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I I I I I ~ I I I I cardiovascular Effects of ETS Exposure: Comments on Biological Plausibility of Proposed Mechanisms 1 I

Table of Contents A. Coronary Heart Disease Al. xajor events associated with atherosclerosis I I I I I I I 1 A2. The'.tiology of atherosclerosis remains unknown B. Summary of epidemiological studies relating cardiovascular effects with exposure to ETS C. commeats on deficiencies and lack of biological plausibility in the mechanisms proposed for the cardiovascular efAfects of ETS C1. Thrombus formation and platelet activation: Does- exposure to ETS contribute to an altered platelet function? C2. Vascular wall injury: Is ETS exposure associated with endothelial cell injury? C3. Does ETS exposure alter the uptake or the composition of lipids? C4. Is ETS exposure associated with increased proliferation of s.m.ooth muscie cells? . . ....... . ......... C5. What is the biological relevance of exposure to ETS on oxygen supply and cardiac functions? C6. How appropriate is it to extrapolate findings from animal studies to investigations involving human subjects? C7. Confounding D. An alternative explanation for the observed effects of ETS ............. D1. Psychoactive responses to ETS D2. Psychoactive factors and pathogenesis of atherosclerosis B. conclusion I

I I I I I I I A. Coronary Heart Disease Heart disease and related cardiovascular ailments are the primary cause of death in all developed countries and in many developing countries. Coronary heart disease (CHD), which accounts for a quarter of the 21 million deaths each year among Americans, is a complex clinical composite of a more fundamental vascular pathology affecting circulation (1). The majority of these deaths _..:.... _ are due to myocardial or cerebral infarction, severe atherosclerosis being the principal cause, accounting for 90% of CHD mortalities (1). CHD is known to have a substantial diagnostic error (2). In addition, a significant percentage (36% in women and 38.7% in men) of CHD among'adults aged k65 years is subclinical (3), suggesting that assessment of CHD-linked morbidity and mortality, based on traditional clinical parameters, may be imprecise (4). Unfortunately, these factors, insofar as CHD is concerned, are rarely considered in large-scale epidemiologic studies. Al. Major events associated with atherosclerosis Atherosclerosis refers to the process in which cholesterol- laden, hemorrhagic deposits, referred to as atheromas, are formed in the tunica intima and media of large and medium sized arteries. Although atheromas develop in all arteries, they are more common in areas of high'blood turbulence, such as coronary arteries and aorta. In the case of coronary arteries, damage of endothelium lining the arterial wall triggers a series of events, culminating Y

I I I I I I I I I I I in the attachment of cholesterol and related lipids to damaged - endothelial cells. Cholesterol intermingles with cells of the lining, and develops into a plaque. With time the plaque, soft and fibrous at first, stiffens and weakens the artery wall (5). The arteries become brittle and more vulnerable to tears and hemorrhages. The thickened vascular wall, in addition to becoming prone to coronary thrombosis, also compromises the vessel lumen and causes a decrease in blood flow. Since coronary arteries supply the ,, heart with blood, the "narrowing of the arteries° mav eventually show itself in the form of clinical symptoms. The person may experience angina.pectoris,-or severe chest pains, when the heart is insufficiently oxygenated or placed under extra demands, e.g., rigorous physical exercise. Another clinical manifestation of atherosclerosis is myocardial infarction which can result in fatal destruction of heart tissues. Fiqure l illustrates the sequence of events that result in atheroma formation. The whole process is believed to be initiated by some form of injury, arising from systemic and local changes in the arterial network, to endothelial cells lining the arteries. Subsequent to endothelium damage, atherosclerotic lesions develop over time and are thought to be the collective end-product of three somewhat inter-dependent events: (i) proliferation of previously quiescent smooth muscle cells and activation of macrophages recruited to site of damage, (ii) deposition of large amounts of connective tissue matrix proteins, e.g., collagen, elastic fibers, proteoglycan, around the smoQth muscle cells, and (iii) lipid I

