ABSTRACT This is a K23 resubmission application for Dr. Brian Mac Grory, a vascular neurology investigator pursuing patient-oriented clinical research focused on the identification of novel populations with underexplored cerebrovascular disorders requiring personalized secondary prevention strategies. Based on his own preliminary data and recent publications, the central hypothesis of this proposal is that central retinal artery occlusion (CRAO) – a form of ischemic stroke affecting the retina – may be an indicator of underlying cardiac disease and a sentinel of future, potentially lethal, cardioembolic stroke. CRAO is formally recognized as a form of ischemic stroke but there is an incomplete understanding of its mechanistic underpinnings, with most research to-date focused on its association with carotid artery stenosis. Testing this application’s central hypothesis will address a fundamental knowledge gap about the mechanisms of CRAO. This K23 award proposes to generate key preliminary data linking CRAO with cardioembolic substrates and set the stage for a future, multi-center, observational study that will definitively test this hypothesis. Dr. Mac Grory will leverage a very large population-based dataset (the Medicare 5% Sample) as well as both retrospective and prospective institutional cohorts. Specific Aims 1A & 1B will determine the association of each of atrial fibrillation and left ventricular failure with the development of CRAO. Specific Aims 2A & 2B will determine the association of cardiac, serum and ultrasonographic biomarkers of embolic risk with CRAO and their interplay with carotid artery stenosis. As part of this proposal, Dr. Mac Grory will undertake a linked, didactic training plan with the goal of developing as an independent investigator through acquisition of the following key skills: 1) Biostatistics in observational research including advanced causal inference methodology, 2) Data science applied to administrative claims databases, 3) Prospective, observational study design, and 4) Vascular biomarker interpretation. Advanced training in these areas will permit Dr. Mac Grory to realize his long-term career goal of becoming an independent clinical investigator who leverages interdisciplinary expertise to provide insights in to the management of understudied cerebrovascular disorders. In pursuit of this goal, Dr. Mac Grory has assembled a mentoring team with distinct though complementary skillsets in stroke medicine, comparative effectiveness research, causal inference methodology, cardiac electrophysiology, and neuro-ophthalmology. Results supportive of this application’s central hypothesis would reveal a new population who may harbor occult cardioembolic disease. Results that are neutral or negative with respect to this central hypothesis would be equally valuable as they would allow us to refine the future study of CRAO by focusing on atherothrombotic mechanisms. With the preliminary data and training obtained from the ...