Metabolic Adaptation and Functional Recovery of Hibernating Myocardium

描述（申请人提供）：血运重建术可改善冬眠心肌患者的功能和预后，但残留的左室功能障碍是常见的。造成这种情况的机制尚不清楚，但功能障碍与心肌瘢痕程度不成比例，这可能反映了残留的心肌细胞重塑。在之前的资助期内，我们证明了从慢性昏迷到冬眠心肌的进展伴随着凋亡诱导的心肌细胞损失、代偿性心肌细胞肥大和代谢适应，从而降低了区域能量利用。虽然蛋白质组学特征与胎儿和衰竭的肌细胞相似，但区域功能和代谢的下调限制了氧化应激，最终阻止了进一步的细胞凋亡。在更新应用中，我们将确定维持心肌细胞活力的对缺血的代谢适应是否最终限制了血运重建后的功能恢复。我们提出了一个翻译的方法，平行生理，蛋白质组学和线粒体功能研究的猪存活的慢性功能失调的心肌。蛋白质组学分析将用于在已建立的无显著纤维化的可存活功能失调心肌猪模型中鉴定候选线粒体蛋白。这些将与线粒体呼吸和候选酶活性的体外功能测定相结合。类似于在患者身上使用的治疗干预将使我们能够识别负责适应的分子途径中的可塑性，并确定它们在残余收缩功能障碍中的重要性。目的1验证了线粒体蛋白表达和功能的区域改变区分冬眠和慢性休克心肌的假设。目的2验证经皮冠状动脉血运重建术后线粒体和收缩功能障碍持续存在的假设，并确定功能恢复的时间过程。目的3验证了冠状动脉内混合治疗AdvFGF-5（可使线粒体蛋白质组学变化正常化并独立于血管生成改善功能）加速和增强血运重建术后功能恢复的假设。我们的长期目标是利用这项研究开发新的策略来逆转缺血性心肌病患者的心肌功能障碍，从而减少心力衰竭和猝死导致的死亡和残疾。

DESCRIPTION (provided by applicant): Revascularization improves function and prognosis in patients with hibernating myocardium yet residual LV dysfunction is common. The mechanisms responsible for this are unclear but the dysfunction is disproportionate to the degree of myocardial scarring raising the possibility that it reflects residual myocyte cellular remodeling. During the previous funding period, we demonstrated that the progression from chronically stunned to hibernating myocardium is accompanied by apoptosis-induced myocyte loss, compensatory myocyte hypertrophy and metabolic adaptations that reduce regional energy utilization. While the proteomic profile is similar to the fetal and failing myocyte, the downregulation in regional function and metabolism limits oxidative stress to ultimately prevent further apoptosis. In the renewal application, we will determine whether the metabolic adaptations to ischemia which preserve myocyte viability ultimately limit functional recovery after revascularization. We propose a translational approach with parallel physiological, proteomic and mitochondrial functional studies in swine with viable chronically dysfunctional myocardium. Proteomic profiling will be used to identify candidate mitochondrial proteins in established swine models of viable dysfunctional myocardium that do not have significant fibrosis. These will be coupled with in vitro functional assays of mitochondrial respiration and candidate enzyme activity. Therapeutic interventions similar to those used in patients will allow us to identify plasticity in the molecular pathways responsible for adaptation and determine their importance in residual contractile dysfunciton. Aim 1 tests the hypothesis that regional alterations in mitochondrial protein expression and function distinguish hibernating from chronically stunned myocardium. Aim 2 tests the hypothesis that mitochondrial and contractile dysfunction persist after percutaneous coronary revascularization and determines the time course of functional recovery. Aim 3 tests the hypothesis that hybrid therapy with intracoronary AdvFGF-5 (which normalizes mitochondrial proteomic changes and improves function independently of angiogenesis) accelerates and enhances functional recovery after revascularization. Our long-term objective is to use this research to develop new strategies to reverse myocardial dysfunction in patients with ischemic cardiomyoapthy which will reduce death and disability from heart failure and sudden death.