Mitochondria in Hypertrophied RV and Surgical Ischemia

心功能不全的发展是先天性心脏病治疗成功的主要限制因素。尤其是法洛四联症(TOF)患者，右室(RV)功能障碍和肾性异常(如心律失常和猝死)是长期发病率和死亡率的主要原因。TOF患者进行性收缩功能障碍的病因是多因素的；它包括发紫、长期暴露在异常血流动力学负荷下、手术留下疤痕(脑室切开术)，或许还有遗传因素。TOF的外科修复通常需要一次或多次的心肌缺血-再灌注，这是导致细胞凋亡和坏死的重要原因。心肌细胞丢失会 由于残余血流动力学施加的负荷，TOF儿童的耐受性尤其差 反常现象和未来的增长。最近的证据表明，线粒体在调节细胞的凋亡性和坏死性死亡方面起着重要的作用。基于这一信息和我们实验室的初步数据，我们认为肥厚的婴儿右心室在缺血再灌注后特别容易受到线粒体介导的损伤和细胞死亡的影响。应用一种新的恒压负荷右室肥厚模型 对于婴幼儿，拟议的实验将是第一次：1)确定线粒体通透性转换孔形成在肥大的婴幼儿RV心肌缺血再灌注后引起收缩和能量功能障碍、细胞凋亡和坏死的作用；2)测试针对这一机制的临床相关治疗。在急性实验中被发现有效的干预措施随后将在工作心脏移植模型中进行测试，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丢失、心肌细胞恢复的长期结果变量有什么影响 功能、炎症和纤维化。这些转化研究将提供有价值的新机制信息和新的治疗靶点。这一结果也可能适用于大量其他先天性心脏缺陷，其中右室因解剖异常或因为它是全身室而承受异常负荷。

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.