Clinical Utility of Endothelial Function in PAD

描述(申请人提供)：外周动脉疾病(PAD)会导致相当大的发病率和死亡率，决定疾病进展和治疗反应的确切因素在很大程度上尚不清楚，除了他们严重的肢体缺血或移植失败的风险外，PAD患者患冠心病的风险也显著增加，尤其是在血管手术的压力下，很明显，需要新的方法来进行最佳的风险评估和治疗。以内皮功能为靶点是评估心血管疾病风险的传统方法的重大新背离。这一建议的中心假设是内皮功能障碍是PAD和冠心病事件的关键中介，检测内皮功能将有助于PAD患者的风险评估和治疗。申请者最近的研究有力地支持了这一观点，并确立了血管手术后PAD患者内皮功能障碍的预后价值。一个关键的悬而未决的问题是，逆转内皮功能障碍是否会直接降低风险。这一发现将更有力地证实内皮功能障碍是PAD和冠心病风险的中介，并进一步验证其临床实用性。我们提出以下具体目标：1.确定逆转内皮功能障碍是否能改善PAD患者的围手术期风险。接受选择性血管手术的患者将在手术前一个月开始接受大剂量阿托伐他汀(80毫克/天)、抗坏血酸(500毫克/天)或安慰剂的随机双盲治疗，手术后持续一个月。血管功能的非侵入性评估将在基线和手术前立即进行。患者将在术后30天内接受心血管事件(心源性死亡、心肌梗死、不稳定心绞痛和中风)的监测。目的是确定血管功能的改善是否独立地预测结果(无论哪种治疗方法产生改善)。2.确定内皮功能障碍是否预示PAD患者的长期(2年)PAD和冠心病风险。3.确定氧化应激和炎症的系统标志物是否与内皮功能障碍、长期PAD和冠心病风险有关。这项工作将为PAD的发病机制和治疗提供新的信息。

DESCRIPTION (provided by applicant): 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.