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

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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.