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Reference: Paci, M, Hyttinen, J, Rodriguez, B et al., (2015). Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on effects of ionic current block. British journal of pharmacology, 172 (21), 5147-5160.Citable link to this page:

 

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

Abstract: 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.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.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).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.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's versionNotes:Copyright © 2015 The Authors. British Journal of Pharmacology published by John Wiley and Sons Ltd on behalf of British Pharmacological Society.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Bibliographic Details

Publisher: Wiley

Publisher Website: http://onlinelibrary.wiley.com/

Journal: British journal of pharmacologysee more from them

Publication Website: http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1476-5381

Issue Date: 2015-11

pages:5147-5160Identifiers

Urn: uuid:cbd6441e-c62d-43d5-99cf-a2684e8a174a

Source identifier: 539378

Eissn: 1476-5381

Doi: https://doi.org/10.1111/bph.13282

Issn: 0007-1188 Item Description

Type: Journal article;

Language: eng

Version: Publisher's version Tiny URL: pubs:539378

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Autor: Paci, M - - - Hyttinen, J - - - Rodriguez, B - institutionUniversity of Oxford Oxford, MPLS, Computer Science grantNumberSenior R

Fuente: https://ora.ox.ac.uk/objects/uuid:cbd6441e-c62d-43d5-99cf-a2684e8a174a



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