Endothelial Function and Peripheral Vein Bypass Graft Remodeling

我是哈佛医学院的外科讲师，也是 布里格姆妇女医院的血管和血管内手术。下面概述了我的计划 成为翻译血管研究领域的独立临床医生兼科学家和临床试验者。我的 提案以激动人心的学术环境和多学科合作为基础 由哈佛医学院、哈佛公共卫生学院和麻省理工学院 技术。许多PAD患者进展为严重的肢体缺血。自体静脉仍然是最多的 搭桥手术的导管经久耐用，但失败率仍然很高(5年内为30%-50%)。我有过 先前显示，这些患者具有C反应评估的独特的炎症表型 蛋白质(CRP)。此外，基线C反应蛋白水平升高可预测不良的心血管和静脉。 外周搭桥术后移植物相关事件。C反应蛋白升高患者的搭桥术 在静脉被植入动脉循环后的最初几个月，表现出较少的适应性扩张，这 预示着1年后移植肾功能变差。血浆C反应蛋白水平与肱动脉血流量呈负相关 冠状动脉内皮功能；然而，目前尚不清楚CRP是否与静脉移植内皮细胞相关 功能。这项建议试图阐明内皮功能、炎症和 移植静脉在动脉环境中的适应性。我将确定系统性(AS)与 通过评估移植物特异性内皮功能对早期静脉移植物重塑的影响。 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 确定炎症生物标记物与静脉移植物内皮细胞激活之间的关系- 特定的内皮功能。我的最后一个假设是，通过强化他汀类药物来减少全身炎症 治疗(阿托伐他汀80 mg)将通过改善内皮功能来改善移植静脉的早期适应性。这 假说将通过强化剂量与常规剂量阿托伐他汀的随机对照试验来验证 在围手术期的情况下。这些研究将为理解正常和 人静脉移植物愈合的异常适应过程，并将有直接的临床意义 识别新的生物标记物、替代终点和现有治疗静脉移植失败的机制。

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.