Effects of Mechanical Unloading on Myocardial Function and Structure in Humans

描述(由申请人提供)： 在美国，终生心力衰竭的风险为20%，而这种诊断每年的死亡率高达13%。降低心力衰竭死亡率和再住院率已被确定为VA系统的主要战略目标。左心室辅助装置(LVAD)已成为治疗最晚期心力衰竭患者的常用方法。左心室反搏被用作移植的桥梁或永久治疗。通过LVAD支持恢复正常心输出量的好处已经得到了很好的描述，但我们对LVAD诱导的心肌水平机械卸载的影响和可能的后果的了解仍然有限。在一部分患者中，LVAD卸载可导致左心功能的持续改善，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。我们推测，非搏动性LVAD卸载对心功能的有利影响与特定的临床特征、特定的组织结构变化以及血管重塑、胶原代谢和能量代谢的分子通路的特定改变有关。在LVAD患者中连续检查心肌组织的可行性(在植入LVAD时获得，在移植时再次获得)，同时具有连续检查心功能(通过超声心动图)的能力，这为我们提供了一个独特的机会，可以直接在人类身上验证这一假设。我们建议在盐湖城VAMC和里士满VAMC的研究人员进行的一项前瞻性研究中检验这一假设。我们已经在接受左心室反搏作为移植桥梁的患者中进行了试点调查。我们已经制定了监测心脏功能以及组织采集、处理和分析的方案。特别是，我们实施了数字组织病理学的新方法，以准确评估心肌重塑的一些变化。我们的初步数据证实，大约25%的患者左心功能得到改善。在组织水平上，心肌细胞肥厚消退，微血管密度增加，但胶原含量增加。我们的初步数据证实了我们的研究实现上述目标的可行性：1.证明心肌恢复是LVAD卸载后的结果，可以用功能和结构描述符来定义；2.确定内皮细胞到间质的转变(EMT)是否有助于LVAD卸载过程中出现的结构变化；3.确定与心肌功能恢复相关的特定代谢变化。如果能够确定有利于功能心肌改善的结构和分子变化，这将为鉴定和测试治疗方法开辟道路，这些治疗方法与LVAD卸载相结合，可能会增强晚期心力衰竭患者的心肌功能恢复和再生程度。如果只在患有晚期心力衰竭的退伍军人中实现心肌恢复，这将是一项重大的治疗进步。

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.