The therapeutic approach of inductive lethal arrhythmia by inhibiting Ca2+ leak through the cardiac ryanodine receptor in hypertrophic cardiomyopathy

肥厚型心肌病（HCM）是一种以左心室严重肥厚为特征的心肌疾病。在HCM患者中，它是年轻时致命性心律失常导致猝死的原因。HCM患者中诱导性室性心律失常的医学方法仍然难以捉摸。在此，我们假设舒张期Ca ~（2+）通过Ryanodine受体（RyR 2）漏出是HCM心律失常发生的重要调节因素之一。为了验证这一假设，我们研究了Ca 2+泄漏通过RyR 2在家族性肥厚性心肌病相关心肌肌钙蛋白T突变转基因小鼠（TG）模型中的致病作用。TG心肌细胞中β-肾上腺素能刺激诱导通过缺陷RyR 2的舒张期Ca 2+渗漏。丹曲林和钙调蛋白激酶II抑制剂可通过稳定RyR 2抑制Ca 2+渗漏。上述结果提示，稳定RyR 2和抑制Ca 2+漏出可能在HCM致死性心律失常的发病机制中起一定作用。

Hypertrophic cardiomyopathy(HCM) is known to be a myocardial disorder characterized by severe hypertrophy of the left ventricule. In HCM patients, it is the cause of sudden death by lethal arrhythmia in younger age. Medical approach against inductive ventricular arrhythmia in HCM patients remains elusive. Here, we hypothesized that diastolic Ca2+ leak through Ryanodine receptor (RyR2) is one of the important factor of regulating arrhytmogenesis in HCM. To verify this hypothesis, we investigated the pathogenic role of Ca2+ leak through RyR2 in transgenic mouse (TG) model of Familial Hypertrophic cardiomyopathy-related cardiac troponin T mutation. Diastolic Ca2+ leak through defective RyR2 is induced by beta-adrenergic stimulation in TG cardiomyocytes. Dantrolene and Calmodulin-kinaseII inhibitor can inhibit Ca2+ leak by stabilizing RyR2. These results might suggest that the stabilization of RyR2 and inhibiting Ca2+ leak might play a role for the pathogenesis of lethal arrhythmia in HCM.