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 comprehensive five year training plan that presents an outstanding mechanism for a mentored career development award. The Candidate is a trained Endocrinologist and faculty member within the Division of Endocrinology at the Massachusetts General Hospital and Harvard Medical School with an investigative focus on mechanisms for cardiometabolic disease in HIV. The Candidate has assembled a robust mentoring team headed by Steven Grinspoon, MD (Massachusetts General Hospital) and Gail Adler MD, PhD (Brigham and Women's Hospital), both internationally recognized in their respective fields of HIV CVD risk assessment and mineralocorticoid physiology and well-funded. In addition, the Candidate will be supported by a diverse team of advisors providing sophisticated training in areas of cardiovascular imaging, biomarker science, nutrition and metabolism, HIV immunology and statistics. Moreover, the research infrastructure and educational tools available through the Harvard Catalyst and the Program in Nutritional Metabolism at Massachusetts General Hospital will provide a comprehensive training experience. The Candidate has demonstrated outstanding productivity in the early stages of her investigative career and would benefit from advanced mentorship and instruction to address the novelty of this grant proposal, which leverages concepts in physiologic algorithms for metabolic phenotyping, regulation and safety of a randomized controlled trial, mineralocorticoid systems physiology, radiographic modalities for non-invasive CVD risk assessment, immunophenotyping, and rigorous data handling for longitudinal data sets. HIV is a model of acquired chronic inflammation and CVD, and in this regard, these studies and research principles will serve as a paradigm in the long-term for advanced clinical and translational investigations focused on hormonal contributions to further inflammatory processes in HIV and other at risk populations, including obesity. To that end, funding from the K23 award will critically allow the Candidate to continue on a promising trajectory towards independence as a clinician scientist in patient-oriented research.