Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on effects of ionic current block.
OBJECTIVE
Two new technologies are likely 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 for pharmacological safety assessments. Here, we systematically compared 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.


METHODS
In silico AP models of ventricular-like and atrial-like hiPSC-CMs and hAdultV-CM were used to simulate the main effects of four degrees of block of the main cardiac transmembrane currents.


RESULTS
Qualitatively, hiPSC-CM and hAdultV-CM APs showed similar responses to current block, consistent with results from experiments. However, quantitatively, hiPSC-CMs were more sensitive to block of (i) L-type Ca(2+) currents due to the overexpression of the Na(+) /Ca(2+) exchanger (leading to shorter APs) and (ii) the inward rectifier K(+) current due to reduced repolarization reserve (inducing diastolic potential depolarization and repolarization failure).


CONCLUSIONS
In silico hiPSC-CMs and hAdultV-CMs exhibit a 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.
Department of Electronics and Communications Engineering, Tampere University of Technology, BioMediTech, Tampere, Finland.
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http://orcid.org/0000-0003-0510-1444
M
Paci
Department of Electronics and Communications Engineering, Tampere University of Technology, BioMediTech, Tampere, Finland.
J
J
Hyttinen
Department of Computer Science, University of Oxford, Oxford, UK.
B
B
Rodriguez
Department of Electrical, Electronic and Information Engineering 'Guglielmo Marconi', University of Bologna, Cesena (FC), Italy.
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S
Severi
D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D003198:Computer Simulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type