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Cross - site comparison of excitation-contraction coupling using impedance and field potential recordings in hiPSC cardiomyocytes

Bot, Corina T. and Juhasz, Krisztina and Häusermann, Fabian and Liudmila , Polonchuk and Traebert, Martin and Stölzle-Feix2, Sonja (2018) Cross - site comparison of excitation-contraction coupling using impedance and field potential recordings in hiPSC cardiomyocytes. Journal of pharmacological and toxicological methods. ISSN 10568719

Abstract

Introduction: Since 2005 the S7B and E14 guidances from ICH and FDA have been in place to assess a potential drug candidate’s ability to cause long QT syndrome. To refine these guidelines, the FDA proposed the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, where the assessment of drug effects on cardiac repolarization was one subject of investigation. Within the myocyte phase II study, effects of pharmaceutical compounds on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were assessed and this article will focus on an evaluation of the proarrhythmic potential of 23 drugs in four hiPSC-CM cell lines.
Methods: Experiments were performed on the CardioExcyte 96 at different sites. A combined readout of contractility (via impedance) and electrophysiology endpoints (field potentials) was performed.
Results: Our data demonstrates that hERG blockers such as Dofetilide and further high risk categorized compounds prolong the field potential duration. Arrhythmic events were detected in both impedance as well as EFP recordings. Intermediate risk compounds induced arrhythmia in almost all cases at the highest dose. In the case of low risk compounds, either a decrease in FPDmax was observed, or not a significant change.
Discussion: All sources of hiPSC-CMs are sensitive enough to detect delayed or shortened repolarization and arrhythmia after drug application and can provide predictive cardiac electrophysiology data. However, the baseline electrophysiological parameters vary between iPS cells from different sources.

Item Type: Article
Date Deposited: 07 Aug 2018 00:45
Last Modified: 07 Aug 2018 00:45
URI: https://oak.novartis.com/id/eprint/35695

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