Emerging factors in the pathophysiology of endothelial dysfunction in HIV+ women

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Human immunodeficiency virus positive (HIV+) individuals are living longer with antiretroviral therapy (ART) but are now experiencing coronary artery disease (CAD) as an important cause of death, especially as they age. Because this CAD is not well explained by conventional CAD risk factors, we hypothesize that changes that occur in body composition in HIV result in increased metabolically-active visceral adipose tissue (VAT) in the abdomen and around the coronary arteries (epicardial adipose tissue: EAT) that releases inflammatory cytokines contributing systemically and locally to the fundamental processes accelerating CAD in HIV+ individuals. The increased local inflammation resulting from EAT may contribute to the process of coronary endothelial dysfunction which plays a critical role in the progression and clinical manifestations of CAD, and is a marker for sub-clinical disease, an independent predictor of adverse cardiac events, and a potential target for medical interventions. Moreover in HIV+ women other factors may be important in endothelial dysfunction such as a reduced ovarian reserve and other hormonal abnormalities that commonly affect women with HIV. We recently developed noninvasive, reproducible MRI-based methods to measure coronary endothelial function (CEF). This new ability to noninvasively evaluate CEF offers a means to probe mechanisms contributing to CAD pathophysiology HIV+ women and men. We propose in this application to determine 1) whether CEF and markers of inflammation and EAT are inversely related in HIV + people, 2) whether this relationship differs in women compared with men living with HIV and 3) whether reduced ovarian reserve is associated with endothelial abnormalities in HIV+ women. We will determine in HIV+ people whether reduced CEF can be explained, at least in part, by increased inflammation. Together these studies will offer new pathophysiologic insights into HIV-associated vascular disease, and how the pathophysiology may differ between women and men living with HIV. These studies are critical first steps to better understanding sex-differences in vascular disease that develops commonly in HIV. The proposed study is clinically feasible in the proposed time period, and could be used to design future therapeutic intervention studies, and may offer a fundamentally new understanding of the most important contributing factors of endothelial dysfunction in HIV.