Mitochondria in Hypertrophied RV and Surgical Ischemia

室性功能障碍的发展是先天性心脏病成功治疗的主要限制。法洛四联症（TOF）患者尤其如此，他们的右心室（RV）功能障碍和肾异常（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，手术疤痕（脑室切开术），也可能是遗传因素。TOF的手术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有力原因。心肌细胞的损失

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.