I I I I I I I I I I I accumulation in the form of foam cells within smooth muscle cells and macrophages, and as deposits within the extracellular matrix surrounding these cells. A2. The etiology of atherosclerosis remains unknown Despite the strides that have been made in vascular biology in recent years, including those at the molecular level, the etiology of atherosclerosis remains uncertain. This uncertainty is reflected in the following question:!'what is the nature or mechanism of the primary injury of the vessel wall which appears to initiate the process of atherogenesis?" Based on leads provided by epidemiological investigations, suggestions have been made of association between atherosclerotic disease and a series of pathologies, habits of the population, genetic, biochemical, physiological and environmental.factors, all of which influence directly and/or indirectly the early development, frequency, severity and prognosis of atherosclerosis. These have come to be known as coronary risk factors (CRF). CRFs can range from more esoteric risks such as noise, and behavior, to more commonly accepted risks such as elevated plasma LDL cholesterol levels, lowered HDL cholesterol levels, triglyceride and beta/alpha lipoprotein ratio, serum clotting times, fibrinogen concentrations, cigarette smoking, high blood pressure, obesity, diabetes mellitus, and sedentary lifestyles (7-20). It is also .. important to note that the classical risk factors, such as hypercholesterolemia, hypertension, hemodynamic stresses, smoking, which have been traditionally cited for their predisposing roles I

leading to endothelial cell injury - both, in animal and human ,._ studies - are still unable to account for the mechanism of atherogenesis, or predict >50% of new cases of the disease (21). To summarize, because of the multifactorial nature of CHD, in which magnitude and severity of disease are influenced both by duration of exposurP and by the particular combination of the CRFs, it is extremely unlikely that an increase in the risk of CHD may be traced and assigned exclusively to a single CRF. B. Summary of epidemiological studies relating cardiovascular effects and ETS exposure ETS is a combination of smoke emitted from the burning cigarette and smoke exhaled by the smoker. It consists of a vapor and a particulate phase, formed by a multifaceted kinetic process (22). The particulate phase of ETS is created when combustion_ components are emitted into the atmosphere. These components act as "nuclei" for condensation of vapor phase material. The final droplets of ETS are in a dynamic state of flux which is influenced by humidity, dissipation, and dilution (22, 23). The effects of ETS exposure are dependent upon many factors, such as bioavailability of particulate and vapor_phase constituents, as well as duration and level of exposure (24). The relationship between exposure to ETS and incidence of CHD is a subject of controversy. Reasons for not associating between the two include the following: (i) ETS exposure occurring over an extended period of time involves multiple, ill-defined modes of exposure and is subject to

t 1 I I I I I I I known and unknown quantification/measurement errors (22-24). Given •that CHD is associated with many CRFs and requires years of incubation to surface clinically, it is unlikely that a significant , risk is attributable to ETS exposure. (ii) Of the numerous epidemiological studies that examine possible associations between CHD and ETS exposure (25-34), only three of the studies, involving exposure at home to spousal ETS, report a statistically significant association between ETS and CHD (26, 28, 34). In the single study to assess the health effects of workplace ETS exposure, no statistically significant association , . was found (34). Since, by their very nature, epidemiologic studies deal with masses of data, it is unclear whether sample homogeneity can be maintained and whether the quality of the observations can be preserved. Furthernaore, there is often confounding of effects. Indeed, issues such as indices for ETS exposure; lifestyle factors; ,.... _ _ _. and misclassifications, in relation to the purported effects of ETS, have not been completely resolved. . _ .............. .... ........... (iii) Although probable carcinogens such as benzo(a)pyrene (H(a)P) and dimethylnitrosamine (DMNA) have been detected in sidestream tobacco smoke (in some cases, in concentrations exceeding those present in mainstream tobacco smoke (23)), they are substantially diluted when present in ETS. In addition, with the addition of carbon monoxide, it is not known whether and how many of the potentially harmful chemical components present in ETS can gain access to the cardiovascular system in concentrations sufficient to do damage. i

