iPSC-Cardiomyocyte Models of Brugada Syndrome-Achievements, Challenges and Future Perspectives

Abstract

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias.

Keywords: brugada syndrome; electrophysiology; iPSC-cardiomyocytes; induced pluripotent stem cells; inherited cardiac arrhythmia.

Figure 1

Ventricular action potential and underlying ionic currents (adapted from [32,61,63]). Schematic representation of human ventricular and human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) action potential waveforms (a) with indicated in grey: action potential (AP) phases (on ventricular AP waveform) as well as action potential amplitude (APA), action potential duration (APD) and resting membrane potential (RMP) (on iPSC-CM AP waveform). Bottom panel represents the relative magnitude of the underlying ionic currents (b) together with the list of genes (in black) encoding alpha and auxiliary (beta) ion channel protein subunits (in red) which cooperate in generation of the represented ion currents (created with biorender.com December 2020).

Figure 2

Summary of the main findings from the reviewed BrS iPSC-CM models, advantages and disadvantages of the model, as well as future perspectives for the use of iPSC-CMs in BrS research. (Generated with Biorender.com March 2021).