Research Traffic-Related Air Pollution and QT Interval: Modification by Diabetes, Obesity, and Oxidative Stress Gene Polymorphisms in the Normative Aging Study Emmanuel S. Baja,1 Joel D. Schwartz,1 Gregory A. Wellenius,2 Brent A. Coull,3 Antonella Zanobetti,1 Pantel S. Vokonas,4,5 and Helen H. Suh1 1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 2Department of Community Health, Brown University, Providence, Rhode Island, USA; 3Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA; 4Veterans Affairs Normative Aging Study, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA; 5Department of Internal Medicine, Boston University, Boston, Massachusetts, USA Background : Acute exposure to ambient air pollution has been associated with acute changes in cardiac outcomes, often within hours of exposure. o Bjectivs : We examined the effects of air pollutants on heart-rate–corrected QT interval (QTc), an electrocardiographic marker of ventricular repolarization, and whether these associations were modified by participant characteristics and genetic polymorphisms related to oxidative stress. Methods : We studied repeated measurements of QTc on 580 men from the Veterans Affairs Normative Aging Study (NAS) using mixed-effects models with random intercepts. We fitted a qua- dratic constrained distributed lag model to estimate the cumulative effect on QTc of ambient air pol- lutants including fine particulate matter ≤ 2.5 µm in aerodynamic diameter (PM2.5), ozone (O3), black carbon (BC), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2) concentrations during the 10 hr before the visit. We genotyped polymorphisms related to oxidative stress and analyzed pollution–susceptibility score interactions using the genetic susceptibility score (GSS) method. r esult : Ambient traffic pollutant concentrations were related to longer QTc. An interquartile range (IQR) change in BC cumulative during the 10 hr before the visit was associated with increased QTc [1.89 msec change; 95% confidence interval (CI), –0.16 to 3.93]. We found a similar association with QTc for an IQR change in 1-hr BC that occurred 4 hr before the visit (2.54 msec change; 95% CI, 0.28–4.80). We found increased QTc for IQR changes in NO2 and CO, but the change was statistically insignificant. In contrast, we found no association between QTc and PM2.5, SO2, and O3. The association between QTc and BC was stronger among participants who were obese, who had diabetes, who were nonsmokers, or who had higher GSSs. c onclusi : Traffic-related pollutants may increase QTc among persons with diabetes, persons who are obese, and nonsmoking elderly individuals; the number of genetic variants related to oxida- tive stress increases this effect. k ey words : air pollution, diabetes, distributed lags, genes, obesity, oxidative stress, QT interval, smoking, traffic. Environ Health Perspect 118:840–846 (2010). doi:10.1289/ehp.0901396 [Online 1 March 2010] life-threatening ventricular arrhythmias. These findings suggest a possible biological path- way linking an acute effect of air pollution on increased risk of ventricular repolarization, cardiovascular arrhythmias, and cardiac death. However, the effect of air pollution on repolari- zation parameters in other populations at risk should be addressed and confirmed. We hypothesized that short-term expo- sures to traffic-related air pollutants may be associated with increases in ventricular repo- larization, as measured by changes in the heart-rate–corrected QT interval (QTc) on the electrocardiogram (ECG), and that par- ticipant characteristics and genes related to oxidative stress may modify this association. Thus, in this study, we investigated the asso- ciation between ambient air pollution [black carbon (BC), carbon monoxide (CO), NO2, ozone (O3), PM ≤ 2.5 µm in aerodynamic diameter (PM2.5), and sulfur dioxide (SO2)] and a measure of ventricular repolarization, the QTc, among men residing in commu- nities in the Boston, Massachusetts (MA), area to examine whether this association is modified by participant characteristics and by genetic susceptibility to oxidative stress. We evaluated these aims using data from a prospective longitudinal study of 580 elderly male participants of the Veterans Affairs (VA) Normative Aging Study (NAS). Materials and Methods Study population. The NAS is an ongoing longitudinal study of aging, which was estab- lished in 1963 by the Veterans Administration (Bell et al. 1972). Briefly, 2,280 community- dwelling, healthy men living in the Greater Address correspondence to E.S. Baja, Exposure, Epidemiology, and Risk Program, Harvard School of Public Health, 401 Park Dr., Suite 422 Landmark Center West, Boston, MA 02115 USA. Telephone: (617) 384-8848. Fax: (617) 384-8745. E-mail: ebaja@hsph.harvard.edu Supplemental Material is available online (doi:10.1289/ehp.0901396 via http://dx.doi.org/). This work was supported by grants from the National Institute of Environmental Health Sciences (ES014663-01A2 and P01 ES09825) and from the U.S. Environmental Protection Agency (EPA R827353 and R83241601). The authors declare they have no actual or potential competing financial interests. Received 28 August 2009; accepted 1 March 2010. ovlume 118 | number 6 | June 2010 • Environmental Health Perspectives Evidence from epidemiologic studies shows a consistent association between increased ambient air pollution and increased daily hospital admission (Lee et al. 2007; Santos et al. 2008; Schwartz 1999; Zanobetti and Schwartz 2006) and premature death (Pope et al. 2004; Schwartz 1994). Studies have further shown that the pollution-mediated impacts were largest for cardiovascular- related illness and deaths (von Klot et al. 2009; Zanobetti and Schwartz 2007). Several biological mechanisms by which air pollution can elicit cardiovascular morbidity and mor- tality have been identified, including oxida- tive stress (Gurgueira et al. 2002), autonomic dysfunction (Gold et al. 2000), and systemic inflammation (Peters et al. 2001b; Ruckerl et al. 2006), leading to endothelial dysfunc- tion (O’Neill et al. 2005), atheromatous plaque (Sun et al. 2005; Suwa et al. 2002), and thrombosis (Baccarelli et al. 2008). However, the specific underlying biologi- cal pathways are not fully understood, and the identification of these pathways warrants further study. 840 Of particular interest are recent studies that suggest that myocardial infarctions risk (Peters et al. 2001a, 2004), inflammation (Ruckerl et al. 2006), and cardiac repolarization changes (Henneberger et al. 2005; Yue et al. 2007) may be associated with exposures to air pollu- tion on time scales of less than a day. Because standards for particles and nitrogen dioxide (NO2) currently involve longer-term averages, these studies suggest that the relation of hourly peaks in air pollution with indicators of cardio- vascular health should be examined. Of the cardiovascular health indicators, irregularities in myocardial repolarization may be especially important because they can lead to the development of cardiac arrhythmias. Two panel studies of patients with cardiovascular dis- ease, which were conducted in East Germany, showed evidence of an immediate effect of air pollution on ventricular repolarization dura- tion, morphology, and variability (Henneberger et al. 2005; Yue et al. 2007). Ljungman et al. (2008) found that patients with implantable cardioverter defibrillators also showed evidence of rapid effects of air pollution on the risk of