Plausible biological mechanisms remain elusive to explain the association between daily fluctuations in air pollution and increased mortality rates. Specifically, airborne particulate matter (PM) has been identified as the constituent of air pollution that is most culpable in correlating with increased mortality rates. Pathophysiologic mechanisms leading to tachycardia and bradycardia appear potential processes that increase PM-induced risk of mortality in humans and animal models. Because epidemiology studies also identify aging as a risk factor, we developed a unique model to define risk associated with terminal senescence based on a series of pathophysiological assays. HYPOTHESIS: Senescent-dependent changes in the neurohumoral regulation of the heart during PM exposure manifest acute instability in cardiac function resulting from imbalances in the autonomic nervous control and altered atrial natriuretic peptide regulation.
Specific aim 1 characterizes specific pathophysiologic variables associated with loss of homeostasis in senescent mice of different inbred mouse strains.
Specific aim 2 determines the interactive effects of terminal senescence and acute PM exposure on heart rate regulation and cardiac function. Here, we postulate that only terminally senescent animals are susceptible to the acute cardiac effects of PM exposure.
Specific aim 3 determines the interactive role of innate susceptibility factors in acute PM-induced imbalances in autonomic neural regulation of heart rate, blood pressure and cardiac function. The focus of this aim considers PM-induced cardiac functional changes owing to genetic susceptibility factors.
Specific aim 4 tests whether senescent-dependent susceptibility to PM-induced cardiovascular dysfunction evolves from adverse modifications in atrial natriuretic peptide (ANP) regulation. In the final aim, cardiac mechanisms surrounding right ventricular function and pulmonary hypertension are considered important factors in PM-induced susceptibility. The interaction between aging and PM exposure obliterates the cardioprotective effects of ANP leaving the heart acutely susceptible to instability. In summary, the proposed studies are significant because they represent a multidisciplinary approach that will advance our understanding of the adverse cardiac health effects of air pollution exposure in the elderly ? ?
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