Research Aging Study Prospective Cohort Study of Lead Exposure and Electrocardiographic Conduction Disturbances in the Department of Veterans Affairs Normative Ki-Do Eum,1 Linda H. Nie,2 Joel Schwartz,1 Pantel S. Vokonas,3 David Sparrow,3 Howard Hu,4 and Marc G. Weisskopf 1 1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 2School of Health Sciences, Purdue University, West Lafayette, Indiana, USA; 3Veterans Affairs Boston Healthcare System and Boston University School of Medicine and Public Health, Boston, Massachusetts, USA; 4Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA Background : No studies have examined the association between cumulative low-level lead expo- sure and the prospective development of electrocardiographic conduction abnormalities, which may mediate the association between lead and several cardiovascular end points. o Bjectiv : We prospectively examined the association between lead exposure and the development of electrocardiographic conduction abnormalities. Methods : We assessed blood lead, bone lead—a biomarker of cumulative lead exposure— measured with K-shell X-ray fluorescence, and electrocardiographic end points among 600 men in the Normative Aging Study who were free of electrocardiographic abnormalities at the time of the baseline ECG. Of these men, we had follow-up data from a second electrocardiogram for 496 men 8.1 (SD = 3.1) years later, on average. We used repeated measures linear regression to analyze change in electrocardiographic conduction timing and logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for developing specific conduction disturbances and adjusted for potential confounders. r sulte : Mean (± SD) blood (5.8 ± 3.6), patella bone (30.3 ± 17.7), and tibia bone (21.6 ± 12.0) lead concentrations were similar to those found in samples from the general U.S. population and much lower than those reported in occupationally exposed groups. Compared with those in the lowest tertile of tibia lead, those in the highest had a 7.94-ms (95% CI, 1.42–14.45) increase in heart rate–corrected QT (QTc) interval and a 5.94-ms increase in heart rate–corrected QRS (95% CI, 1.66–10.22) duration > 8 years. Those in the highest tertile of tibia lead also had increased odds of QT prolongation (QTc ≥ 440 msec; OR = 2.53; 95% CI, 1.22–5.25) and JT prolongation (heart rate–corrected JT > 360 msec; OR = 2.53; 95% CI, 0.93–6.91). Results were weaker for patella lead. No associations were identified with blood lead. c onclusi : This study suggests that low-level cumulative exposure to lead is associated with worse future cardiac conductivity in the ventricular myocardium, as reflected in QT interval characteristics. k ey words : ECG, electrocardiographic conduction, environmental exposure, epidemiology, lead, prospective study. Environ Health Perspect 119:940–944 (2011). doi:10.1289/ehp.1003279 [Online 17 March 2011] (JTc) intervals and in QRSc duration among the same participants in the NAS as the previ- ous report of findings. Materials and Methods Study population. This prospective cohort study was conducted within a subgroup of the NAS, a cohort study of aging established by the U.S. Veterans Administration (VA) in 1963. The VA recruited 2,280 men who were living in the Greater Boston area who were free of known chronic medical conditions such as heart disease, hypertension, diabetes mellitus, cancer, peptic ulcer, gout, recurrent asthma, bronchitis, and sinusitis (Bell et al. 1966). The details on the cohort, as well as the subgroup in which bone lead levels were measured, have been described elsewhere Address correspondence to M.G. Weisskopf, Department of Environmental Health, Environmental and Occupational Medicine and Epidemiology, Harvard School of Public Health, Landmark Center, 401 Park Dr., P.O. Box 15697, Boston, MA 02215 USA. Telephone: (617) 384-8872. Fax: (617) 384- 8994. E-mail: mweissko@hsph.harvard.edu The authors gratefully acknowledge the research assistance of H. Guan and the enthusiastic coopera- tion of the NAS participants. This study was funded primarily by grants from the National Institute of Environmental Health Sciences (NIEHS; RO1-ES05257, K01-ES012653, and P42-ES05947) and by the NIEHS Center Grant (P30-ES0002). K-D.E. was supported in part by the Korea Research Foundation Grant (KRF-2008-357- E00019), which is funded by the Korean Government. Subjects were evaluated for bone lead levels in the outpatient General Clinical Research Center, Brigham and Women’s Hospital with support from the National Institutes of Health (grant NCRR GCRC M01RR02635). The K-shell X-ray fluorescence instrument used in this work was developed by ABIOMED, Inc., of Danvers, Massachusetts, with support from NIH (grant SBIR 2R44 ES03918-02). The Normative Aging Study (NAS) is supported by the Research Services and the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center. The views expressed in this paper are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs. The authors declare they have no actual or potential competing financial interests. Received 1 December 2010; accepted 16 March 2011. ovlume 119 | number 7 | July 2011 • Environmental Health Perspectives Lead is ubiquitous in the environment and has been associated with cardiovascular mor- tality (Lustberg and Silbergeld 2002; Menke et al. 2006; Schober et al. 2006; Weisskopf et al. 2009) and cardiovascular disease (Navas- Acien et al. 2007), which is the leading cause of death worldwide (Lopez et al. 2006) and accounts for 26% of total deaths in the United States (Heron et al. 2009). One possible mechanism for these cardiovascular effects of lead is electrocardiographic conduction abnormalities that have been shown to predict future cardiovascular disease and mortality (Chugh et al. 2009; Dekker et al. 2004). Cross-sectional studies among highly exposed workers have explored associations between lead exposure and electrocardio- graphic conduction abnormalities, although with somewhat inconsistent results (Kopp et al. 1988). Only one previous study has explored these associations among people exposed at general environment levels well below those seen in occupational settings (Cheng et al. 940 1998). That study among participants in the Normative Aging Study (NAS) of the U.S. Department of Veterans Affairs (VA) found an association of cumulative lead exposure with higher heart rate–corrected QT (QTc) interval and heart rate–corrected QRS (QRSc) dura- tion, and with higher risk of intraventricular conduction defect (IVCD), but only among men < 65 years of age. That study, however, considered lead exposure and conduction abnormalities measured at the same time and therefore had to include people with existing conduction deficits. No prospective follow-up study has been performed to assess the asso- ciation of lead exposure with change in these parameters over time among those participants who were free of disturbances at baseline. In the present study, we investigated the potential association between lead exposure biomarkers at baseline and future QT prolon- gation, IVCD, and atrioventricular conduc- tion defect (AVCD), as well as changes over time in the QTc and heart rate–corrected JT