In addition to the fact that all of the published I I I I I I I I ~ I i I I ; epidemiological studies attempting to show an adverse effect of ETS on CHD have problems in experimental design, data analysis and result interpretation, it is also important to emphasize that for CHD/ETS association to be valid, biologically plausible mechanisms must be established. My conclusion, based on a critical evaluation of currently available scientific data, is that the proposed link between exposure to ETS and increased risk of CHD is not warranted. C. Comments on deficiencies and lack of plausibility in the biological mechanisms proposed for the cardiovascular effects of ETS C1. Thrombus formation and platelet activation: Does exposure to ETS contribute to an altered platelet function? A thrombus is an abnormal manifestation of normal hemostasis occurring on the internal surface of blood vessels. Thrombus formation requires a concerted interaction between the endothelium and platelets, and appears to proceed in the following manner. Protection afforded by the vascular endothelium against platelet aggregation and adhesion (35-37) is lost upon injury of the endothelium, resulting in a state in which arterial thrombosis is greatly predisposed. Damaged endothelium enhances platelet _ .11. ., aggregation and responsiveness to a number oagonists, and induces platelet adherence to the subendothelial components, concomitant with platelet activation and release of a number of mediators, - e.g., thromboxane A2, which aggregate new platelets. In parallel,

thrombin is generated on the platelet surface to further stimulate these reactions. Several conditions known to increase cardiovascular disease are also associated with increased platelet aggregation; in contrast, polyunsaturated fatty acids decrease platelet aggregation and protect against vascular diseases (38-40). The OSHA IAQ proposal states that "there is evidence that ETS I I I I I I I I I I exposure can cause platelets to become more easily activated thus predisposing the platelets to become involved in forming clots and atherosclerotic plaques." To support this claim, OSHA cites the study by Burghuber et al. (41), which involved placing non-smokers in a confined environment (i8mZ room) and exposing them for an extended period of time (20 min) to ETS generated by testers smoking "30 heavy brand" cigarettes. The proposal fails to note that such artificial experimental settings are unlikely to be present in real-life situations. Moreover, the 1 mM ADP used to induce irreversible platelet aggregation is unrealistically high .... . and is at least 10-20 times greater than the physiological concentration of ADP. Another cited study, by Davis et al. (42), also involved a non-standard platelet aggregation method. Platelet aggregation is widely recognized to be subject to a variety of artifacts such as the drawing of blood, presence of anticoagulant, and centrifugation (43). Platelet reactivity also displays donor variation, circadian and seasonal changes (44-46), and extraordinary sensitivity to aggregating agents (47). In general, there is poor correlation between platelet aggregation and atherogenic potential of an agent. For example, although saturated 9 I

I I I I I I I I I fatty acid diets are regarded to be atherogenic, they have no demonstrable effect on platelet function (48). Active smoking studies do not show a correlation between smoking and thrombi incidence. In fact, smoking may actually exert a "protective" effect in certain situations. Haire et al. (49) investigated the response of fibrinolytic system to active smoking and observed no difference between control subjects and healthy . male smokers challenged with "smoking two cigarette within 15 min". ..... .... Smoking has no effect on regional cerebral blood flow and on platelet aggregation in the normal aged volunteers (50) Doll and Peto found no association between mortality from thromboembolism and smoking (107). A protective effect of cigarette smoking on venous thromboembolic disease has been observed after myocardial infarction and surgery (52, 53). In patients undergoing emergency laparotomy, cigarette smokers had a significantly lower incidence of deep venous thrombosis than pipe smokers or nonsmokers (54). When smokers refrained from smoking and were then challenged with a cigarette, no difference in collagen-induced platelet aggregation, thromboxane B2 production by platelets, plasma . ..... . .. . thromboglobulin and plasma fibrinopeptide A levels, could be observed before and after smoking, showing that acute smoking did not induce a prothrombotic state (55). Cholesterol-fed rabbits did not show hypersensitivity of platelets to agonists (56). Thus,-- there is no concrete and consistent evidence for increased platelet reactivity due to ETS exposure. C2. Vascular wall injury: Is ETS exposure associated with endothelial 10

cell injury? The initiation of atherosclerosis requires some form of 1 I I I I ~ ~ I "injury" to be sustained by the arterial endothelium, although the nature of such °injury" is not well understood; genetic and environmental factors, singly or interactively, could be involved. The report of Davis and coworkers was cited in the OHSA IAQ proposal to support the claim that endothelial cell damage is ,4 induced by ETS exposure (42). The assay used for quantifying circulating endothelial cells, however, was bascu on the method of leucoconcentration first described by Hladovec and Rossman (57), in which only "presumed" endothelial cells were isolated. Davis et al. did not consider confounding by perceptual reactivity to ETS and the fact that several vasoactive compounds have been shown to cause an increase in endothelial cell count (58, 59). ~ C3. Does ETS exposure alter the uptake or the composition of lipids? According to the OHSA IAQ proposal, ETS "increases the lipolysis that increases levels of plasma free fatty acids, which result in enhanced synthesis of LDL". Moreover, ETS was suggested to have implications "in altering blood lipids". How relevant are these statements to our current understanding of the role of lipids in atherosclerosis? Although excess cholesterol is considered the primary culprit of atherosclerosis, it has become clear, within the past few years, that what has traditionally been regarded as the danger of cholesterol is, more precisely, the danger of high LDL and low HDL. 11 I

