Clinical and Metabolic Signature of Recovered Myocardium in Human Heart Failure

心力衰竭患者恢复心肌的临床和代谢特征 摘要： 据报道，在一些晚期疾病中，心肌结构和功能有了显著改善 心力衰竭(HF)患者接受左心辅助装置(LVAD)诱导的“机械卸载”。 与其他心力衰竭疗法不同，其他疗法也与显著的心肌改善有关，这 易处理和特定的LVAD人群为我们提供了治疗前心肌组织的途径 应答者和非应答者，这使我们能够开始探测具有 改进的潜力。我们的中心假设是，提炼这一“签名”将导致一种理性的治疗 治疗严重心力衰竭的方法，将揭示适用于所有阶段和严重心力衰竭的更广泛的恢复原则。 实现和定义LVAD患者的“反应”需要一系列的诊断和治疗 而且，正如先进的高频多中心登记的现实世界所显示的那样，这是具有挑战性的。因此，在那里 迫切需要一种选择程序，能够可靠地预测谁会对LVAD做出回应，谁不会对此做出回应 心理治疗。该计划还将使我们能够开发这样的预测模型，除了我们的研究 驱动心肌恢复的机制。首先，我们将提供一个临床上相关的心脏衰竭的‘签名’ 有复苏的潜力。遵循派生-验证方法，我们将开发一种心肌 使用心肌结构和/或功能参数以及临床特征进行恢复评分。 这一评分将创建一种精确的算法，用于选择在LVAD介入之前可能恢复的患者， 丰富装置移植和持续恢复的标准 增加真实世界的发病率和支持LVAD的复苏的可持续性。第二，我们假设 特定的新陈代谢适应推动心肌恢复。我们在检查心肌梗死后的初步数据 来自正常供者和LVAD患者的组织提示LVAD后糖酵解与 线粒体中间体可能表明通过保护心脏的戊糖磷酸增加了流量 路径。我们已经开发了方法学，并将采用新的和强大的体内代谢流量研究 使用稳定同位素、线粒体呼吸测量和额外的代谢测试来测试这一点 假设。 这一项目为临床功能、结构和体内的紧密结合提供了难得的机会 人体心力衰竭及其恢复的机制研究。所获得的生理学见解为临床提供了 将影响我们在晚期心力衰竭患者中的实践的特征和生物标志物。他们还揭示了 新的生物学见解有助于我们对心肌恢复的临床和基础科学理解 适用于所有阶段和严重程度的心衰。

Clinical and Metabolic Signature of Recovered Myocardium in Human Heart Failure Summary: Remarkable improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients undergoing “mechanical unloading” induced by left ventricular assist devices (LVAD). Unlike other HF therapies, which have also been associated with significant myocardial improvement, this tractable and specific LVAD population provides us access to pre-treatment myocardial tissue from both responders and non- responders which has enabled us to start probing the “signature” of myocardium that has the potential to improve. Our central hypothesis is that refining this “signature” will lead to a rational therapeutic approach in severe HF and will reveal broader recovery principles applicable to all stages and severity of HF. Achieving and defining “response” in LVAD patients requires a battery of diagnostic and therapeutic protocols and, as shown in the real world of advanced HF multicenter registries, this is challenging. Thus, there is a critical need for a selection process that can reliably predict who will and who will not “respond” to LVAD therapy. This program will also enable us to develop such a predictive model in addition to our studies of the mechanisms driving myocardial recovery. First we will provide a clinically relevant ‘signature’ of failing hearts with the potential for recovery. Following a derivation- validation approach we will develop a myocardial recovery score using myocardial structural and/ or functional parameters together with clinical characteristics. This score will create a precise algorithm for selection of patients likely to recover prior to LVAD intervention, enrich the criteria for device explantation and sustained recovery following LVAD intervention and likely increase the real world incidence and sustainability of LVAD enabled recovery. Second, we hypothesized that specific metabolic adaptations drive myocardial recovery. Our preliminary data after examining myocardial tissue from normal donors and LVAD patients suggests a post- LVAD mismatch in glycolytic versus mitochondrial intermediates that might indicate increased flux through the cardioprotective pentose phosphate pathway. We have developed methodology and will employ novel and powerful in vivo metabolic flux studies using stable isotopes, mitochondrial respiratory measurements and additional metabolic assays to test this hypothesis. This project offers a rare opportunity to closely integrate clinical function, structure and in vivo mechanistic studies in human HF and recovery. The physiological insights derived are providing clinical characteristics and biomarkers that will impact our practice in advanced HF patients. They are also revealing novel biological insights that inform both our clinical and basic science understanding of myocardial recovery applicable to all stages and severity of HF.