© 2005 American Thoracic Society doi: 10.1164/rccm.2508004
Cardiopulmonary Health Effects of Air Pollution:Is a Mechanism Emerging?Brody School of Medicine at East Carolina University Greenville, North Carolina Three articles appear in this issue of the Journal that further our understanding of the clinical consequences of air pollution, its physiologic effects, and its mechanisms. In the first article by Foras-tiere and colleagues (pp. 1549–1555), out-of-hospital cardiovascular death in Rome, Italy is shown to be positively associated with levels of ambient ultrafine particles, PM10 and CO (1). The exposure–risk relationship is linear, and aged adults are at highest risk. As such, the article shows a strong link between air pollution and out- of-hospital cardiac deaths, a result that differs from two previous studies conducted in the Seattle metropolitan area that found no association (2, 3). The second article by Schwartz and colleagues (pp. 1529–1533) provides evidence that oxidative stress transduces the physiologic response to particle air pollution (4). This conclusion is inferred from the observation that individuals lacking the gene glutathione S-transferase M1 (GSTM1), encoding an enzyme scavenging oxygen free radicals, show an increased sensitivity to inspired particulate matter as evidenced by greater changes in heart rate variability (HRV). Moreover, statins, which are known to have antioxidant and antiinflammatory properties in the cardiovascular system, mitigate against the effects of ambient particle air pollution to decrease HRV in subjects lacking the GSTM1 allele. In the third article, Romieu and colleagues (pp. 1534–1540) show that PM2.5 is associated with decreased HRV in a cohort of aged Mexican adults, and dietary supplementation with n-3 polyunsaturated fatty acid (PUFA) abrogated this response (5). Together, the articles by Schwartz and Romieu show that genetic polymorphisms or drugs modulating oxidant stress can mitigate against the effect of particulate air pollution, thereby providing evidence for oxidant stress as one of the mechanisms explaining the effect of particle air pollution on the cardiovascular system. The article by Forastiere and colleagues presents new data from Rome, Italy collected between 1998 and 2000, and associates out-of-hospital death due to coronary heart disease with levels of air pollution. Specifically, a case–crossover study design was used to investigate the relationship of out-of-hospital deaths to levels of several measured air pollutants: PM10, PM2.5, CO, NO2, NO, SO2, and O3. Particle number count (PNC) was not measured directly, but was imputed based on a predictive model created by estimating the relationship between measured PNC during 2001 and 2002 and the other constituents described above. It is important to consider that although 5,144 subjects formed the data set, 15,424 subjects were excluded because they had a myocardial infarction during the three years before death, or had deaths recorded in hospital, one day after discharge, or within 28 days after an admission for ischemic disease. This restriction of the data set probably produced a study population highly enriched with individuals having new ischemic or arrhythmic events; conditions hypothesized to be provoked by exposure to ambient air particle pollution. Thus, the characteristics of the study population compare favorably to the subjects included in two studies of out-of-hospital death that did not identify such an association (2, 3). In this study, PNC serves as a surrogate for ultrafine particles originating, for the most part, from local traffic sources. The findings that PNC and CO are associated with short-term risk of out-of-hospital cardiac death are compatible with the hypothesis that traffic-related ultafine particles or those originating from combustion increase risk of cardiac death. These observations agree with an increased risk of myocardial infarction after exposure to traffic (6), or to increased long-term risk of cardiopulmonary death among people living near major roads (7). With respect to short-term risk, it is speculated that the terminal event is initiated by myocardial ischemia. In the hypothesized scenario, air pollution increases oxidant stress and proinflammatory mediators, decreases vagal tone, increases platelet aggrega-tion, and shifts the hemostatic process toward thrombosis. Proinflammatory molecules increase instability of atherosclerotic plaques and further increase the likelihood of thrombosis and ischemia. In the ischemic heart diminished vagal tone then increases the likelihood of ventricular fibrillation and sudden cardiac death. The articles by Schwartz and colleagues (4) and Romieu and colleagues (5) use HRV as the primary cardiovascular endpoint. Schwartz and colleagues (4) present data showing that the presence of an allele for the glutathione S-transferase (GSTM1) gene abrogates the effect of PM2.5 on changes in HRV. The role for particulate induced oxidant stress is further supported by the observation that obesity, a clinical condition associated with elevated oxidant stress, enhances the effect of particle air pollution on changes in HRV. These