When high cholesterol reflects a disproportionally high LDL, then high total cholesterol is unhealthy. If, on the other hand, total cholesterol is high because HDL is high, then it is not dangerous. Accordingly, the newest research places more emphasis on the value of total cholesterol/HDL: a ratio of less than 3.5 is most ....... ....... .. .. desirable, one that•lies between 3.5 and 4.5 is considered normal, . , and anything over 7.0 is regarded to be dangerous (60, 61). When such an empirical relationship is applied to the study of Moskowitz et al. (62), in which the profile of blood lipor-rotein .. ...:. . ... ... ... was investigated in "adolescent children whose parents smoked", no I ~ ~ I I I I ~ I I effect of exposure to parental ETS was apparent. HDL cholesterol levels are known to be affected by diet, alcohol consumption, and physical activity (63-65). Likewise, the chemical composition of plasma LDL is modulated by lifestyle factors (66). In a recent study, Mehrabian et al. (67) showed that an increase in HDL cholesterol levels, resulting from an over- expression of the apoprotein AII gene, is accompanied by an unexpected promotion rather than retardation of aortic fatty streak development, suggesting that the relationship between HDL and atherosclerosis is complex and not totally understood. There is yet another aspect of lipoprotein that deserves some comment, especially in connection with smoking and ETS exposure, which mainly relates to the role of LDL as a risk factor for CHD. It has been suggested that the oxidation of LDL is closely linked to the process of atherogenesis (68); it has been known for some time that isolated LDL is highly susceptible to oxidation and that ~ ~ 12 ~ ~ ~ ~ ~ ~

the products of ox.ida.tion are_cytotoxic as well as chemotactic for , _ _ monocytes (69, 70). Furthermore, oxidized LDL is capable of delivering an excess of cholesteryl esters to target cells, via a receptor-independent and therefore unregulated mechanism. Accordingly, cigarette smoke, by virtue of its ability to release free radicals, might be expected to enhance the susceptibility of LDL to peroxidative modification (71). Contrary to expectation, however, smoking does not constitute a risk for CHD in Far East countries with a high prevalence of smoking, as the average plasma LDL and the LDL/HDL ratio in those populations is relatively low (72). Recent studies also suggest that native and oxidized LDL exhibit a complex, agonist-specific effect on platelet activation (73). In sum, there is no evidence to show that plasma LDL/HDL are modulated by ETS in such a way as to exert atherogenic potential. C4. Is ETS exposure associated with increased proliferation of smooth muscle cells? An increase in vascular smooth muscle cell (SMC) proliferation is thought to play a role in atherosclerosis. While SMC in normal arteries of adult animals reside in a state of quiescence, they can be induced to proliferate and ultimately migrate into the intima by autocrine and paracrine mechanisms, mediated via a variety of chemical, mechanical, or biologic factors (74-80). . . ... . .. ...... .... . _ _ Two explanations have been offered on the "quiescence-to- . ........ ........... .:... .... ....., ... ......... ......... ...................... .................... ........... _. proliferation" transition of smooth muscle cells. The "response-to- injury" injury" hypothesis suggests that systemic and local changes in the 13

