Exploration of the pathogenic mechanisms of inherited cardiomyopathies caused by cardiac troponin T mutations

扩张型心肌病(DCM)是一组以心脏扩张和收缩功能障碍为特征的遗传性和获得性疾病，可导致心力衰竭和猝死，是心脏移植的主要适应症。在细胞骨架和肌瘤蛋白的基因中发现了导致DCM的突变。我们已经建立了由心肌肌钙蛋白T缺失突变ΔK210引起的扩张型心肌梗死小鼠模型。突变小鼠心脏增大，猝死发生率高，没有心力衰竭的迹象。对突变小鼠心脏切片的组织学检查显示，双侧脑室明显扩张，并伴有轻度至中度纤维化。超声心动图测量显示，突变小鼠的左心室射血分数明显小于野生型小鼠，这表明突变小鼠的心脏在体内收缩功能降低。突变小鼠的离体工作心脏制剂dp/dt_&lt；max&gt；而dp/dt_&lt；min&gt；无明显变化。然而，在突变小鼠中没有发现明显的心输出量减少，这表明心脏扩大可以完全代偿。使用遥测系统记录心电的研究强烈表明，尽管心脏的机械性能得到了很好的补偿，但心肌肌钙蛋白T的缺失突变ΔK210导致了由于心脏电生理异常而导致的高猝死发生率。

Dilated cardiomyopathy (DCM) represents a heterogeneous group of inherited and acquired disorders characterized by cardiac dilation and systolic dysfunction, which leads to heart failure and sudden death, being the primary indication for cardiac transplantation. DCM-causing mutations have been found in the genes for cytoskeletal and sarcomeric proteins. We have created a knock-in mouse model for DCM caused by the deletion mutation ΔK210 in cardiac troponin T. Mutant mice developed enlarged hearts and showed a high incidence of sudden death with no sign of heart failure. Histological examination of cardiac sections from mutant mice showed a significant dilation of both ventricles with mild to moderate fibrosis. Echocardiography measurements showed that the ejection fraction of left ventricle was significantly smaller in mutant mice than in wild-type mice, indicating a reduced systolic function of mutant mice hearts in vivo. Isolated working heart preparations from mutant mice showed a decreased dP/dt_<max> with no significant change in dP/dt_<min>. However, no significant reduction in cardiac output was found in mutant mice, suggesting a complete compensation by ventricular enlargement. Studies using a telemetry system for ECG recording strongly suggested that the deletion mutation ΔK210 in cardiac troponin T results in a high incidence of sudden death due to a cardiac electrophysiological abnormality despite well-compensated mechanical performance of the heart.