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，也是布莱根妇女医院血管和血管内外科的副外科医生。以下概述了我在转化血管研究和临床试验中成为一名独立的临床医生和科学家的计划。我的提案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令人振奋的学术环境和多学科合作。许多PAD患者进展为严重肢体缺血。自体静脉仍然是搭桥手术中最持久的导管，但失败率仍然很高（5年内30-50%）。我之前的研究表明，通过c反应蛋白（CRP）评估，这些患者具有明显的炎症表型。此外，升高的基线CRP水平可预测外周搭桥手术后心血管和静脉移植相关的不良事件。CRP水平升高的旁路移植患者在静脉植入动脉循环后的最初几个月表现出较低的适应性扩张，这预示着1年后移植物功能恶化。血浆CRP水平与肱动脉和冠状动脉内皮功能呈负相关；然而，尚不清楚CRP是否与静脉移植血管内皮功能相关。本研究旨在阐明动脉环境中内皮功能、炎症和静脉移植物适应之间的关系。我将确定全身（由肱动脉评估）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。静脉内皮功能将在体内和离体技术中进行评估。我的第二个目标是确定炎症和内皮活化的生物标志物与静脉移植物特异性内皮功能之间的关系。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80mg）减少全身炎症，可以通过改善内皮功能来改善早期静脉移植适应。这一假设将通过围手术期给予阿托伐他汀强化与常规剂量的随机对照试验来检验。这些研究将为理解人类静脉移植愈合的正常和异常适应过程提供新的见解，并通过确定新的生物标志物、替代终点和现有静脉移植失败治疗的机制，具有直接的临床意义。（摘要结束）

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)