arterial network result in injury to the.endothelial cell lining the arterial tree, thereby eliciting a cascade of events to trigger smooth__muscle cell proliferation (74, 76). A second "monoclonal 1 I I I I ~ ~ I I smooth muscle cell hypothesis" proposes that the monoclonal atherosclerotic plaques may, through viral infections or other insults, be activatad to proliferate uncontrollably. ..... ......... It has been speculated tat the "monoclonal" nature of SMC will permit them to proliferate when exposed to an insult such as ETS. In support of such speculation, polycyclic aromatic hydrocarbons, chemical components in ETS, were reported to induce atherosclerosis in animal studies (86-89). These speculations lack biological plausibility for the following reasons. First, the ,:..._. .. animal species used (86-89), the chicken, develops large atherosclerotic plaques spontaneously by one year of age. Second, administration of the polycyclic hydrocarbons, as a bolus, intramuscularly, in animal studies, is not representative of ETS exposure. Finally, of the many chemicals present in ETS, only a few, such as carbon monoxide, exist as gases under ambient conditions and have the potential to reach the endothelial lining in diluted quantities. Recent studies, however, show that chronic exposure to moderate levels of carbon monoxide did not accelerate atherosclerosis in cockerels (86). Other chemicals in ETS possessing potentially harmful effects, e.g., suspected carcinogens such as 2-naphthylamine, 4-aminobiphenyl, benzo(a)pyrene, N- nitrosodimethylamine, acetamine, formaldehyde, are known to have relatively high vaporization points. Thus, physically, they are 14 I

unable to remain as gases, even at lower ambient temperature, and I still less likely, at the higher temperature of the human body. Thus to imply that risk of exposure to ETS is in part attributed to such chemicals gaining excess to chemically implausible. In conclusion; the existing data do not establish the endothelial lining is an association between ETS exposure and induction of smooth muscle proliferation. C5. What is the biological relevance of exposure to ETS on oxygen supply and cardiac functions? Among the chemical components of ETS, carbon monoxide and nicotine have been suggested as most likely to adversely affect cardiovascular function. Carbon monoxide binds tightly to hemoglobin and diminishes oxygen transport in the blood stream. Nicotine acts in the brain and throughout the body, promoting the release of catecholamines and increasing heart rate and blood ......... pressure. Although high exposure to these substances might impair ;. cardiovascular performance, exposure from ETS would be too low for physiological changes to occur in healthy persons. A number of publications, notably those of Aronow (89, 90), were cited in the OHSA IAQ proposal to support the assertion that ETS exposures leads to an interruption in the coronary circulation, ........ .. ...... . .......... . .... resulting in ischemia. In the Aronow study, it was suggested that the lack of oxygen delivery to tissues may result in lactic acid I accumulation that would irritate the heart and stimulate spontaneous contraction of cardiac muscle in a.non-coordinated 0 i I5 M ~ W .;~ I W N

I ~ ~ I I I I I I I t manner, resulting in compromised cardiovascular function. These studies were largely inconclusive because of deficiencies in study design and data interpretation. For example, the premature , . ventricular contraction data were only recorded in one group after exercise. Moreover, lactate is primarily produced by exercising skeletal and not cardiac muscles (due to the unique distribution and properties of lactate dehydrogenase amongst tissues). Also, the studies lacked controls for confounding. The hypothesis that cigarette smoking has an acute effect on exercise capacity was recently evaluated by subjecting subjects to treadmill exercise (91). No important acute effects on treadmill exercise performance could be demonstrated in active cigarette smokers. Sheps et al. (92, 93) have shown blood that contained as much as 4% carboxyhemoglobin had no adverse effects on patients with ischemic heart disease. Also, in patients with frequent ventricular ectopic activity, exposure to CO producing either 3% or 5% carboxyhemoglobin does not increase arrhythmia frequency of single or multiple beats during rest or exercise (94). It is therefore highly implausible that elevation of CO levels resulting from ETS exposure would show a demonstrable harmful effect. At the cellular level, the work of Gvozdjakova et al. (95) was cited by OSHA as evidence for an effect of ETS exposuze on mitochondrial functions, which conceivably could lead to reduced energy production and..hence compromised cardiac function. The cited studies, however, were poorly performed and lacked proper controls. For example, mitochondrial function was measured inadequately using 16 I

