Mechanisms of Particulate Matter-Induced Cardiac Arrhythmias

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Ting Wang, PhD
Joe G.N. Garcia, MD
Parker B. Francis Fellowship, 2012-2015
Total Dollars: 
Statement of the Problem:  Epidemiologic studies consistently demonstrate strong associations between levels of ambient particulate matter (PM) air pollutants and cardiovascular mortality, hospital admissions, and emergency room visits. Acute and chronic cardiovascular toxicities of PM exposure in human and animal models include heart rate alterations, myocardial ischemia, cardiac arrhythmias, and heart failure. Insights into the biologic mechanisms of PM-mediated cardiac toxicity remain limited, and the exacerbation of heart failure/cardiomyopathy by PM is poorly understood. Specific Aims:  We hypothesize that PM-exacerbated cardiac arrhythmias involves multi-organ dysregulation centrally involving the lung which is superimposed upon a susceptible, cardiac phenotype (heart failure) predisposed to develop PM-mediated cardiac dysfunction. Specific Aim #1 will characterize mechanisms of PM-induced lung inflammation and disruption of vascular integrity which contributes to PMmediated cardiac toxicity. Specific Aim #2 will integrate the dysregulatory role of PM on cardiac ion channel expression and function as a terminal mechanism contributing to PM-mediated cardiac arrhythmias. Experimental Approach:  This application proposes to conduct novel studies to address the mechanistic effects of Chapel Hill ultrafine PM on cardiopulmonary responses in genetically-engineered mice which develop severe congestive heart failure (CHF). The direct cardiopulmonary toxicity following PM challenge will be assessed by cell biologic, physiological, electrophysiological and toxicogenomic tools in order to elucidate the role of PM-induced lung vascular hyperpermeability, pulmonary inflammation, and cardiac ion channel dysregulation in cardiomyopathic electrical aberrations. Significance of the Results:  Together, utilizing multidisciplinary approaches, these studies will provide novel molecular mechanistic insights into PM-mediated cardiac arrhythmia generation and potentially facilitate translation of this information into novel therapeutic strategies for patients at risk for adverse PM-induced cardiac outcomes.
Exposure to ambient particulate matter air pollution (PM) worsens a variety of cardiovascular diseases including heart failure and can lead to the development of fatal arrhythmias. We will investigate mechanisms of PM-mediated cardiac arrhythmias in mouse models. We propose that PM toxicity involves lung vascular leakage, autonomic dysfunction, and heart ion channel dysregulation. The presence of heart failure is a key predisposing factor for these adverse effects of PM and contributes to the cardiac arrhythmias induced by PM.