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

Tutkimustuotosvertaisarvioitu

Yksityiskohdat

AlkuperäiskieliEnglanti
Sivut5147 - 5160
JulkaisuBritish Journal of Pharmacology
DOI - pysyväislinkit
TilaJulkaistu - 2015
OKM-julkaisutyyppiA1 Alkuperäisartikkeli

Tiivistelmä

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.

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