Clinical Utility of Endothelial Function in PAD

内皮功能在 PAD 中的临床应用

• 批准号: 6803031
• 负责人: Joseph A. Vita
• 金额: $ 99.97万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803031
• 关键词: angina pectoris; angiocardioultrasonography; ascorbate; atherosclerosis; atorvastatin; biomarker; cardiovascular disorder chemotherapy; cardiovascular disorder risk; cardiovascular function; cardiovascular surgery; clinical research; clinical trials; human therapy evaluation; inflammation; ischemia; myocardial infarction; oxidative stress; patient oriented research; peripheral blood vessel disorder; postoperative complications; preoperative state; stroke; sudden cardiac death; vascular endothelium; vascular resistance

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.

描述（由申请人提供）：外周动脉疾病（PAD）会产生相当大的发病率和死亡率，而决定疾病进展和治疗反应的确切因素仍然很大程度上未知。除了严重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着增加，特别是在血管手术的压力下，显然需要新的方法来进行最佳的风险评估和治疗。 以内皮功能为目标代表了评估心血管疾病风险的传统方法的一个重大新突破。 该提案的中心假设是内皮功能障碍是 PAD 和冠心病事件的关键介导因素，测量内皮功能将增强 PAD 患者的风险评估和治疗。 申请人最近的研究强烈支持这一论点，并确立了内皮功能障碍对于接受血管手术的 PAD 患者的预后价值。 一个尚未解决的关键问题是逆转内皮功能障碍是否会直接降低风险。 这一发现将更牢固地确立内皮功能障碍作为 PAD 和冠心病风险的中介因素，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可以改善 PAD 患者的围手术期风险。转诊择期血管手术的患者将从手术前一个月开始，以随机、双盲的方式接受高剂量阿托伐他汀（80 毫克/天）、抗坏血酸（500 毫克/天）或安慰剂治疗，持续一个月手术后。将在基线时和手术前立即进行血管功能的非侵入性评估。 术后 30 天期间将监测患者的心血管事件（心源性死亡、心肌梗塞、不稳定型心绞痛和中风）。 目标是确定血管功能的改善是否独立预测结果（无论哪种治疗产生改善）。 2. 确定内皮功能障碍是否可以预测 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全身标志物是否与内皮功能障碍以及长期 PAD 和冠心病风险相关。 这项工作将为 PAD 的发病机制和治疗提供新的信息。