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Air Pollutants: Cardiovascular Effects and Mechanisms

Ann Bonham, Chao-Yin Chen, Barbara Horwitz, Kent Pinkerton, Michael Kleeman,
and Nipavan Chiamvimonvat
University of California–Davis, Davis, CA

EPA Grant Number: RD831918

Project Description:

Epidemiological studies link exposure to airborne particulates with mass aerodynamic diameter less than or equal to2.5 µm (PM2.5) and cardiovascular consequences including ventricular arrhythmias and sudden cardiac death. The causes are poorly understood, but reduced heart rate variability (HRV) is particularly compelling since it is an index of impaired cardiac vagal regulation and is associated with increased susceptibility to ventricular arrhythmias and sudden death. Moreover, the elderly appear to be particularly susceptible. The challenge is to link the epidemiological findings to causes and mechanisms. Toward that end, we propose to test three hypotheses: (1) that exposure (3, 7, 14, and 28 days) to ambient air pollutants reduces HRV by causing neuroplasticity in the intrinsic or synaptic excitability of cardiac vagal neurons in the nucleus ambiguus (NA) which control HRV; (2) that the decreased HRV and mechanisms are different in summer vs. winter due to season-dependent particulate composition; and (3) that the decreased HRV and mechanisms are exaggerated in the elderly. We will test the hypotheses by five objectives, using state-of-the-art inhalation facilities to deliver environmentally relevant and comprehensively characterized “real world” particulate pollutants in the form of concentrated ambient air particles (CAPs) of the PM2.5 fraction to a mouse model shown to exhibit reduced HRV in response to indoor air PM2.5 exposure. Mice of median age 3-4 months (age equivalent to young adult humans) and of 26-28 months (age equivalent to elderly humans) will be exposed to one of the following: CAPs PM2.5 in summer (when motor vehicle exhaust contributes 43% and wood smoke contributes 1% to total PM2.5); filtered air (FA) as a summer control group; CAPs PM2.5 in winter (when vehicle exhaust contributes 22 % and wood smoke 21%) and FA as a winter control group. Mice will be studied after 3, 7, 24, and 28 days exposures. Objective 1 will determine if PM2.5 exposure reduces HRV, by quantifying overall 24-h HRV, diurnal changes in HRV, and heart rate recovery following an acute stressor (exercise) in conscious, freely moving mice. Objectives 2 and 3 will use patch clamping to determine if the PM2.5 exposure-induced decrease in HRV is mediated by decreased intrinsic excitability of NA cardiac vagal neurons through changes in specific potassium channel conductances. Objectives 4 and 5 will determine if the PM2.5 exposure-induced decrease in HRV is mediated by decreased synaptic excitability via enhanced inhibitory (l-aminobutyric acid) and/or reduced excitatory (glutamatergic) mechanisms. The results should provide a model and mechanisms for cardiovascular consequences to air pollution and should improve public awareness of PM2.5.


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