Hoekstra Maaike, Mummery Christine L, Wilde Arthur A M, Bezzina Connie R, Verkerk Arie O
Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands.
Front Physiol. 2012 Aug 31;3:346. doi: 10.3389/fphys.2012.00346. eCollection 2012.
Cardiac arrhythmias are a major cause of morbidity and mortality. In younger patients, the majority of sudden cardiac deaths have an underlying Mendelian genetic cause. Over the last 15 years, enormous progress has been made in identifying the distinct clinical phenotypes and in studying the basic cellular and genetic mechanisms associated with the primary Mendelian (monogenic) arrhythmia syndromes. Investigation of the electrophysiological consequences of an ion channel mutation is ideally done in the native cardiomyocyte (CM) environment. However, the majority of such studies so far have relied on heterologous expression systems in which single ion channel genes are expressed in non-cardiac cells. In some cases, transgenic mouse models have been generated, but these also have significant shortcomings, primarily related to species differences. The discovery that somatic cells can be reprogrammed to pluripotency as induced pluripotent stem cells (iPSC) has generated much interest since it presents an opportunity to generate patient- and disease-specific cell lines from which normal and diseased human CMs can be obtained These genetically diverse human model systems can be studied in vitro and used to decipher mechanisms of disease and identify strategies and reagents for new therapies. Here, we review the present state of the art with respect to cardiac disease models already generated using IPSC technology and which have been (partially) characterized. Human iPSC (hiPSC) models have been described for the cardiac arrhythmia syndromes, including LQT1, LQT2, LQT3-Brugada Syndrome, LQT8/Timothy syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). In most cases, the hiPSC-derived cardiomyoctes recapitulate the disease phenotype and have already provided opportunities for novel insight into cardiac pathophysiology. It is expected that the lines will be useful in the development of pharmacological agents for the management of these disorders.
心律失常是发病和死亡的主要原因。在年轻患者中，大多数心源性猝死都有潜在的孟德尔遗传病因。在过去15年里，在识别不同的临床表型以及研究与原发性孟德尔（单基因）心律失常综合征相关的基本细胞和遗传机制方面取得了巨大进展。对离子通道突变的电生理后果的研究理想情况下是在天然心肌细胞（CM）环境中进行的。然而，迄今为止，大多数此类研究都依赖于异源表达系统，即单个离子通道基因在非心肌细胞中表达。在某些情况下，已经建立了转基因小鼠模型，但这些模型也有显著的缺点，主要与物种差异有关。体细胞可以被重编程为诱导多能干细胞（iPSC）这一发现引起了广泛关注，因为它提供了一个机会，可以生成患者和疾病特异性的细胞系，从中可以获得正常和患病的人类心肌细胞。这些基因多样的人类模型系统可以在体外进行研究，并用于解读疾病机制以及识别新疗法的策略和试剂。在这里，我们回顾了利用iPSC技术已经生成并已（部分）表征的心脏病模型的现状。已经描述了用于心律失常综合征的人类iPSC（hiPSC）模型，包括LQT1、LQT2、LQT3 - 布加综合征、LQT8/蒂莫西综合征和儿茶酚胺能多形性室性心动过速（CPVT）。在大多数情况下，hiPSC衍生的心肌细胞重现了疾病表型，并已经为深入了解心脏病理生理学提供了新的机会。预计这些细胞系将有助于开发用于治疗这些疾病的药物。
