This proposal describes a 4-year training program designed to develop Dr. Dominic Chow as an independent investigator in the field of cardiovascular autonomic research related to human immunodeficiency virus type 1 (HIV-1). His long term goal is to study the pathogenesis of cardiovascular disease (CVD) in HIV disease. Dr. Chow is an internist and pediatrician specializing in HIV medicine at the University of Hawaii. Findings from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial funded by the NIAID, NIH which assessed the safety and efficacy of antiretroviral structured treatment interruption (STI) strategies in a multi-center trial of 5,472 participants, showed increased morbidity and mortality from CVD in those who interrupted antiretroviral therapy (ART) compared to those who continued to utilize ART. One hypothesis to explain this relatively prompt (within months) increase in CVD risk associated with STI is that viremia induced by discontinuation of ART leads to an increase in cardiovascular autonomic dysfunction in a population already vulnerable to autonomic dysfunction. Cardiovascular autonomic dysfunction in the general population has been associated with increased arrhythmia, cardiomyopathy and acute myocardial infarction. Thus, the candidate's hypothesis is that the presence of viremia leads to increased cardiovascular autonomic dysfunction. A prospective study involving 3 groups of patients as they undergo alterations in their ART is proposed to test the critical components of this hypothesis.
The specific aims are 1) to assess and correlate autonomic function by indirect testing [cardiovagal, adrenergic, and quantitative sudomotor axon reflex (QSART) tests] to the presence or absence of plasma HIV RNA in the 3 groups of subjects undergoing changes in ART, 2) to assess and compare autonomic (sympathetic) function by direct testing [muscle sympathetic nerve activity (MSNA)] in the presence or absence of plasma HIV RNA, 3) to determine if the relationship of plasma catecholamines (dopamine, noradrenaline and adrenaline) and inflammatory markers [C-reactive protein and tumor necrosis factor] are elevated with sympathetic activity and presence or absence of plasma HIV RNA, and 4) to determine if the relationship between sympathetic activity and flow-mediated brachial artery dilation (a marker of endothelial function and early atherosclerosis development) are inversely correlated with respect to the presence or absence of plasma HIV RNA. The career development plan proposed here incorporates mentoring and a patient-oriented research experience that will provide the foundation for comprehensive clinical research. The significance of this work will be to understand the interrelationships between the autonomic nervous system and the development of CVD in HIV disease.
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