Project Summary This proposal will evaluate the novel role of renin-angiotensin-aldosterone system (RAAS) activation as a key driver of inflammatory mediated cardiovascular disease (CVD) in HIV and represents a substantial investigative departure from understanding the traditional physiologic role of the RAAS in regulating sodium balance and blood volume. There is a considerable rise in non-AIDS related morbidity and mortality secondary to cardiovascular complications among those HIV patients well treated on antiretroviral therapy (ART), and studies show that HIV patients are at a two-fold increased risk for CVD compared to the general population. In support of this, cardiac imaging studies from our group demonstrate critical evidence that HIV patients have a higher prevalence of a vulnerable type of coronary plaque, more inflamed and prone to rupture. Overall, combined use of ART and conventional agents, such lipid and glucose lowering medications, are not completely effective for CVD risk reduction in HIV. In this regard, no current FDA approved strategies are available to significantly lower the risk of CVD in the HIV population. Therefore, CVD in HIV presents an unmet public health challenge that demands investigation of a novel therapeutic target, which importantly leverages an HIV-related mechanism. In this regard, preliminary data from the Candidate demonstrate that HIV patients have increased aldosterone in association with excess visceral adiposity and insulin resistance compared to non-HIV individuals during a RAAS activated state. Moreover, the Candidate has shown that the RAAS activated state stimulates a pro- inflammatory milieu among the HIV population. An important sequela of progressive inflammation is atherosclerotic disease. Taken together, these novel data suggest a unique metabolic phenotype in HIV with clinical relevance to CVD and provides the strong rationale for a physiologically based strategy to reduce RAAS activation in HIV-related CVD via mineralocorticoid receptor (MR) antagonism. In Aim I, the Candidate will perform a detailed and controlled physiologic investigation of the RAAS using sophisticated algorithms to assess differences in generalized and vascular inflammation during a RAAS activated vs. RAAS suppressed state. In Aim II, the Candidate will evaluate the clinical benefit of manipulating this hormonal system through implementation of a randomized, double-blinded placebo controlled trial evaluating first in the field effects of MR blockade on arterial inflammation in HIV. This study will use cardiac 18F-FDG-PET/CT technology, which takes advantage of a biologic approach to identify macrophage-rich vulnerable plaque through active tissue metabolism, to characterize arterial inflammation. Both Aims will be conducted in parallel, but are independent explorations that will provide new information to the field assessing RAAS physiology, inflammation, and CVD in the HIV population. The current K23 proposal is a comp...