findings are consistent with animal studies showing that inhalation of concentrated air particles increases oxidant levels in the lung and in the heart (8). Decreased vagal control of the heart is probably mediated through pulmonary responses to particles. These responses are not fully understood, but may be related to activation of pulmonary receptors and/or localized inflammatory responses dependent on oxidant stress. A less likely explanation for these results is the transmigration of ultrafine particles through the olfactory bulb into the central nervous system. Romieu and colleagues designed a study to assess the effect of n-3 PUFA supplementation (2 g/day of fish oil) on abrogating the effect of PM2.5 on HRV in a cohort of aged men and women in Mexico City. As in other studies, same-day levels of PM2.5 de-creased HRV in aged adults. Importantly, n-3 PUFA prevented the PM2.5-associated decrease in HRV. Previous studies have shown that n-3 PUFA has beneficial effects on oxidant stress, pro-and anti-inflammatory cytokines, platelet function, lipid profiles, endothelial and vascular function, and cardiac electrical properties. Therefore, in the context of the results of Schwartz and colleagues, the capacity of n-3 PUFA to prevent the decrease of HRV associated with particle air pollution is likely attributed to n-3 PUFA's effect on oxidant stress. Together, these studies indicate that ambient particle air pollution is associated with increases in out-of-hospital cardiac deaths and decreased autonomic control of the heart, an effect modulated at least in part by oxidant stress. Yet, as discussed previously, not all studies (2, 3) agree with these findings. Two recent articles may provide insight into these differences and furnish a rationale for future investigations to understand them. Liao and colleagues (9) recently confirmed that increased PM10 was associated with decreased autonomic control among middle-aged persons from four separate regions within the United States, and this was especially apparent in those with cardiovascular disease. Thus, evidence exists that the aged consistently show a loss of autonomic control of the heart in response to air particle pollution. Yet, Sullivan and colleagues (10) found no difference in HRV among 34 aged adults in response to increases in PM2.5. It is important to note that the study occurred in the Pacific Northwest, the same region of the country where other investigations detected no associations between sudden death (2, 3), myocardial infarction (11), hospital admissions or emergency department visits (12), and air particle pollution. These regional differences in outcome, consistent across endpoints, implicate source or constituents of particle air pollution as a factor driving the pathophysiologic response. Complications of atherosclerosis represent one of our most challenging public health problems. Apart from short-term risks, epidemiologic studies have linked air pollution to increased long-term risk. The Harvard Six Cities Study (13) showed that mortality from lung cancer and cardiopulmonary disease was positively associated with levels of air pollution, and most strongly associated with fine particles. These observations were recently confirmed in the Cancer Prevention II study (14). Within this cohort, for each 10 µg/m3 increase in annual average exposure to PM2.5, deaths from ischemic heart disease, arrhythmias, heart failure, and cardiac arrest increased from 8 to 18%, while mortality as-sociated with respiratory causes was only weakly associated. Such findings suggest that chronic exposure to particle air pollution might contribute to the acceleration of atherosclerosis, such as that observed in animal models exposed chronically to particulate matter, or among people living in Los Angeles, where intimal medial thickness was associated with levels of chronic ambient particle air pollution exposure (15). Because atherosclerosis is a process strongly modulated by oxidant stress and inflammation, the studies by Schwartz and Romieu suggest therapeutic strategies that may prevent acceleration of atherosclerosis due to particle exposure. Of course, there is no evidence at present justifying treatment of people with statins or n-3 PUFA who are at risk for air pollution's adverse effects. Yet, statins and fish oil are underused among patients having clinical indications for their use. As such, increased use of statins and fish oil, when indicated, may offer an opportunity to evaluate whether short-term risk of particle air pollution can be modified. For now, health benefits can be achieved through public awareness about environmental risks such as air pollution, extreme temperatures, and humidity. Individuals in sensitive groups, such as those with heart disease and with COPD, should take precautions and limit exposures on high pollution days. Information is now available in the media and at web sites supported by the U.S. Environmental Protection Agency, as well as individual states to guide physicians and the public. FOOTNOTES Conflict of Interest Statement: W.E.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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