Endothelial Function and Peripheral Vein Bypass Graft Remodeling

内皮功能和外周静脉旁路移植物重塑

基本信息

批准号：
8123237
负责人：
Christopher Dean Owens
金额：
$ 12.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8123237
关键词：
Accounting Activities of Daily Living Acute Angioplasty Arteries Attenuated Autologous Biological Assay Biological Markers Biological Preservation Biology Blood Circulation Blood Vessels Bypass C-reactive protein Caliber Clinical Coronary Coronary artery Data Dose E-Selectin Endothelium Environment Event Exhibits Failure Functional disorder Gene Expression Healed Histologic Hospitals Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hyperplasia Implant Inflammation Inflammatory Institutes Interdisciplinary Study Ischemia LDL Cholesterol Lipoproteins Leukocytes Limb Salvage Limb structure Lower Extremity Measurement Measures Mediating Medicine Methodology Methods Molecular Operative Surgical Procedures Outcome P-Selectin Patients Peripheral Pharmacology Phenotype Plasma Process Public Health Schools Randomized Controlled Trials Research Research Personnel Resolution Rho-associated kinase Risk Saphenous Vein Scientist Serum Specimen Surgeon Surrogate Endpoint Technology Testing Thrombomodulin Time Ultrasonography Vasodilation Veins Venous Woman abstracting atorvastatin brachial artery clinical epidemiology clinically relevant graft failure graft function graft healing healing hemodynamics human NOS3 protein implantation improved in vivo inflammatory marker insight instructor medical schools monocyte preimplantation programs reconstruction response shear stress

项目摘要

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)

描述（由申请人提供）：我是哈佛医学院的外科讲师和布莱根妇女医院血管和血管内外科部门的副外科医生。以下概述了我成为转化血管研究领域的独立临床科学家和临床试验师的计划。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所带来的刺激性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导管，但失败率仍然很高（5 年内为 30-50%）。我之前已经证明，通过 C 反应蛋白 (CRP) 评估，这些患者具有独特的炎症表型。此外，基线 CRP 水平升高可预测外周搭桥手术后心血管和静脉移植相关不良事件。 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，这预示着一年后移植物功能较差。 CRP 血浆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 是否与静脉移植物内皮功能相关。该提案旨在阐明动脉环境中内皮功能、炎症和静脉移植适应之间的关系。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。将通过体内和离体技术评估静脉的内皮功能。我的第二个目标是确定炎症生物标志物和内皮激活与静脉移植物特异性内皮功能之间的关联。我的最终假设是，通过强化他汀类药物治疗（阿托伐他汀 80 毫克）减少全身炎症将通过改善内皮功能来改善早期静脉移植物的适应。这一假设将通过围手术期给予强化剂量与常规剂量阿托伐他汀的随机对照试验进行检验。这些研究将为理解人静脉移植愈合的正常和异常适应性过程提供新的见解，并将通过识别新的生物标志物、替代终点和现有静脉移植失败疗法的机制而具有直接的临床意义。（摘要完）