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Abstract
There is a need for improved in vitro models of inherited cardiac diseases to better understand basic cellular and molecular mechanisms and advance drug development. Most of these diseases are associated with arrhythmias, as a result of mutations in ion channel or ion channel-modulatory proteins. Thus far, the electrophysiological phenotype of these mutations has been typically studied using transgenic animal models and heterologous expression systems. Although they have played a major role in advancing the understanding of the pathophysiology of arrhythmogenesis, more physiological and predictive preclinical models are necessary to optimize the treatment strategy for individual patients. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have generated much interest as an alternative tool to model arrhythmogenic diseases. They provide a unique opportunity to recapitulate the native-like environment required for mutated proteins to reproduce the human cellular disease phenotype. However, it is also important to recognize the limitations of this technology, specifically their fetal electrophysiological phenotype, which differentiates them from adult human myocytes. In this review, we provide an overview of the major inherited arrhythmogenic cardiac diseases modeled using hiPSC-CMs and for which the cellular disease phenotype has been somewhat characterized.
Highlights
The unlimited source of human induced pluripotent stem cell-derived cardiomyocytes provides new opportunities to create in vitro models of healthy and diseased human cardiac cells that can be used in drug safety and efficacy testing
Unlike adult human ventricular myocytes, which are characterized by a positive force frequency relationship (FFR) due to increased sarcoplasmic reticulum (SR) Ca load at higher frequencies [35], most differentiation protocols result in hiPSC-CMs with a neutral or negative FFR [36,37]
Long QT syndrome (LQTS) is an inherited cardiac disorder characterized by delayed ventricular repolarization as demonstrated by an abnormal QT interval prolongation on the surface ECG [45] with increased risk of developing a polymorphic ventricular tachycardia known as Torsades de Pointe (TdP) and sudden cardiac death [46]
Summary
The unlimited source of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides new opportunities to create in vitro models of healthy and diseased human cardiac cells that can be used in drug safety and efficacy testing. It is anticipated that major clinical applications will eventually include diagnosis and personalized treatment to predict therapeutic responses (beneficial or harmful) in individual patients with arrhythmogenic syndromes in vitro [2,3]. This approach, called “clinical trials in a dish” has been embraced by the Food and Drug Administration (FDA) in an effort to further develop and validate more predictive models to support drug development [4,5,6]. We first outline arrhythmogenic diseases modeled using hiPSC-CMs and describe the various experimental approaches used to investigate disease mechanisms and drug response
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