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

改善儿茶酚胺能多形性室性心动过速的诊断和治疗：临床与基础科学的结合

• 批准号: 287718088
• 负责人: Professorin Dr. Kaomei Guan
• 金额: --
• 依托单位: Department of Physiology and Pharmacology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/287718088?language=en
• 关键词: Improving; Diagnosis; Treatment; Catecholaminergic; Polymorphic

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.

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，其发病率为1/10000，可导致心源性猝死。它是涉及离子通道的最致命的病理之一，最常见的是由于兰尼碱受体2（RYR 2）的突变。CPVT的特征是运动或情绪诱发的室性心律失常，而静息心电图和心脏结构无异常，这使得诊断困难。目前，无论是最佳的危险分层工具，也没有有效的干预CPVT治疗心脏病学家。该提案汇集了全球临床领导者和基础科学家，他们在遗传性心律失常疾病以及国家和国际登记方面具有专业知识。本CPVT研究计划的总体目标是根据个体的风险状况制定合理化治疗的有效策略，从而降低发病率并预防心源性猝死。为了实现这一目标，我们将建立一个国际CPVT登记处和相应的生物库，以识别相关的新基因，将基因型与表型相关联，并生成用于临床的风险预测算法。此外，我们将通过进行基础研究，包括开发可以在体外重现CPVT表型的患者特异性多能干细胞衍生的心肌细胞，来增强我们对CPVT中RYR 2突变的理解。通过根据人口统计学、家族史、临床表现、遗传学和功能特征对CPVT患者进行风险分层，我们旨在改善患者结局并挽救生命。

项目成果

Genetic variation in GNB5 causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (IK,ACh)

• DOI: 10.1242/dmm.037994
• 发表时间: 2019-01
• 期刊: Disease Models & Mechanisms
• 影响因子: 4.3
• 作者: C. Veerman;I. Mengarelli;C. D. Koopman;R. Wilders;S. V. van Amersfoorth;Diane Bakker;R. Wolswinkel;Mariam Hababa;T. D. de Boer;K. Guan;J. Milnes;Elisabeth M. Lodder;J. Bakkers;A. Verkerk;C. Bezzina

Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates

• DOI: 10.3390/ijms21072589
• 发表时间: 2020-04-01
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Knottnerus, Suzan J. G.;Mengarelli, Isabella;Bezzina, Connie R.
• 通讯作者: Bezzina, Connie R.

Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression

• DOI: 10.1126/scitranslmed.aan0724
• 发表时间: 2018-09-12
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Mohamed, Belal A.;Hartmann, Nico;Toischer, Karl
• 通讯作者: Toischer, Karl