Effects of Mechanical Unloading on Myocardial Function and Structure in Humans

描述（由申请人提供）： 在美国，心力衰竭的终生风险为20%，并且这种诊断具有13%的高年死亡率。降低心力衰竭死亡率和再入院率已被确定为VA系统的主要战略目标。 左心室辅助装置（LVAD）已成为最晚期心力衰竭患者的常用疗法。LVAD被用作移植的桥梁或永久性治疗。通过LVAD支持恢复正常心输出量的益处已得到充分描述，但我们对LVAD诱导的心肌水平机械卸载的影响和可能后果的理解仍然有限。在一部分患者中，LVAD卸载导致左心室功能持续改善，但与这种功能恢复相关的临床或病理特征尚未得到很好的描述。我们假设非脉动LVAD卸载对心脏功能的有利影响与特定的临床特征、组织水平的特定结构变化以及血管重塑、胶原蛋白周转和能量代谢的分子途径的特定改变相关。在LVAD患者中进行心肌组织系列检查（在LVAD植入时获得，并在取出时再次获得）的可行性以及同时进行心脏功能系列检查（通过超声心动图）的能力为我们提供了一个独特的机会来直接在人体中测试这一假设。我们建议在一项由湖城VAMC和里士满VAMC的研究人员进行的前瞻性研究中检验这一假设。 我们在接受LVAD作为移植桥梁的患者中进行了试点研究。我们已经开发了用于监测心脏功能以及组织采集、处理和分析的协议。特别是，我们已经实施了数字组织病理学的新方法，以准确地评估心肌中的一些重塑变化。我们的初步数据证实，约25%的患者左心室功能改善。在组织水平上，LVAD卸载导致心肌细胞肥大的消退和微血管密度的增加，但也增加了胶原蛋白含量。我们的初步数据确立了我们的研究在实现所述目标方面的可行性：1.证明心肌恢复是LVAD卸载的结果，并且可以通过功能和结构描述符来定义。确定内皮细胞向间质细胞转化（EMT）是否有助于LVAD卸载中观察到的结构变化，以及3.确定与心肌功能恢复相关的特定代谢变化。 如果能够识别出有利于功能性心肌改善的结构和分子变化，这将为识别和测试与LVAD卸载相结合的疗法开辟道路，这些疗法可以增强晚期心力衰竭患者的心肌功能恢复和再生程度。实现心肌恢复，如果只是在一个子集的退伍军人与先进的心力衰竭，将代表一个重大的治疗进展。

DESCRIPTION (provided by applicant): The lifetime risk of heart failure in the United States is 20% and this diagnosis carries a high annual mortality of 13%. Reduction of heart failure mortality and readmission rate has been identified as a major strategic goal within the VA system. Left ventricular assist devices (LVADs) have become a frequently used therapy for patients with the most advanced forms of heart failure. LVADs are used as a bridge to transplant or as permanent therapy. The benefits of restoring normal cardiac output through LVAD support are well described, but our understanding of the effects and possible consequences of LVAD- induced mechanical unloading at the level of the myocardium remains limited. In a subset of patients, LVAD unloading results in sustained improvement of left ventricular function, but the clinical or pathologic features associated with this functional recovery are not well described. We hypothesize that the favorable effects of non-pulsatile LVAD unloading on cardiac function are associated with specific clinical features, specific structural changes at the tissue level and specific alterations in molecular pathways of vascular remodeling, collagen turnover and energy metabolism. The feasibility of serial examination of myocardial tissue in LVAD patients (obtained at the time of LVAD implant and again at the time of explant) with the concurrent ability to serially examine cardiac function (through echocardiography) provides us with a unique opportunity to test this hypothesis directly in humans. We propose to test this hypothesis in a prospective study to be conducted by investigators at the Salt Lake City VAMC and the Richmond VAMC. We have carried out pilot investigations in patients who received LVADs as a bridge to transplant. We have developed protocols for the monitoring of cardiac function and for tissue acquisition, processing and analysis. In particular, we have implemented novel methods of digital histopathology to accurately evaluate a number of remodeling changes in the myocardium. Our preliminary data confirmed that improvement of left ventricular function is seen in approximately 25% of patients. On the tissue level, LVAD unloading resulted in regression of cardiomyocyte hypertrophy and an increase in microvasculature density but also an increase in collagen content. Our preliminary data establishes the feasibility of our study in achieving the stated aims to: 1.To demonstrate that myocardial recovery results from LVAD unloading and can be defined by functional and structural descriptors, 2. To determine whether endothelial to mesenchymal transition (EMT) contributes to structural changes seen in LVAD unloading, and 3. To identify specific metabolic changes associated with recovery of myocardial function. If structural and molecular changes that favor functional myocardial improvement can be identified, this will open the way for identification and testing of therapies which, in combination with LVAD unloading, may enhance the degree of myocardial functional recovery and regeneration in patients with advanced heart failure. Achieving myocardial recovery, if only in a subset of veterans with advanced heart failure, would represent a major therapeutic advance.