Endothelial Function and Peripheral Vein Bypass Graft Remodeling

描述(申请人提供)：我是哈佛医学院的外科讲师，布里格姆妇女医院血管和内血管外科的副外科医生。以下概述了我的计划，成为一名独立的临床医生-翻译血管研究的科学家和临床试验者。我的提案利用了哈佛医学院、哈佛公共卫生学院和麻省理工学院创造的激动人心的学术环境和多学科合作。许多PAD患者进展为严重的肢体缺血。自体静脉仍然是搭桥手术最耐用的管道，但失败率仍然很高(5年内为30-50%)。我之前已经证明，根据C-反应蛋白(CRP)的评估，这些患者具有明显的炎症表型。此外，基线C反应蛋白水平升高可预测周围血管搭桥术后不良心血管和静脉移植物相关事件。在CRP水平升高的患者中，搭桥在静脉植入动脉循环后的头几个月表现出较少的适应性扩张，这预示着一年后移植物功能变差。血浆C反应蛋白水平与肱动脉和冠状动脉内皮功能呈负相关；然而，目前尚不清楚C反应蛋白是否与静脉移植物内皮功能相关。这项建议试图阐明动脉环境中血管内皮功能、炎症和静脉移植物适应性之间的关系。我将确定全身性(通过臂动脉评估)和静脉移植物特异性内皮功能与早期静脉移植物重塑的关系。静脉的内皮功能将在体内和体外技术中进行评估。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(阿托伐他汀80 mg)减少全身炎症，将通过改善内皮功能来改善移植静脉的早期适应。这一假设将通过围术期强化剂量阿托伐他汀与常规剂量阿托伐他汀的随机对照试验来验证。这些研究将为理解人类静脉移植物愈合的正常和异常适应过程提供新的见解，并将通过识别新的生物标志物、替代终点和现有治疗静脉移植物失败的机制而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)