7. Project Summary/Abstract In the US, nearly half of the 1.1 million people with HIV (PHIV) are aged 50 and older. This aging HIV population is uniquely vulnerable to select cardiovascular (CV) comorbidities, including myocardial infarction (MI). Women with HIV (WHIV) face the highest HIV-attributable risk of MI: a 3-fold increased risk vs. non-HIV- infected women. Given the public health impact of MI-related morbidity and mortality, strong imperatives exist to better understand mechanisms underlying MI risk among WHIV. Characterization of pathways predisposing WHIV to MI will enable the development of rational MI prevention strategies and the targeted delivery of such strategies to women in need. Through this proposal, our interdisciplinary team will combine state-of-the-art non-invasive CV imaging with detailed molecular immune cell and endothelial cell phenotyping to define mechanisms predisposing WHIV to MI. Studying a prospectively recruited cohort of WHIV vs. non-HIV-infected women, we will explore a well-substantiated central hypothesis: Among women, HIV infection prompts systemic monocyte activation and endothelial cell pathology, predisposing to increased arterial inflammation. Arterial inflammation and endothelial cell pathology, in turn, promote not only non-calcified epicardial artery plaque but also coronary microvascular dysfunction. We plan to show that arterial inflammation and coronary microvascular dysfunction represent thus far neglected but potentially critical mechanisms of HIV-attributable MI risk among women – missing puzzle pieces (Aims 1-2). We also aim to delineate - on a molecular level - how circulating monocyte and vascular endothelial cell phenotypes differ among WHIV vs. non-HIV-infected women. Finally, we will investigate how pathologic monocyte/endothelial cell phenotypes may engender arterial inflammation, non-calcified epicardial artery plaque, and/or coronary microvascular dysfunction among WHIV (Aim 3). Confirmation of our central hypothesis will introduce a paradigm-shift in conceptualizing HIV- attributable MI risk among women – focused not only on macroscopic atherosclerotic plaque in the epicardial arteries but also on arterial inflammation and coronary microvascular dysfunction. Moreover, our work on mechanistic pathways engendering CV pathology among WHIV will inform the design of future research in the field. Specifically, we anticipate our work will suggest that strategies to mitigate monocyte honing to the vasculature (e.g. CCR2 blockade) or strategies to improve vascular endothelial cell function (e.g. metformin) should be tested for ability to forestall or reverse the key pathologic processes driving MI risk among WHIV. Further, our work will enable future studies on cardioprotective interventions among WHIV to be powered to the most appropriate CV surrogate risk endpoints – those which are found in this study to differ most strikingly among women with vs. without HIV. As MI is a highly-morbid, age...