PRESERVATION OF ENDOTHELIAL DEPENDENT RELAXATION

描述(由申请人提供)： 心血管疾病是美国发病率和死亡率的主要原因，每五例死亡中就有一例是心血管疾病造成的。冠状动脉旁路移植术(CABG)是治疗晚期冠状动脉疾病(CAD)最有效的治疗方法之一，外周血管搭桥术(PBG)是治疗周围血管疾病保肢的最有效方法之一。用于搭桥狭窄和闭塞动脉粥样硬化病变的最常见的管道是大隐静脉。大隐静脉(HSV)是从下肢采集的，准备用作动脉管道。因此，单纯疱疹病毒代表着一个自体移植的“器官”，很少有人关注单纯疱疹病毒的器官保存。HSV失败的主要原因是内膜增生，这是对损伤的一种反应。这项研究的假设是，在采集和制备过程中减少对HSV的损伤将保护内皮功能和内皮的有益作用(抗血栓、抗炎和对平滑肌的生长抑制作用)。这项研究的具体目的是：#1：优化手术采集和准备过程中保存HSV内皮功能的技术；#2：确定在准备过程中优化内皮功能是否可以减少内膜增生的发生。单纯疱疹病毒代表了一个独特的介入机会，因为静脉代表着一个自体移植器官。虽然在心脏血运重建期间进行了大量的研究工作以寻求心肌保护(心脏停搏液)，但很少有人关注用于心脏血管重建的管道的保存 动脉重建，单纯疱疹病毒。这项工作将加深我们对静脉移植失败机制的理解，改善静脉移植在收获和准备过程中的保存，并改变外科医生将管道视为需要仔细保存的移植器官的行为。这项建议的目的是开发提高HSV功能细胞活性的方法，并证明这些方法可以改善内膜增生。这一建议的潜在影响将加深我们对目前移植物准备技术中损伤对随后发生的内膜增生的作用的理解。这项建议还将开发出最优的静脉准备技术，可以很容易地转化为临床。未来的方向将决定优化HSV的保存技术和内皮功能是否会改善CABG和外周搭桥手术后的临床结果。在收获过程中预防内皮损伤是一种简单、直接的方法，可以减少与静脉移植失败相关的发病率、死亡率和成本。

DESCRIPTION (provided by applicant): Cardiovascular diseases are the leading cause of morbidity and mortality in the United States and are responsible for one out of every five deaths. Coronary artery bypass grafting (CABG) is one of the most effective treatments for advanced coronary artery disease (CAD) and peripheral bypass grafting (PBG) for the treatment of limb salvage in peripheral vascular disease. The most common conduit used to bypass stenotic and occlusive atherosclerotic lesions is the saphenous vein. The saphenous vein (HSV) is harvested from the lower extremity and prepared for use as an arterial conduit. As such, the HSV represents an autologous transplanted "organ" and little attention has been directed at organ preservation of the HSV. The leading cause of HSV failure is the development of intimal hyperplasia, a response to injury. The hypothesis of this investigation is that reducing injury to the HSV during harvest and preparation will preserve endothelial function and the salutary effects of the endothelium (antithrombotic, anti-inflammatory, and growth-inhibitory effects on the smooth muscle). The specific aims of this investigation are to: #1: Optimize techniques to preserve HSV endothelial function during surgical harvest and preparation; and #2: Determine if optimizing endothelial function during preparation reduces the development of intimal hyperplasia. HSV represents a unique opportunity for intervention in that the vein represents an autologous transplant organ. While significant research effort has pursued myocardiac preservation (cardioplegia) during cardiac revascularization, very little attention has been given to preservation of the conduit used for the arterial reconstruction, the HSV. This work will enhance our understanding of the pathogenesis of vein graft failure, improve preservation of the vein graft during harvest and preparation, and modify surgeon behavior in terms of treating the conduit as a transplanted organ that requires careful preservation. The goal of this proposal is to develop approaches to enhance HSV functional cellular viability and demonstrate that these approaches ameliorate intimal hyperplasia. The potential impact of this proposal will enhance our understanding of the role of injury during current graft preparation techniques on the subsequent development of intimal hyperplasia. This proposal will also develop optimal vein preparation techniques that can be readily translated into the clinic. Future directions will determine if optimizing preservation techniques and endothelial function of HSV will improve clinical outcomes following CABG and peripheral bypass procedures. Preventing endothelial injury during harvest represents a simple, straight forward approach to reduce the morbidity, mortality, and costs associated with vein graft failure.