one concentration of glutamate, instead of a number of substrates, studied over a broad range of physiologically relevant concentrations. I I I I I r I I In conclusion, there is no solid support for the notion that ....... ......... .... .... . ETS exposure compromises cardiac functions. C6. How appropriate is it to extrapolate findings from animal studies to investigations involving human subjects? Recently Zhu et al. (97) suggested that the elevated Sudan IV- stainable lipid streaks in both the aorta and pulmonary arteries of stainable New Zealand rabbits fed a high cholesterol diet followed by exposure to a "low" and "high"..concentr.ation of ETS for an extended period of time is evidence for ETS-induced endothelial damage and hence atherosclerosis. Although the use of cholesterol-fed rabbits is a traditional and easy way of initiating atherosclerosis, the high plasma cholesterol levels produced in this way are even higher than in patients with familial hypercholesterolemia. Thus, such a model is relevant only to a small atherogenesis-prone proportion of the human population and ..differs considerably from native atherosclerosis in most humans. Moreover, in the absence of other supporting evidence, it is not appropriate to interpret measured lipid streaks as being equivalent to the development of atherosclerosis. Such fatty streaks and intimal thickening have been found in most Finish and American children (98), some as young as three years (regardless of community prevalence of adult artery ..... .... . . ... .. ... . . ... disease) (99, 100), leading some to question their importance. Indeed, biliary obstruction, which can result from CNS-triggered

t ~ ~ ~ I I I I I I I I I I muscle spasm but bears no relation to atherosclerosis, also , promotes lipid deposition in vessel wall. Finally, the question of whether animal studies have predictive values in humans must also be addressed. Species differences are known to exist in susceptibility to carcinogens and other environmental•agents (101-105). Information such as route of exposure, bioavailability, and dose response obtained by using animal models must be properly and carefully evaluated before the findings can be relevantly extrapolated to humans. These types of issues, in relation to ETS exposure studies using animals, clearly have not been adequately addressed. C7. Confounding It is clear that loss of functional integrity of-the vascular endothelium is a primary initiating event in the etiology of- atherosclerosis.' Endothelial cells interact with blood components and the abluminal tissues, thus playing an active role in many aspects of vascular functions. Nutrition may play an important role in the atherosclerotic disease process. There is evidence that certain vitamins and minerals prevent some metabolic and physiological perturbations of the vascular endothelium (106-112). For example, inadequate intake of vitamin C could predispose endothelial cells to damage. Vitamin C is essential for the maintenance of the body's cornective tissue- the "glue" that holds the cell together. Even though enough of the vitamin may be present to prevent scurvy, sub-optimal amounts may lead to weakening of the connective tissue bo 18 I

cells, thus making them more vulnerable to disruption. The involvement of nutrients as a ma jor confounding factor has not been systematically addressed in epidemiological and laboratory studies dealing with the cardiovascular effects of ETS exposure. .. ....... .... D. An alternative explanation for the observed effects of ETS D 1. Psychoactive response to ETS The distinct odor of ETS and the likelihood that it could act as an irritant for some individuals (59) raises the possibility that the claimed effects of'ETS exposure on endothelium is no more than a simple psychoactive response which in turn triggers vasospastic perturbations. Over time, vasospastic episodes produce vasospasm which initiates endothelial injury and the sequelae of ....... :.:: events culminating in atherosc2erosis A vasospastic theory indeed has been proposed to explain a myriad of human diseases, including atherosclerosis, by suggesting that an increased sympathetic nervous activity could lead to focal spasm resulting in a reduction .. of oxygen supply (113, 114). D. Psychoactive factors and pathogenesis of atherosclerosis Indeed, behavioral and psychosocial factors have been implicated in the pathogenesis of atherosclerosis for decades. Animal studies have demonstrated that the sympathetic arousal invoked by,psychosocial variables, commonly known as "stress", is accompanied by endothelial dysfunction of the coronary arteries and aorta, as judged by enhanced immunoglobulin G incorporation and . 19

I I I I I I I I I I endothelial cell replication (115). The demonstration by Pettersson , et al. (116) that chlora lose- induced endothelial celll injury in rabbits is effectively blocked by m.etoprolol, a$1-adrenergic antagonist, further.support the notion that increased sympathetic •~ nervous activity and catecholamines are intimately involved in aortic endothelial-cell damage and possibly atherogenesis. Sbim, manifested not necessarily in the typical hard-driving type A personality, but as anger, frustration, powerlessness, present risks to general health and to the heart. The report of a World Health Organization Expert Committee on the prevention of CHD (117) noted that: "Several behavioral patterns and psychological and social variables have been related to CHD risk..... With respect to stress, or response to stress, the lack of definition and quantitative measurement is severely limiting..... The Expert Committee noted the danger that public and professional misconceptions about stress, whereby.it is assigned a primary role in the genesis of CHD, may divert attention from the demonstrated needs in prevention." The potential importance of psychosocial variables in CHD is further bolstered by the_results of a prospective study by Lehr, Messinger and Rosenman (118). The authors measured 12 biochemical and other biological risk factors, and 12 "social" variables (factual descriptions relating to the social background of the individuals such as parental country of birth, parent's occupation, subject's education, residence, etc). Despite the fact that these , variables do not begin to encompass the full range of psychological 20 I

