Cardiovascular pathophysiology of environmental pollutants.

CARDIOVASCULAR DISEASE (CVD) is the leading cause of mortality in the industrialized world. In the United States alone, it kills 1 million people per year; accounting for over 40% of all deaths (50). Despite significant medical advances, the decline in CVD mortality in the United States that began in the 1960s has leveled off, and recent estimates suggest that it may be even beginning to rise again (33). More alarmingly, CVD is rapidly becoming a major cause of death worldwide, and current projections indicate that between 1990 and 2020, the proportion of worldwide deaths from CVD will increase from 28.9% to 36.3% (58). With the ominous increase in the incidence of diabetes and obesity, both of which profoundly affect cardiovascular health (6), the total burden of CVD in the future may be even greater. Although intensively studied, the reasons underlying the high incidence of CVD remain unclear. Several “risk factors” have been associated with the development of CVD, but it is sobering to consider that many patients suffering from heart disease have no established risk (32), suggesting that quantitatively important determinants of CVD are currently unknown (33). The development of CVD is a result of a chronic and complex interplay between genetic and environmental factors. Whereas genetic makeup is a critical determinant (related to a set of nonmodifiable risk factors such as age, sex, family history, height, and postmenopausal status in women), large changes in the incidence of CVD over the last century indicate that environmental influences are also as important. Multiple studies show that nongenetic factors such as diet, smoking, physical activity, and alcohol intake significantly modify CVD risk (50). In addition, it has been reported that migration of genetically similar populations to new environments alters CVD risk (33), indicating that heart disease is not an inevitable fate of an aging population, but that its development is profoundly modified by the environment. Other contributors of risk, e.g., elevated low-density lipoprotein (LDL) cholesterol, hypertension, diabetes, obesity, reduced high-density lipoprotein (HDL), lipoprotein a, fibrinogen, homocysteine, plasminogen activator inhibitor, and left ventricular hypertrophy are a combination of environmental and genetic factors. Indeed, the term “risk factor” was coined by the Framingham group investigating the epidemiology of CVD (50). Since then there have been extensive and ongoing efforts to establish that environmental factors contribute to the induction, progression, and severity of CVD; although a clear role of environmental pollutants in affecting heart disease is only now beginning to emerge. There are multiple reasons for the delayed appreciation of cardiovascular toxicity as a significant outcome of pollutant exposure. Whereas some of these reasons relate to historical chance or bias, others may be related to the difficulty in demonstrating small changes in CVD risk over the high background levels of the disease. Added to this is the experimental difficulty in demonstrating the effects of pollutants on CVD because only the severity and progression, rather than induction, of the disease are likely to be affected. Such demonstrations require well-established animal models of ongoing CVD, some of which have become available only in the last few years [e.g., the apolipoprotein E-knockout (apoE)or the LDLreceptor null mice] or are still under development (such as those for studying the cardiovascular complications of effect of Type 2 diabetes on CVD). Finally, because the heart and blood vessels are neither the site of primary exposure (as lung, gut, or skin) nor of metabolism and detoxification (e.g., kidney or liver), it has been tacitly assumed that cardiovascular tissues suffer less from exposure to environmental toxins. This assumption is, however, not supported by extensive data demonstrating robust cardiovascular effects of environmental pollutants. The most dramatic example of these is provided by the studies on the cardiovascular effects from smoking, which have consistently demonstrated over the past 30 years that smoking dramatically exacerbates CVD (50). More than 400,000 deaths in the United States per year are due to tobacco smoke-related illness, roughly half of which could be attributed to cardiovascular causes (3). The untoward cardiovascular effects of tobacco smoke and its constituents such as butadiene are graded and appear on exposure to concentrations that are much lower than those that lead to cancer (50, 65). In animal models, exposure to cigarette smoke has been directly shown to increase atherogenesis (25) and myocardial infarct size (99). Moreover, exposure to second-hand cigarette smoke exacerbates atherosclerotic lesion formation and mitochondrial DNA damage in the aorta of apoE-null mice (42), indicating that passive smoking could affect CVD progression synergistically with hypercholesterolemia. The high vulnerability of cardiovascular tissues to environmental pollutants is dramatically underscored by a recent report showing that the hearts of rats exposed to environmental tobacco smoke accumulate as many DNA adducts as the lung (36). When the exposure was stopped, the number of DNA lesions in lung and the tracheal epithelium was diminished, but no significant DNA repair was observed in the myocardium, indicating a relatively high vulnerability of the heart to chronic and cumulative injury caused by environmental toxins (36). In addition to tobacco smoke, other pollutants have also been reported to affect cardiovascular tissues (vide infra). However, the most persuasive data to emerge from such studies relate to the effects of ambient particulate matter on heart disease and CVD mortality. These data point toward a link between the levels of air particulates and CVD and lend support to the notion that pollutants can adversely affect cardiovascular health.