窦房结功能障碍在RYR2基因突变诱发恶性心律失常中的作用机制研究

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited rhythm disorder characterized by the occurrence of potentially life-threatening polymorphic ventricular tachyarrhythmias in conditions of physical or emotional stress. The underlying cause is a dysregulation in intracellular Ca handling due to mutations in the sarcoplasmic reticulum(SR) calcium release channel（Ryanodine Receptor 2 calcium channel）. If the sinus node dysfunction is present. Correspondingly, the diastolic period of the myocardium will be prolonged, and there will be enough time for the SR load to reach the threshold of calcium spontaneous release, thus promoting the occurrence of ventricular arrhythmias. Hence, the sinus bradycardia that is sometimes observed in CPVT patients may be another primary defect caused by CPVT related mutations. Dependent on that RyR2A165D+/- mice had a clear CPVT phenotype and sinus node dysfunction, we planned to apply electrophysiological and calcium signal experiments, remote body surface electrocardiogram and other methods to study the role of sinus node dysfunction as a modulator of arrhythmia risk and potential therapeutic target. This study will provide new pathogenesis of CPVT and provide new ideas for the treatment of CPVT and prevention of sudden cardiac death.

儿茶酚胺敏感性多形性室速(CPVT)是一种遗传性恶性室性心律失常，其发病机制存在诸多争议。最新研究提示窦房结功能障碍存在于CPTV患者部分亚群中，但其在CPVT中的作用仍不明确。本项目前期研究通过临床CPVT病例筛选出RyR2-A165D突变，基因突变小鼠再现了典型的CPVT表型，而且观察到同临床病例一致的窦性心动过缓。据此我们假设，如果CPVT同时存在窦房结功能障碍，会导致心肌的舒张期相应延长，使肌浆网钙负荷有足够的时间到达钙自发释放的阈值，从而促进室性心律失常的发生。我们计划综合运用电生理技术和激光共聚焦钙成像、远程心电图等技术，明确RyR2-A165D基因突变与窦房结功能障碍的相关性，明确窦房结功能障碍是否是CPVT的独立危险因子，阐明窦房结功能障碍在CPVT的致病发病中可能的协同促进机制，探索窦房结功能障碍作为CPVT治疗全新靶点的可能性。

儿茶酚胺敏感性多形性室速(CPVT)是一种遗传性恶性室性心律失常，其发病机制存在诸多争议。最新研究提示窦房结功能障碍存在于CPTV患者部分亚群中，但其在CPVT中的作用仍不明确。本项目前期研究通过临床CPVT病例筛选出RyR2-A165D突变，基因突变小鼠再现了典型的CPVT表型，而且观察到同临床病例一致的窦性心动过缓。我们运用电生理技术和激光共聚焦钙成像、远程心电图等技术，明确RyR2-A165D基因突变与窦房结功能障碍的相关性，明确窦房结功能障碍是否是CPVT的独立危险因子，阐明窦房结功能障碍在CPVT的致病发病中可能的协同促进机制，探索窦房结功能障碍作为CPVT治疗全新靶点的可能性。