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Int. J. Mol. Sci. 2017, 18(12), 2634; doi:10.3390/ijms18122634

Frequency-Dependent Multi-Well Cardiotoxicity Screening Enabled by Optogenetic Stimulation

1
Institute of Physiology I, Medical Faculty, University of Bonn, 53127 Bonn, Germany
2
Nanion Technologies GmbH, 80636 Munich, Germany
3
Present address: Institute for Nanoelectronics, Department of Electrical Engineering and Information Technology, Technische Universität München, 80339 Munich, Germany
4
Part of the Ncardia Group, Axiogenesis AG, 50829 Cologne, Germany
5
Research Training Group 1873, University of Bonn, 53127 Bonn, Germany
*
Authors to whom correspondence should be addressed.
Received: 30 October 2017 / Revised: 28 November 2017 / Accepted: 30 November 2017 / Published: 6 December 2017
(This article belongs to the Special Issue Optogenetic Approaches in Neuroscience)
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Abstract

Side effects on cardiac ion channels causing lethal arrhythmias are one major reason for drug withdrawals from the market. Field potential (FP) recording from cardiomyocytes, is a well-suited tool to assess such cardiotoxic effects of drug candidates in preclinical drug development, but it is currently limited to the spontaneous beating of the cardiomyocytes and manual analysis. Herein, we present a novel optogenetic cardiotoxicity screening system suited for the parallel automated frequency-dependent analysis of drug effects on FP recorded from human-induced pluripotent stem cell-derived cardiomyocytes. For the expression of the light-sensitive cation channel Channelrhodopsin-2, we optimised protocols using virus transduction or transient mRNA transfection. Optical stimulation was performed with a new light-emitting diode lid for a 96-well FP recording system. This enabled reliable pacing at physiologically relevant heart rates and robust recording of FP. Thereby we detected rate-dependent effects of drugs on Na+, Ca2+ and K+ channel function indicated by FP prolongation, FP shortening and the slowing of the FP downstroke component, as well as generation of afterdepolarisations. Taken together, we present a scalable approach for preclinical frequency-dependent screening of drug effects on cardiac electrophysiology. Importantly, we show that the recording and analysis can be fully automated and the technology is readily available using commercial products. View Full-Text
Keywords: optogenetics; field potential; long QT syndrome; cardiotoxicity screening; heart rate; cardiomyocytes; induced pluripotent stem cells optogenetics; field potential; long QT syndrome; cardiotoxicity screening; heart rate; cardiomyocytes; induced pluripotent stem cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Rehnelt, S.; Malan, D.; Juhasz, K.; Wolters, B.; Doerr, L.; Beckler, M.; Kettenhofen, R.; Bohlen, H.; Bruegmann, T.; Sasse, P. Frequency-Dependent Multi-Well Cardiotoxicity Screening Enabled by Optogenetic Stimulation. Int. J. Mol. Sci. 2017, 18, 2634.

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