Effects of ultraﬁne and ﬁne particulate and gaseous air pollution on cardiac autonomic control in subjects with coronary artery disease: The ULTRA study KIRSI L. TIMONEN, a,b ESKO VANNINEN, b JEROEN DE HARTOG, c ANGELA IBALD-MULLI, d BERT BRUNEKREEF, c DIANE R. GOLD, e JOACHIM HEINRICH, d GERARD HOEK, c TIMO LANKI, a ANNETTE PETERS, d TUULA TARKIAINEN, b PEKKA TIITTANEN, a WOLFGANG KREYLING f AND JUHA PEKKANEN a a UnitofEnvironmentalEpidemiology,NationalPublicHealthInstitute,Kuopio,Finland b DepartmentofClinicalPhysiologyandNuclearMedicine,UniversityofKuopioandKuopioUniversityHospital,Kuopio,Finland c InstituteforRiskAssessmentSciences,UniversityofUtrecht,Utrecht,TheNetherlands d GSF,InstituteofEpidemiology,Neuherberg,Germany e ChanningLaboratory,BrighamandWomen’sHospitalandtheHarvardMedicalSchool,Boston,MA,USA f GSF,InstituteforInhalationBiology,Neuherberg,Germany Previous studies have shown an association between elevated concentrations of particulate air pollution and cardiovascular morbidity and mortality. Therefore, the association between daily variation of ultraﬁne and ﬁne particulate air pollution and cardiac autonomic control measured as heart rate variability (HRV) was studied in a large multicenter study in Amsterdam, the Netherlands, Erfurt, Germany, and Helsinki, Finland. Elderly subjects (n ¼ 37 in Amsterdam, n ¼ 47 in both Erfurt and Helsinki) with stable coronary artery disease were followed for 6 months with biweekly clinical visits. During the visits, ambulatory electrocardiogram was recorded during a standardized protocol including a 5-min period of paced breathing. Time and frequency domain analyses of HRV were performed. A statistical model was built for each center separately. The mean 24-h particle number concentration (NC) (1000/cm 3 ) of ultraﬁne particles (diameter 0.01–0.1 mm) was 17.3 in Amsterdam, 21.1 in Erfurt, and 17.0 in Helsinki. The corresponding values for PM2.5 were 20.0, 23.1, and 12.7 mg/m 3 . During paced breathing, ultraﬁne particles, NO 2 , and CO were at lags of 0–2 days consistently and signiﬁcantly associated with decreased low-to-high frequency ratio (LF/HF), a measure of sympathovagal balance. In a pooled analysis across the centers, LF/HF decreased by 13.5% (95% conﬁdence interval: 20.1%, 7.0%) for each 10,000/cm 3 increase in the NC of ultraﬁne particles (2-day lag). PM2.5 was associated with reduced HF and increased LF/HF in Helsinki, whereas the opposite was true in Erfurt, and in Amsterdam, there were no clear associations between PM2.5 and HRV. The results suggest that the cardiovascular effects of ambient ultraﬁne and PM2.5 can differ from each other and that their effect may be modiﬁed by the characteristics of the exposed subjects and the sources of PM2.5. Journal of Exposure Science and Environmental Epidemiology (2006) 16, 332–341. doi:10.1038/sj.jea.7500460; published online 5 October 2005 Keywords: particulateairpollution,epidemiology,heartratevariability,electrophysiology,nervoussystem,autonomic. Introduction There is growing epidemiological evidence on adverse effects of particulate air pollution on cardiovascular health. These effects include increased hospital admissions and mortality (Schwartz, 1999; Samet et al., 2000; Brunekreef and Holgate, 2002). The pathophysiological link between air pollution and the cardiovascular system is not known, but it has been proposed that high particle concentrations, particularly in the ultraﬁne range, are able to provoke alveolar inﬂammation, which in turn might release mediators capable of exacerbating lung disease and increasing blood coagulability in susceptible individuals (Seaton et al., 1995). Alternatively, it has been hypothesized that an increase in air pollution levels could modify autonomic nervous control of the heart in subjects with existing cardiovascular disease and thus lead to increased morbidity and mortality (Watkinson et al., 1998; Stone and Godleski, 1999; Godleski et al., 2000). In addition, it has been shown that inhaled ultraﬁne particles diffuse rapidly into the systemic circulation, and this process could account for extrapulmonary effects of air pollution (Nemmar et al., 2002). Heart rate variability (HRV) is a measure of the autonomic control of the heart. A decreased overall HRV is a predictor of mortality in subjects with prior myocardial infarction (Tsuji et al., 1994; Task Force, 1996). The results of previous smaller studies conducted among elderly suggest Received 7 June 2004; accepted 1 September 2005; published online 5 October 2005 1. Address all correspondence to: Dr. K.L. Timonen, Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Puijonlaaksontie 2, PO Box 1777, FIN-70211 Kuopio, Finland. Tel.: þ 358-17-173311. Fax: þ 358-17-173244. E-mail: Kirsi.Timonen@kuh.ﬁ Journal of Exposure Science and Environmental Epidemiology (2006) 16, 332–341 r 2006 Nature Publishing Group All rights reserved 1053-4245/06/$30.00 www.nature.com/jes