Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science

儿茶酚胺能多形性室性心动过速(CPVT)是一种遗传性心律失常综合征，发病率为1/10000，可导致心脏性猝死。它是涉及离子通道的最致命的病理之一，最常见的原因是兰诺定受体2(RYR2)的突变。CPVT以运动性或情绪性室性心律失常为特征，无静息心电图和心脏结构异常，诊断困难。目前，治疗心脏病的医生既没有最佳的危险分层工具，也没有针对CPVT的有效干预措施。这项建议将全球临床领导者和基础科学家聚集在一起，他们在遗传性心律失常状况以及国内和国际登记方面拥有专业知识。这项CPVT研究计划的总体目标是开发一种有效的策略，根据个人的风险状况合理地进行治疗，从而减少发病率和预防心脏性猝死。为了实现这一目标，我们将建立一个国际CPVT登记系统和一个相应的生物库，以便能够识别相关的新基因，将基因与表型相关联，并生成用于临床的风险预测算法。此外，我们将通过开展基础研究来加强我们对CPVT中RYR2突变的理解，包括开发患者特有的多潜能干细胞来源的心肌细胞，这些细胞可以在体外概括CPVT的表型。通过根据人口学、家族史、临床表现、遗传学和功能特征进行风险分层治疗CPVT患者，我们的目标是改善患者预后和挽救生命。

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome with a prevalence of 1 in 10 000 that causes sudden cardiac death. It is one of the most lethal pathologies involving ion channels and is most commonly due to mutations in the ryanodine receptor 2 (RYR2). CPVT is characterized by exercise- or emotion-induced ventricular arrhythmias without abnormalities in resting ECG and cardiac structure, which makes the diagnosis difficult. At present, neither optimal risk stratification tools nor effective interventions for CPVT are available to the treating cardiologists. This proposal brings together global clinical leaders and basic scientists with expertise in inherited arrhythmia conditions and national and international registries. The overall objective of this CPVT research program is to develop an effective strategy for rationalizing therapies based on the risk profile of an individual, thereby reducing morbidity and preventing sudden cardiac death. To achieve this objective, we will establish an international CPVT registry and a corresponding biobank to enable identification of relevant new genes, to correlate genotype with phenotype, and to generate risk prediction algorithms for clinical use. Further, we will enhance our understanding of RYR2 mutations in CPVT by performing basic research including the development of patient-specific pluripotent stem cell-derived cardiomyocytes that can recapitulate the CPVT phenotype in vitro. By treating CPVT patients according to risk stratification based on demographics, family history, clinical presentation, genetics, and functional characteristics, we aim to improve patient outcomes and save lives.