Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on ionic current block effects

Background and purpose. Two new technologies hold the promise to revolutionize cardiac safety and drug development: in vitro experiments on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and in silico human adult ventricular cardiomyocyte (hAdultV-CM) models. Their combination was recently proposed as a potential replacement for the present hERG-based QT study in safety pharmacology assessment. Here, we systematically compare in silico the effects of selective ionic current block on hiPSC-CM and hAdultV-CM action potentials (APs), to identify similarities/differences and to illustrate the potential of computational models as supportive tools for evaluating new in vitro technologies. Experimental approach. In silico AP models of ventricular-like and atrial-like hiPSC-CMs and hAdultV-CM are used to simulate the main effects of four degrees of block of the main cardiac transmembrane currents. Key results. Qualitatively, hiPSC-CM and hAdultV-CM APs show similar responses to current block, consistent with experiments. However, quantitatively, hiPSC-CMs display stronger sensitivities to block of (i) L-type Ca2+ current due to the overexpression of the Na+-Ca2+ exchanger (leading to shorter APs) and (ii) inward rectifier K+ current due to reduced repolarization reserve (inducing diastolic potential depolarization and repolarization failure). Conclusions and Implications. In silico hiPSC-CMs and hAdultV-CMs exhibit similar response to selective current blocks. However, overall hiPSC-CMs show greater sensitivity to block, which may facilitate in vitro identification of drug-induced effects. Extrapolation of drug effects from hiPSC-CM to hAdultV-CM and pro-arrhythmic risk assessment can be facilitated by in silico predictions using biophysically-based computational models. Keywords hiPSC-derived cardiomyocytes, in silico models, action potential, cardiotoxicity assessment.Peer reviewe