamin C levels were reduced in smokers, as well monocytes isolated from smokers had greater adhesion to the umbilical endothelial cells. Dietary supplementation of vitamin C for 10 days significantly increased plasma vitamin C levels in smokers and decreased monocyte adhesion values to that of the non-smoking group. Vitamin C supplementation had no effect on the adhesion of monocytes isolated from the non-smokers. The authors argue that restoring vitamin C levels in smokers by oral supplementation, may reduce monocyte adhesion and thereby limit atherogenesis. Alterations in paraoxonase, an enzyme associated with HDL that protects agains oxidative modification of lipoproteins, activity and concentration have also been observed in smokers. In a study by James et al [24] paraoxonase concentration and activity were measured in active smokers, ex-smokers, and never-smoked non-smokers. The activity and concentration of paraoxonase were significantly lower in current smokers compared to non-smokers. Ex-smokers had levels and activity similar to non-smokers. The results of this study suggest that smoking is independently associated with significant decreases in serum paraoxonase activity and concentration. Low serum paraoxonase is associated with more severe coronary artery disease and a lower antioxidant capacity. The data from this study support the hypothesis that smoking modifies serum paraoxonase such that there is an increased risk of coronary artery disease due t a diminished capacity to protect lipoproteins from oxidative modification. In order to further describe the pathogenesis of environmental smoke-induced atheroma Penn et al. [25] exposed cockerels to either side stream smoke or filtered air for up to six hours a day, five days a week. The abdominal aorta from each cockerel was cut into ten segments and the plaque index was measured as mean plaque cross-sectional area divided by mean luminal circumference X 100. There were significantly greater plaque indexes in the cockerels exposed to the side-stream smoke. This relatively brief exposure to side-stream smoke early in life was sufficient to enhance atherosclerotic plaque development. Wells [26] has shown that short-term exposure of 20 minutes to eight hours results in increased platelet sensitivity and decreased ability of the heart to receive and process oxygen, exacerbating the effects of myocardial ischemia. Longer exposure results in plaque buildup and modifications of plasma lipids and blood cholesterol. The available epidemiological studies suggest that passive smoking increases the rate of mortality due to coronary artery disease by 20 to 70%. The application of the United States Environmental Protection Agency protocol for estimating the number of deaths from smoking to data from 1985, suggest that 62,000 individuals died in the US as a result of environmental exposure to tobacco smoke. He argues that clinicians should council their patients to avoid exposure to tobacco smoke in the home, at work, and in transportation settings. Though experimental studies clearly demonstrate a relationship between exposure to environmental tobacco smoke and heart disease, a number of epidemilogical studies involving large populations exist which support the hypothesis in vivo. It is estimated that in Norway 300-500 non-smokers die of heart disease annually as a result of long-term exposure to tobacco smoke [27]. In the United States 37,000 deaths from coronary artery disease are attributed to environmental exposure to tobacco smoke, accounting for nearly 70% of all deaths associated with passive smoking [27]. Environmental tobacco smoke is a complex mixture of chemicals. Both active and passive smoking expose individuals to the same chemicals, but at different concentrations. In situations where people are exposed to an amount of nicotine corresponding to their smoking � of a cigarette, they will be exposed to an amount of nitrosodimethylamine corresponding to their smoking about 5 cigarettes [27]. Exposure of children to environmental tobacco smoke is associated with increased risk of lower respiratory tract infections, asthma, and middle ear infections [27]. Evidence is beginning to accumulate that suggests that environmental tobacco smoke is a risk factor for Sudden Infant Death Syndrome [27]. It is safe to say that environmental tobacco smoke is a serious health concern. Attention must be paid to individuals who are at risk for developing cancer and heart disease due to exposure to tobacco smoke either in the home or on the job. A literature review focusing on the link between passive smoking and the risk of coronary artery disease published by Lam and He [28] calculated pooled odds ratio based on data from all original papers and reviews. Ten perspective studies, nine case-controlled studies, and one cross-sectional study were found. Nearly all studies showed positive associations between environmental tobacco smoke and coronary artery disease. A small number of the studies were statistically significant with dose-response relationships apparent. Six of the reviews evaluated calculated pooled estimates of the relative risks, which ranged from 1.23 to 1.51. Other studies reviewed showed that exposure to cigarette smoke could produce additional cardiovascular effects such as ischemia and stroke. Kritz et al. [29] analysed 10 epidemiological studies and found a significant dose-response effect relating the development of coronary artery disease to environmental tobacco smoke. They suggest that non-smokers are more susceptible to the cardiovascular effects of tobacco smoke and that side-stream smoke contains higher concentrations of gas constituents, including carbon monoxide. Pathophyiological and biochemical data after short and long term exposure demonstrates alterations in both endothelial cell and platelet function increasing the prevalence of endothelial dysfunction and platelet aggregation. Therefore, passive smoking is a relevant risk factor for heart disease morbidity and mortality. A paper by Steenland [30] reviewed nine epidemiologic studies and several experimental studies in an effort to evaluate the risk of cardiovascular disease in association with environmental tobacco smoke. The relative risk for never-smokers living with current or former smokers has ranged from 0.9 to 3.0 in the nine different studies. Several of the studies demonstrated a dose-response relationship after controlling for other risk factors. Evidence from this epidemiological data suggests that environmental tobacco smoke can damage the cardiovascular system in both the short and long term resulting in the deaths of nearly 35,000 to 40,000 never-smokers and long-term former-smokers per year in the United States due to second-hand smoke. Steenland states that an individual male never-smoker living with a current smoker is estimated to have approximately 9.6% chance of dying of coronary artery disease by the age of 74, compared with a 7.4% chance for a male never-smoker living with a non-smoker. Further evidence for the relationship between passive smoking and cardiovascular disease comes from a study by Garland et al. [31]. Here the authors tested the hypothesis that non-smoking women exposed to their husbands cigarette smoke would have a higher risk of fatal cardiac events. Married women aged 50-79 who had never smoked were classified according to the husbands self-reported smoking status as: never smoked, former smoker, or current smoker. After 10 years, non-smoking wives of current or former smokers had a higher total death rate from ischemic heart disease than women whose husbands never smoked. Additional epidemiolog
