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

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Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on ionic current block effects. / Paci, Michelangelo; Hyttinen, Jari; Rodriguez, Blanca; Severi, Stefano.

julkaisussa: British Journal of Pharmacology, 2015, s. 5147 - 5160.

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@article{9fd764a5ea11481dbc25711a3dd57974,
title = "Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on ionic current block effects",
abstract = "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.KeywordshiPSC-derived cardiomyocytes, in silico models, action potential, cardiotoxicity assessment.",
keywords = "hiPSC-derived cardiomyocytes, in silico models, action potential, cardiotoxicity assessment",
author = "Michelangelo Paci and Jari Hyttinen and Blanca Rodriguez and Stefano Severi",
year = "2015",
doi = "10.1111/bph.13282",
language = "English",
pages = "5147 -- 5160",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley",

}

RIS (suitable for import to EndNote) - Lataa

TY - JOUR

T1 - Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on ionic current block effects

AU - Paci, Michelangelo

AU - Hyttinen, Jari

AU - Rodriguez, Blanca

AU - Severi, Stefano

PY - 2015

Y1 - 2015

N2 - 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.KeywordshiPSC-derived cardiomyocytes, in silico models, action potential, cardiotoxicity assessment.

AB - 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.KeywordshiPSC-derived cardiomyocytes, in silico models, action potential, cardiotoxicity assessment.

KW - hiPSC-derived cardiomyocytes

KW - in silico models

KW - action potential

KW - cardiotoxicity assessment

U2 - 10.1111/bph.13282

DO - 10.1111/bph.13282

M3 - Article

SP - 5147

EP - 5160

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

ER -