Peripheral arterial disease (PAD) produces considerable morbidity and mortality, and the precise factors that determine disease progression and the responses to therapy remain largely unknown, In addition to their risk for critical limb ischemia or graft failure, PAD patients also have markedly increased risk for coronary heart disease, particularly during the stress of vascular surgery, It is clear that new approaches are needed for optimal risk assessment and therapy. Targeting endothelial function represents a major new departure from traditional methods for assessing cardiovascular disease risk. The central hypothesis of this proposal is that endothelial dysfunction is a critical mediator of both PAD and coronary heart disease events and measuring endothelial function will enhance both the risk assessment and therapy in PAD patients. Recent studies by the applicants strongly support this contention and establish the prognostic value of endothelial dysfunction in PAD patients undergoing vascular surgery. A key unresolved question is whether reversing endothelial dysfunction will directly reduce risk. This finding would more firmly establish endothelial dysfunction as a mediator of both PAD and coronary heart disease risk and further validate its clinical utility. We propose the following specific aims: 1. To determine whether reversing endothelial dysfunction ameliorates perioperative risk in PAD patients. Patients referred for elective vascular surgery will be treated with high dose atorvastatin (80 mg/day), ascorbic acid (500 mg/day), or placebo in a randomized, double blind, fashion beginning a month prior to surgery and continuing for a month after surgery. Non-invasive assessment of vascular function will be performed at baseline and immediately prior to surgery. Patients will be monitored for cardiovascular events (cardiac death, myocardial infarction, unstable angina, and stroke) in the 30-day postoperative period. The goal is to determine whether improvement in vascular function independently predicts outcome (irrespective of which treatment produces the improvement). 2. To determine whether endothelial dysfunction predicts long-term (2-year) PAD and coronary heart disease risk in PAD patients. 3. To determine whether systemic markers of oxidative stress and inflammation relate to endothelial dysfunction and long-term PAD and coronary heart disease risk. This work will provide novel information about the pathogenesis and management of PAD.
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