Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells

Abstract

Long QT syndrome (LQTS) is a potentially severe arrhythmogenic disorder, associated with a prolonged QT interval and sudden death, caused by mutations in key genes regulating cardiac electrophysiology. Current strategies to study LQTS in vitro include heterologous systems or animal models. Despite their value, the overwhelming power of genetic tools has exposed the many limitations of these technologies. In 2010, human-induced pluripotent stem cells (hiPSCs) revolutionised the field and allowed scientists to study in vitro some of the disease traits of LQTS on hiPSC-derived cardiomyocytes (hiPSC-CMs) from LQTS patients. In this concise review we present how the hiPSC technology has been used to model three main forms of LQTS and the severe form of LQTS associated with mutations in calmodulin. We also introduce some of the most recent challenges that must be tackled in the upcoming years to successfully shift hiPSC-CMs from powerful in vitro disease modelling tools into assets to improve risk stratification and clinical decision-making.

The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

“…In the presence of a suitable substrate, EADs constitute a trigger for developing TdP, which can degenerate into ventricular fibrillation [52]. Detailed description of the various types of LQTS are described in multiple comprehensive reviews [3,48,[53][54][55][56][57][58][59][60][61]. More recently, a new clinical entity related to, but nevertheless distinct from LQTS, known as calmodulinopathy, has been described and studied in patient-derived hiPSC-CMs [62].…”

“…hiPSC-CMs generated from LQTS8 patients are characterized by irregular contraction, altered Ca handling, increased APD, and irregular electrical activity [112]. Of the LQTS that are not associated with mutations in gene encoding ion channels, LQTS14 and LQTS15 (associated with mutations in the gene encoding calmodulin 1 and 2, respectively) are the only ones that have been modeled using patient specific hiPSC-CMs [3,[113][114][115]. LQTS-associated CaM mutations, also called calmodulinopathies, are known to alter the Ca/CaM binding affinity [116], and involve multiple potential targets such as I Ca,L [115].…”

“…Importantly, hiPSC-CMs also have the potential to become an essential tool to better understand the genetic basic of human cardiovascular diseases [1]. 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].…”

Human Induced Pluripotent Stem Cells Derived from a Cardiac Somatic Source: Insights for an In-Vitro Cardiomyocyte Platform

“…To date, it has been widely described how hiPSC-CMs are able to recapitulate molecular and functional aspects of human heart pathophysiology, thus providing a good tool for disease modelling and development of personalized therapy that involves a pharmacological treatment. A wide range of genetic cardiomyopathies has been modelled using hiPSC-CMs [131], for example familiar long QT (LQT) syndromes [4,[85][86][87]132,133], Brugada syndrome [134,135], Catecholaminergic polymorphic tachycardia (CPVT) [136,137] and atrial fibrillation [138,139].…”

RNA-Based Strategies for Cardiac Reprogramming of Human Mesenchymal Stromal Cells

“…In vitro generated cardiomyocytes are an important tool for cardiovascular research, as they can be utilized for disease modelling or for the development of drug screening assays to assess the cardiac toxic risk of established or newly synthesized drugs [37][38][39]. Moreover, promising preclinical data suggests the therapeutic potential of generated cardiomyocytes for the treatment of cardiac diseases to overall improve heart regeneration and function [40,41].…”