Endothelial Activation and Microangiopathy in HIV-related Cardiovascular Disease

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 DESCRIPTION (provided by applicant): Now that antiretroviral therapy (ART) has greatly reduced morbidity and mortality from opportunistic infections, a major challenge HIV care providers and their patients face is an elevated risk of premature or accelerated cardiovascular disease, often resulting in premature death. A growing body of evidence suggests that endothelial activation accompanies HIV infection, whether treated or untreated. Evidence for endothelial activation includes increased blood concentrations of the proteins released by activated endothelial cells, including soluble vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion marker 1 (ICAM-1), E- selectin, and an elevated angiopoietin 2 (ANG-2): angiopoietin 1 (ANG-1) ratio. Endothelial activation also increases release of the adhesive protein von Willebrand factor from endothelial storage granules, promoting platelet adhesion to the vessel wall, resulting in accelerated atherosclerosis in large vessels and platelet occlusion i small vessels, leading to microinfarcts and a form of "microangiopathy." This application aims to use prospectively collected data and samples from the CFAR Network of Integrated Clinical Systems (CNICS) research network to determine whether biomarkers of endothelial activation (ANG2:ANG1 ratio, sVCAM-1) and coagulation (VWF antigen, active VWF) are elevated prior to development of MI among HIV-infected patients taking ART and to elucidate the mechanisms by which HIV-associated endothelial dysfunction and altered hemostasis/thrombosis lead to premature or accelerated cardiovascular disease in persons living with HIV infection. The project teams a clinical epidemiologist with >10 years of HIV research experience (co-PI Graham) with an expert on thrombosis and hemostasis (co-PI López), a translational researcher renowned for his work on biomarker discovery and validation (co-I Liles), and experienced investigators from the CNICS Consortium (co-I Crane and consultant Hunt). This multi-disciplinary team will use an innovative translational approach to investigate the importance of endothelial activation and hemostasis/thrombosis biomarkers in primary myocardial infarction among HIV-infected persons, using valuable stored repository samples. This study will leverage the rigorously adjudicated patient outcomes in the CNICS cohort through the use of an innovative case-control design that will match cases and controls on time since ART initiation and ART regimen, thereby minimizing medication effects. Existing collaborations and proximity of the investigators, combined with the world-class facilities and resources of the University of Washington and Puget Sound Blood Center, will ensure successful implementation of this project. This work is a vital precursor to the development of strategies aimed at reversing or minimizing atherosclerosis and its clinical consequences by targeting underlying inflammation, endothelial dysfunction, and altered hemostasis with medications or other treatment regimens.