factors, perceptions and life events that influence people, the I I I ~ I I I I social variables were reported to be important predictors of CHD. In a discriminant analysis comparing CHD cases with CHD-free controls, a "parental religious difference factor" was the second- . ...... ... ........ best discriminant, and "father's occupation" and "behavior pattern" were more •discriminating than eight of the biological risk factors. Of the biological risk factors, only age, systolic pressure, smoking and serum cholesterol levels contributed in the discriminant analysis, and these did not account for much c+f the predictable variance. The potential causal role of psychological variables or mental stress in CHD was further supported by Rozanski et al (119) using CHD patients. The.ir research showed that some mental stressors can induce elevation in arterial pressure and abnormalities in heart wall motions in ways comparable to that induced by exercise in CHD patients. Moreover, the mental-stressor-induced minor ischemia occurred at lower heart rates than that produced by exercise. In these studies, four mental stress tasks (simulated public speaking on a personal subject, doing arithmetic, reading aloud, and the Stroop color-word task) were compared with the effects of exercise. Nearly 60% of the patients had heart wall motion abnormalities (assessed by radionuclide ventriculography) while performing the mental tasks, with 36% showing a fall in left ventricular ejection fraction of at least 5% points (reflecting the inability of the heart to respond flexibly). The public speaking task also produced ischemic changes as.large as exercise, even though it was not rated 21 I

by the patients as being more tension-producing, anxiety-provoking, or arousing-challenging than the arithmetic or Stroop tasks. This study strongly suggests that mental stress can have silent and I I I I I I I I I I I significant effects on the cardiovascular system. The importance of "stress" as a risk factor for CHD in humans has been supported ry animal studies. Animal models have shown that chronic exposure to stress potentiates coronary artery .. atherogenesis among animals of high social rank, independent of the concomitant variability in the animals serum lipid concentration. The sympathetic arousal invoked by social manipulation is ..... ........ ......... accompanied by endothelial dysfunction of the coronary arteries and aorta, as evidenced by enhanced immunoglobulin G incorporation and endothelial cell replication (120). Indeed, certain personality features such as chronic anger ranks with, or even exceeds cigarette smoking, obesity and a high fact diet as a powerful risk factor for early death (121). Personality traits most clearly linked to heart disease and other health disorders are hostility, suspiciousness, aggressiveness and a volatile temper. Hostile people often have a more reactive sympathetic nervous system than others, and their bodies tend to produce abnormally high levels of catecholamines. These hormones can stimulate a wide spectrum of effects, raising blood pressure, quickening the heart beat, and dilating the pupils. over time, excessive adrenaline and insufficient acetylcholine can lead to a host of problems, including stiffening of the arteries from constantly elevated blood pressure and the heart weakens from 22 I

I I I I I I I I I I I I I k overexertion. Stress hormones also have been shown to damage the liver and kidney and to release too'much fat from fat stores, which could explain why those who are hostile as teen-agers have high cholesterol levels as adults. In a study based_upon a random population sampling comprising 1/3 of all men born in Gothenburg and living in tha city in 1963, Wilhelmsen reported that psychological stress and low social class are independent risk factors for coronary heart disease, with an associated relative risk of 1.6 and 1.3, respectively, as compared to a relative risk of 2.3 for active smokers in a multivariate analysis involving 7495 subjects followed for 11.8 years. In fact, as far as stroke is concerned, multivariate analysis showed that psychological stress (RR=1.7) actually ranked higher than active smoking (RR=1.5) (122). The influence of emotional states on the frequency of cardiovascular diseases and fatalities is most vividly illustrated by a recent publication showing that the perceived threat of annihilation in connection with the Iraqi missile war produced a sharp rise in the incidence of acute myocardial infarction and sudden death in Israeli civilians. Peak incidence closely coincided with onset of the war (123). E. Conclusion The average citizen is exposed daily to both anthropogenic and natural contaminations from air, water, soils, food, and wastes. These exposures occur both indoors and outdoors and vary according to the life-style of the individuals as well as the area in which 23 I

