Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias - PubMed (original) (raw)

Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias

Maaike Hoekstra et al. Front Physiol. 2012.

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.

Keywords: cardiac arrhythmia syndromes; cardiomyocytes; electrophysiology; heart; human; iPS; induced pluripotent stem cells.

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Figures

Figure 1

Figure 1

(A) Schematic representation of a human ventricular action potential (top panel). Numbers denote the different phases of the ventricular action potential. The dashed line represents phase 4 depolarization normally present in cells from the conduction system and not in ventricular CMs. Underlying ionic membrane currents and their schematic time course are depicted below. (B) Schematic representation of an early afterdepolarization (EAD) and its underlying mechanism. (C) Schematic representation of a delayed afterdepolarization (DAD) and its underlying mechanism. INa, Na+ current; ICa,L, L-type Ca2+ current; ICa,T, T-type Ca2+ current; Ito1, transient outward current type 1; ICl(Ca), Ca2+ activated Cl− current, also called Ito2; IKur, ultra rapid component of the delayed rectifier K+ current, IKr, rapid component of the delayed rectifier K+ current; IKs, slow component of the delayed rectifier K+ current; IK1, inward rectifier K+ current; If, funny current; INCX, Na+/Ca2+ exchange current.

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