Published: 19 January 2020
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 channelmodulatory 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.
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