Ultrafine Particle Exposure in Humans

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DESCRIPTION (provided by applicant): Hypotheses: Exposure to ambient air particles is associated with increased risk for cardiovascular mortality, cardiac arrhythmias, and myocardial infarction, but the mechanisms are unknown. Dysfunction of the vascular endothelium is critically linked to the pathogenesis of atherosclerotic vascular disease, and factors affecting myocardial repolarization influence the susceptibility to arrhythmias. We will test the hypotheses that: 1) inhalation of ultrafine particles alters endothelial function in nonsmokers and smokers, and 2) inhalation of ultrafine particles alters ventricular repolarization. Specific Aims: 1) Determine in nonsmokers the effects of inhalation of clean air and 50 pg/rn3 carbon UFP on endothelial function, leukocyte activation, and leukocyte oxidant production. 2) Determine in current smokers the effects of inhalation of clean air and 50 pg/rn3 carbon UFP on endothelial function, leukocyte activation, and leukocyte oxidant production. 3) Identify effects of inhalation of clean air and 50 pg/rn3 carbon UFP on cardiac repolarization in nonsmokers and smokers. Methods: Forty-eight healthy nonsmokers will undergo exposures to air and 50 pg/rn3 carbonaceous UFP for 2 hours with intermittent exercise, in a double-blind, randomized, two period crossover study design. Subject groups will be stratified by both age and gender. Before and at intervals after exposure, phlebotomy will be performed and endothelial function will be assessed using flow mediated vascular dilatation of the forearm (FMD). Continuous 24-hour 12-lead ECG monitoring will be obtained with each exposure, and analyzed for changes in ventricular repolarization, heart rate, and heart rate variability. Primary outcomes will be changes in FMD and the duration of ventricular repolarization as measured by the corrected QT interval on the ECG. Secondary outcomes will include markers of blood leukocyte activation and expression of adhesion molecules, plasma endothelins and nitric oxide, heart rate and heart rate variability, and additional measures of cardiac repolarization. Following completion of these studies in nonsmokers, an identical study protocol will be undertaken in current smokers. In both studies we will determine by correlation analysis whether blood markers of systemic inflammation or blood vitamin E levels at baseline influence the cardiovascular responses to UFP. These studies will identify key mechanisms for the cardiovascular effects of exposure to ambient air particles.