Strain induced myopathy in post infarction heart failure

描述（由申请人提供）： 500万美国人患有充血性心力衰竭（CHF）。尽管在血管重建技术方面取得了30年的进展，但冠心病仍占所有CHF病例的70%。一旦确诊，无论治疗如何，5年死亡率为50%。我们假设急性心肌梗死后，梗死范围扩大，导致邻近灌注心肌的伸展。这种拉伸诱导活性氧（ROS）介导的肌细胞凋亡，这导致进行性非缺血性肌病过程，其募集额外的连续的、完全灌注的、重塑的心肌以引起扩张型心肌病、CHF和死亡。本研究利用声学显微阵列定位技术（SAL）对绵羊心肌梗死后左室重构模型进行了研究。SAL量化了12周系列研究期间局部心肌应变和收缩力的变化。以前，我们表明，心肌壁应变和功能障碍在这个绵羊模型的重塑心肌进行性增加。我们现在期望表明，这种进行性心肌功能障碍是应变诱导的ROS介导的心肌细胞凋亡的结果，并且该过程是无情的自我延续。为了定量ROS活性，我们将测量ROS催化的花生四烯酸产物沿着心肌蛋白氧化羰基化和硝化的局部心肌浓度。将使用细胞核和细胞质测量来定量局部肌细胞凋亡。在具体目标2中，我们抑制了梗死扩展，这防止了该模型中的进行性LV扩张。我们预期梗塞抑制将阻止ROS的产生和心肌细胞凋亡，并防止重构心肌的进一步扩展。这些研究解决了梗死后左心室重塑的发病机制，如果我们的假设是正确的，为新的治疗提供了基础，旨在预防导致梗死后CHF和死亡的自我延续的肌病过程。

DESCRIPTION (PROVIDED BY APPLICANT): Five million Americans suffer from congestive heart failure (CHF). Despite 30 years of advances in revascularization techniques coronary disease still accounts for 70% of all cases of CHF. Once the diagnosis is made the 5-year mortality is 50%, regardless of treatment. We hypothesize that following acute myocardial infarction, infarct expansion occurs, which stretches adjacent perfused myocardium. This stretching induces reactive oxygen species (ROS) mediated myocyte apoptosis, which results in progressive non-ischemic myopathic process that recruits additional contiguous, fully perfused, remodeled myocardium to cause dilated cardiomyopathy, CHF and death. This project uses sonomicrometry array localization (SAL) to study a sheep model of post infarction left ventricular (LV) remodeling. SAL quantifies changes in regional myocardial strains and contractility during serial 12 week studies. Previously, we showed that myocardial wall strain and dysfunction increases progressively in this ovine model of remodeled myocardium. We now expect to show that this progressive myocardial dysfunction is the result strain induced ROS mediated myocyte apoptosis and that the process is relentlessly self-perpetuating. To quantify ROS activity, we will measure regional myocardial concentrations of ROS-catalyzed arachidonic acid products along with oxidative carbonylation and nitration of myocardial proteins. Regional myocyte apoptosis will be quantified using both nuclear and cytoplasmic measures. In specific aim 2 we restrain infarct expansion, which prevents progressive LV dilation in this model. We expect that infarct restraint will arrest ROS production and myocyte apoptosis and prevent further extension of remodeled myocardium. These studies address the pathogenesis of post infarction LV remodeling and if our hypothesis is correct, provide the foundation for new therapy designed to prevent the self-perpetuating, myopathic process that causes post infarction CHF and death.