Arrhythmogenic Activity and Channel Remodeling in Ventricles of Dilated Cardiomyopathy (DCM) Model Mice

Abstract

Introduction: Dilated cardiomyopathy (DCM) is a disease characterized by weakened and dilated heart which often leads to lethal arrhythmia and sudden death. Recently a knock-in mouse model of DCM was created by mutation of cardiac troponin T (ΔK210) based on human familial DCM. Because they died suddenly at a high probability during 8-12 weeks old but rarely died before 6 weeks, we compared the properties of cardiac muscles of mutant mice between 4 and 8 weeks to explore the cause of sudden death. Methods and Results: Left ventricular (LV) muscles were isolated from wild type (WT) and homo mutant hearts and were loaded with di-4-ANEPPS. Membrane potential signals were determined using a laser scanning confocal microscope. Gene expression levels were quantified by real-time RT-PCR. In mutant hearts at 8 weeks, spontaneous action potentials were frequently seen and action potential duration was prolonged compared to those from WT. These features were not obvious at 4weeks. Real-time PCR analysis of mutant LV showed age dependent changes in gene expression levels of some K+ channels including Kv4.2. Conclusion: These results suggest that the age-dependent alteration in various ion channels may contribute to both APD prolongation and abnormal automaticity, then enhance susceptibility to lethal arrhythmias in the DCM model mice.