Abstract
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.
Highlights
Cardiac arrhythmias can be life threatening and are a major cause of morbidity and mortality in developed nations (Wolf and Berul, 2008)
A non-selective β-blocker elicited early afterdepolarizations (EADs) only in LQT2-induced pluripotent stem cells (iPSC)-CM. These three studies on LQT2 show that LQT-iPSC-CMs of symptomatic patients show a more severe cellular phenotype than those obtained from asymptomatic patients with the same mutation
The Human iPSC (hiPSC)-CM models described in this review show that it is possible to recapitulate in vitro in the hiPSC-CM system the disease phenotype of patients with Mendelian cardiac rhythm disorders
Summary
Cardiac arrhythmias can be life threatening and are a major cause of morbidity and mortality in developed nations (Wolf and Berul, 2008). The majority of functional studies on specific mutations associated with the Mendelian rhythm disorders have relied on heterologous expression systems, primarily Xenopus oocytes, human embryonic kidney (HEK) cells, and Chinese Hamster Ovary (CHO) cells (Watanabe et al, 2008), in which the mutated ion channel of interest is expressed. Such cellular models have significant shortcomings since they lack important constituents of cardiac ion channel macromolecular complexes that might be required to reproduce the exact molecular and electrophysiological phenotype of the mutation. Further we will discuss in detail the electrophysiological characteristics of hiPSC-CMs and review hiPSC models for cardiovascular diseases, including LQT1, LQT2, LQT3/BrS, LQT8/Timothy syndrome, and CPVT
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