Mitochondria in Hypertrophied RV and Surgical Ischemia

心室功能障碍的发展是成功治疗先天性心脏病的主要限制因素。这在患有法洛四联症（TOF）的患者中尤其如此，其中右心室（RV）功能障碍和收缩异常（诸如节律障碍和猝死）是长期发病率和死亡率的主要原因。TOF中进行性收缩功能障碍的病因是多因素的;它包括发绀、长期暴露于异常血流动力学负荷、手术瘢痕（心室切开术），以及可能的遗传因素。TOF的外科修复通常需要一次或多次心肌缺血-再灌注，这是细胞凋亡和坏死的潜在原因。肌细胞损失将 在TOF儿童中耐受性尤其差，因为残余血流动力学负荷 异常和未来的增长。最近的证据表明，线粒体在调节细胞凋亡和坏死性细胞死亡中起着重要作用。基于这些信息和我们实验室的初步数据，我们认为肥大的婴儿右心室特别容易受到缺血再灌注后心肌介导的损伤和细胞死亡的影响。采用一种新的恒压负荷右室肥厚模型， 婴儿，所提出的实验将是第一个1）确定线粒体渗透性转换孔形成的作用，导致收缩和能量障碍，细胞凋亡和坏死的肥厚婴儿右心室心肌缺血再灌注;和2）测试针对这一机制的临床相关治疗。然后将在工作心脏移植模型中测试在急性实验中发现有效的干预措施，以解决一个至关重要的问题，即线粒体保护策略对心肌细胞损失、心肌细胞恢复和心肌细胞凋亡的长期结果变量的影响。 功能、炎症和纤维化。这些翻译研究将提供有价值的新的机制信息和新的治疗靶点。该结果也可能适用于大量其他先天性心脏病，其中右心室由于解剖异常或因为它是体心室而处于异常负荷下。

The development of ventricular dysfunction is a major limitation to the successful treatment of congenital heart disease. This is particularly true in patients with tetragogy of Fallot(TOF), in whom right ventricular (RV) dysfunction and renated abnormalities such as dysrhythmias and sudden death are major causes of long-term morbidity and mortality. The etiology of progressive contractile dysfunction in TOF is multifactorial; it includes cyanosis, prolonged exposure to abnormal hemodynamic loads, surgical scarring (ventriculotomy), and perhaps genetic factors as well. The surgical repair of TOF usually requires one or more episodes of myocardial ischemia-reperfusion, which is a potent cause of both apoptosis and necrosis. Myocyte loss will be tolerated especially poorly in TOF children due to the loads imposed by residual hemodynamic abnormalities and by future growth. Recent evidence indicates that mitochondria play a prominent role in regulating both apoptotic and necrotic cell death. Based upon this information and preliminary data from our laboratory, we believe that the hypertrophied infant right ventricle is particularly susceptible to mitochondriaily-mediated injury and cell death following ischemia-reperfusion. Using a novel model of constant pressure load RV hypertrophy in the infant, the proposed experiments will be the first to 1 ) define the role of mitochondrial permeability transition pore formation to cause contractile and energetic dysfunction, apoptosis, and necrosis in hypertrophic infant RV myocardium subjected to ischemia-reperfusion; and 2 ) test clinically relevant therapies targeted against this mechanism. Interventions found to be effective in acute experiments will then be tested in a working heart transplant model in order to address a question of critical importance, namely what is the effect of mitochondrial protection strategies on long-term outcome variables of myocyte loss, recovery of myocardial function, inflammation, and fibrosis. These translational studies will provide valuable new mechanistic information and new therapeutic targets. The results are also likely to be applicable to the large number of other congenital heart defects where the right ventricle is under abnormal load due to anatomic abnormalities or because it is the systemic ventricle.