The overall goal of this application is to provide support and training for the applicant towards becoming an independent, patient-oriented clinical investigator in the field of vascular biology. The proposed application builds on the applicant's previous research experience, provides new training, and examines a highly relevant clinical question conducted in a mentor-based environment ideally suited for the completion of this project. The overall objective of the proposed plan is to investigate the importance of examining endothelial function as a predictor of cardiovascular events in patients with atherosclerotic vascular disease. The vascular endothelium regulates vasomotor tone, platelet activity, and inflammation through the synthesis and elaboration of a number of factors including endothelium-derived nitric oxide (EDNO). Endothelium-dependent vasodilation and platelet inhibition are impaired in atherosclerosis and associated conditions, possibly due to increased vascular oxidative stress and reduced NO bioactivity. Loss of normal vascular endothelial function favors a local vasospastic, prothrombotic, and proinflammatory milieu, and is linked to the pathophysiology of cardiovascular events including myocardial infarction, stroke, and unstable angina. However, no study to date has demonstrated that impaired endothelial function is predictive of cardiovascular risk. Patients with peripheral arteriosclerotic disease undergoing vascular surgery have multiple risk factors for endothelial dysfunction, and are at high-risk for perioperative cardiovascular events. Using non- invasive, high-resolution vascular ultrasound analysis of brachial arterial vasomotor function, this project proposes in specific aim 1: to determine whether patients with impaired preoperative vascular endothelial function have increased cardiovascular events at the time of vascular surgery compared to patients with normal endothelial function, and in specific aim 2: to determine whether pretreatment of subjects with impaired endothelial function using the antioxidant ascorbic acid (Vitamin C) reduces perioperative cardiovascular events during vascular surgery. Identifying high-risk subjects with impaired vascular function may lead to potential improvement in management of these patients.
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