Endothelial Function and Peripheral Vein Bypass Graft Remodeling

描述（由申请人提供）：我是哈佛医学院的外科讲师，也是布里格姆妇女医院血管和血管内外科的副外科医生。以下概述了我的计划，成为一个独立的临床科学家在转化血管研究和临床试验。我的建议充分利用了哈佛医学院、哈佛公共卫生学院和麻省理工学院所创造的激励性学术环境和多学科合作。许多PAD患者进展为严重肢体缺血。自体静脉仍然是旁路手术最持久的管道，但失败率仍然很高（5年内为30-50%）。我以前已经表明，这些患者有一个独特的炎症表型，通过C反应蛋白（CRP）评估。此外，基线CRP水平升高可预测外周旁路手术后不良心血管和静脉移植物相关事件。CRP水平升高的患者的旁路移植物在静脉植入动脉循环后的最初几个月内表现出较少的适应性扩张，这预示着1年后移植物功能更差。CRP的血浆水平与肱动脉和冠状动脉内皮功能呈负相关;然而，CRP是否与静脉移植物内皮功能相关尚不清楚。该建议旨在阐明动脉环境中内皮功能、炎症和静脉移植物适应性之间的关系。我将确定全身（通过肱动脉评估）和静脉移植物特异性内皮功能与早期静脉移植物重塑之间的关系。将在体内和离体技术中评估静脉的内皮功能。我的第二个目标是确定炎症和内皮激活的生物标志物与静脉移植物特异性内皮功能之间的关联。我的最后一个假设是，通过强化他汀类药物治疗（阿托伐他汀80 mg）减少全身炎症，将通过改善内皮功能改善早期静脉移植物适应。这一假设将通过一项随机对照试验进行检验，该试验比较了在围手术期给予强化剂量与常规剂量阿托伐他汀。这些研究将为人类静脉移植物愈合的正常和异常适应性过程的理解提供新的见解，并将通过确定新的生物标志物，替代终点和现有静脉移植物失败治疗机制具有直接的临床相关性。 (End摘要）

DESCRIPTION (provided by applicant): I am an Instructor of Surgery at Harvard Medical School and an Associate Surgeon in the Division of Vascular and Endovascular Surgery at Brigham and Women's Hospital. The following outlines my plan to become an independent clinician-scientist in translational vascular research and a clinical trialist. My proposal capitilizes on the stimulating academic environment and multidisciplinary collaborations engendered by Harvard Medical School, Harvard School of Public Health, and Massachussetts Institute of Technology. Many patients with PAD progress to critical limb ischemia. Autologous vein remains the most durable conduit for bypass surgery, yet failure rates remain significant (30-50% over 5 years). I have previously shown that these patients have a distinct inflammatory phenotype as assessed by C-reactive protein (CRP). Moreover, elevated baseline CRP levels are predictive of adverse cardiovascularand vein graft-related events after peripheral bypass surgery. Bypass grafts in patients with elevated CRP levels exhibit less adaptive dilation in the first few months after the vein is implanted in the arterial circulation, which portends worse graft function after 1 year. Plasma levels of CRP correlate inversely with brachial and coronary artery endothelial function; however, it is not known if CRP is correlated with vein graft endothelial function. This proposal seeks to elucidate the relationships between endothelial function, inflammation, and vein graft adaptation in the arterial environment. I will determine the relationship between systemic (as assessed by the brachial artery) and vein graft-specific endothelial function to early vein graft remodeling. Endothelial function of the vein will be assessed both in vivo and ex vivo techinques. My second aim is to determine the association between biomarkers of inflammation and endothelial activation with vein graft- specific endothelial function. My final hypothesis is that reducing systemic inflammation by intensive statin therapy (atorvastatin 80 mg) will improve early vein graft adaptation by improving endothelial function. This hypothesis will be tested by a randomized controlled trial of intensive vs conventional dose atorvastatin given in the peri-operative setting. These studies will provide new insights into the understanding of normal and abnormal adaptive processes of human vein graft healing and will have direct clinical relevance by identifying new biomarkers, surrogate endpoints, and mechanisms of existing therapies for vein graft failure. (End of Abstract)