Lang C N, Koren G, Odening K E
Department of Cardiology and Angiology I, University Heart Center Freiburg, Medical Center - University of Freiburg, Germany; Faculty of Medicine, University of Freiburg, Germany.
Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
Prog Biophys Mol Biol. 2016 Jul;121(2):142-56. doi: 10.1016/j.pbiomolbio.2016.05.004. Epub 2016 May 19.
Long QT syndrome (LQTS) is a rare inherited channelopathy caused mainly by different mutations in genes encoding for cardiac K(+) or Na(+) channels, but can also be caused by commonly used ion-channel-blocking and QT-prolonging drugs, thus affecting a much larger population. To develop novel diagnostic and therapeutic strategies to improve the clinical management of these patients, a thorough understanding of the pathophysiological mechanisms of arrhythmogenesis and potential pharmacological targets is needed. Drug-induced and genetic animal models of various species have been generated and have been instrumental for identifying pro-arrhythmic triggers and important characteristics of the arrhythmogenic substrate in LQTS. However, due to species differences in features of cardiac electrical function, these different models do not entirely recapitulate all aspects of the human disease. In this review, we summarize advantages and shortcomings of different drug-induced and genetically mediated LQTS animal models - focusing on mouse and rabbit models since these represent the most commonly used small animal models for LQTS that can be subjected to genetic manipulation. In particular, we highlight the different aspects of arrhythmogenic mechanisms, pro-arrhythmic triggering factors, anti-arrhythmic agents, and electro-mechanical dysfunction investigated in transgenic LQTS rabbit models and their translational application for the clinical management of LQTS patients in detail. Transgenic LQTS rabbits have been instrumental to increase our understanding of the role of spatial and temporal dispersion of repolarization to provide an arrhythmogenic substrate, genotype-differences in the mechanisms for early afterdepolarization formation and arrhythmia maintenance, mechanisms of hormonal modification of arrhythmogenesis and regional heterogeneities in electro-mechanical dysfunction in LQTS.
长QT综合征（LQTS）是一种罕见的遗传性离子通道病，主要由编码心脏钾离子（K+）或钠离子（Na+）通道的基因发生不同突变引起，但也可由常用的离子通道阻滞剂和QT延长药物引起，因此影响的人群更为广泛。为了开发新的诊断和治疗策略以改善这些患者的临床管理，需要深入了解心律失常发生的病理生理机制和潜在的药理学靶点。已经建立了各种物种的药物诱导和基因动物模型，这些模型有助于识别LQTS中促心律失常触发因素和心律失常发生基质的重要特征。然而，由于心脏电功能特征存在物种差异，这些不同的模型并不能完全概括人类疾病的所有方面。在本综述中，我们总结了不同药物诱导和基因介导的LQTS动物模型的优缺点——重点关注小鼠和兔模型，因为它们是LQTS最常用的可进行基因操作的小型动物模型。特别是，我们详细强调了转基因LQTS兔模型中研究的心律失常发生机制、促心律失常触发因素、抗心律失常药物以及电机械功能障碍的不同方面，以及它们在LQTS患者临床管理中的转化应用。转基因LQTS兔有助于加深我们对复极时空离散在提供心律失常发生基质中的作用、早期后除极形成和心律失常维持机制中的基因型差异、心律失常发生的激素调节机制以及LQTS电机械功能障碍区域异质性的理解。