1 I I I I I I I I I I I I they live. While the adverse health effects resulting from the most dramatic acute,, high level exposures to environmental contaminants that occur in occupation or emergency situations are easy to identify clinically, the effects caused by low level, chronic exposures that occur in ambient environmental settings are much more difficult to determine. An added complication is that while there is a tendency to examine the health effects of pollutants from the perspective of only one environmental media, such exposures are rarely limited to a single media. If these multi- media exposures are actually included as part of the process, the modeling of health effects produced by environmental pollutants can become overwhelmingly complex. It has been suggested that prolonged exposure to ETS may increase the risk of heart disease. Nonetheless, studies focusing on this issue fall far short of providing conclusive evidence for a causal association. Potential confounders deserve continued evaluation as possible bases for spurious positive results in epidemiologic studies. The multifactorial nature and the diversity of heart diseases makes it difficult to determine which confounders are the most important. In conclusion, the issue of ETS and the claimed link to a host of human diseases can not be scientifically resolved on the basis of currently available information. The findings vary in magnitude of effect and consistency among even the positive studies regarding the specific heart diseases that might be most affected. Given the biases and methodological limitations present in each of these 24 I

studies, the significance of the associations is questionable. Thus, the literature on ETS exposure and heart diseases remains equivocal. I I I I I I I I I I I . ~ Q 2 5 'CIT ~ ~ N ~ N

Figure Legend Figure i. stages in the development of atherosclerotic plaque. A, norm..al appearance of the endothelium of an artery. B, endothelial injury results in the adherence of platelets to the damaged area. Platelets stimulate proliferation of smooth muscle cells in the tunica media and intima. C, lipoproteins and cholesterol accumulate along the endothelium. The atheroma enlarges as the process of "endothelial injury-SMC proliferation-lipid accumulation" is repeated. The endothelium is stretched and pushed into the lumen of the artery, forming an atherosclerotic plaque. D, the endothelium may rupture, triggering clot (thrombus) formation. I I I I I I ~ 0  26 L7D _ - W *A W I

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R6terences 1. Robbins, S.L., Angell, M., and Kumar, V. (1981) Basic Pathology, 3rd edition, Philadelphia, PA: Saunders, PP289-299. 2. Stehbens, W.E. (1991) J. Clin. Epidemiology 44, 999-1006. imprecision of the clinical diagnosis of coronary disease in epidemiological studies and atherogenesis. ,.. 3. Kuller, L., Borhani, N., Furberg, C., Gardin, J., Manolio, T., O'Leary, D., Psaty, B., and Robbins, J. (1994) Am. J. Epidemiol. 139, 1164-1179. Prevalence of subclinical atherr%-,clerosis and I I I I I I I I I , cardiovascular study r cardiovascular disease and association with risk factors in the 4. Strong, J.P., Solberg, L.A. and Restrapo, C. (1968) Lab. , Invest. 18, 527-537. Atherosclerosis in persons with coronary heart disease. 5. Kupari, M., Hekali, P., Keto, P., Poutanen, V-P, Tikkanen, M.J., and Standertskjold-Nordenstam, C.G. (1994) Arterioscler. Throm. 14, 386-394. Relation of aortic stiffness to factors modifying the risk of atherosclerosis in healthy people. 6. Ross, R., and Glomset, J.A. (1976) N. Engl. J. Med. 295, 369- 372. The pathogenesis of atherosclerosis. 7. Benfante, R.J., Reed, D.M., MacLean, C.J., and Yano, K. (1989) J. Clin. Epidemiol. 42, 95-104. Risk factors in middle age that predict early and late onset of coronary heart disease. 8. Wu, C.C.., Chen, S.J., and Yen, M.H. (1992) Clin. and Exptl. Pharmacol. and Physiol. 19, 833-838. Effects of noise on blood pressure and vascular reactivities. 27

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