The Impact of Thrombosis and Antithrombotic Therapy on Peripheral Artery Disease

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The applicant, Aaron W. Aday, MD, is an Instructor of Medicine in the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. The applicant's goal is to become an independent cardiovascular investigator studying the thrombotic mechanisms underlying peripheral artery disease (PAD) development. This application for a K23 Mentored Patient-Oriented Research Career Development Award describes a focused plan for the applicant to acquire the research skills and expertise required to transition into an independent investigator under the primary mentorship of Joshua A. Beckman, MD. The proposal centers on the study of thrombosis and antithrombotic therapy in PAD. PAD is a highly prevalent atherosclerotic disease associated with significant cardiovascular morbidity and mortality. However, there remain notable gaps in our knowledge of the biologic pathways involved in PAD development. Recent data suggest important contributions of thrombosis, through both coagulation cascade activation and platelet activation, to the development of PAD. However, the mechanisms of thrombosis and platelet activation contributing to PAD in humans are not fully known. The specific aims of the proposed research are: (Aim 1) to quantify the risk conferred by activation of thrombotic pathways, in addition to traditional cardiovascular risk factors, on PAD using Mendelian randomization; (Aim 2a) to test the hypothesis that low-dose rivaroxaban, a clotting factor Xa inhibitor, improves macro- and microvascular endothelial function in humans with PAD; and (Aim 2b) to test the hypothesis that low-dose rivaroxaban reduces PAR-1- mediated platelet activation while also facilitating thrombolysis and reducing inflammation via downstream signaling. The candidate has a strong background in both clinical vascular genetics as well as epidemiology of PAD. The proposed project will afford him new expertise in several key domains, including (1) genetic epidemiology and Mendelian randomization methods, (2) design and implementation of clinical trials, (3) patient-oriented vascular physiologic studies, and (4) translational investigations of thrombosis and platelet function. Vanderbilt University Medical Center has an ideal environment to support the candidate's investigational career. He will be supported by an outstanding mentorship team with extensive experience in clinical and translational cardiovascular research. However, the proposal will also provide Dr. Aday the opportunity to develop into a leading investigator with unique expertise in genetic epidemiology as well as mechanistic clinical trials focusing on PAD. Data from the proposed studies will also serve as the basis for future mechanistic and interventional studies (i.e. R01) of thrombosis in PAD. The support of this Career Development Award will provide Dr. Aday with the tools necessary to lead his own independent clinical and translational research program.