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)。尽管血运重建技术已经取得了30年的进步，但冠心病仍占所有CHF病例的70%。一旦确诊，无论采用何种治疗，5年死亡率均为50%。我们假设在急性心肌梗死后，会发生梗塞扩大，使邻近的灌流心肌伸展。这种拉伸可诱导活性氧簇(ROS)介导的心肌细胞凋亡，导致进行性非缺血性肌病过程，从而招募更多连续的、完全灌流的、重塑的心肌，从而导致扩张型心肌病、充血性心力衰竭和死亡。本项目利用声学显微阵列定位技术(SAL)研究了绵羊心肌梗死后左室重构的模型。SAL量化了连续12周研究期间局部心肌应变和收缩能力的变化。在此之前，我们发现在这种重塑心肌的绵羊模型中，心肌壁应变和功能障碍逐渐增加。我们现在期望证明，这种进行性的心肌功能障碍是应激诱导的ROS介导的心肌细胞凋亡的结果，并且这个过程是无情的自我延续。为了量化ROS的活性，我们将测量心肌局部ROS催化的花生四烯酸产物的浓度，以及心肌蛋白质的氧化羰化和硝化。局部心肌细胞的凋亡将使用核和细胞质两种方法进行量化。在特定的目标2中，我们抑制了梗塞的扩大，这在这个模型中防止了进行性的左室扩张。我们预计，心肌梗死抑制将阻止ROS的产生和心肌细胞的凋亡，并防止重塑心肌的进一步延伸。这些研究解决了梗死后左室重构的发病机制，如果我们的假设是正确的，则为设计新的治疗方法提供基础，以防止导致梗死后充血性心力衰竭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.