Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings
Yann-Stanislas H. M. Barral, Liudmila Polonchuk, Michael Clerx, David J. Gavaghan, Gary R. Mirams, Ken Wang
Abstract
During drug development, candidate compounds are extensively tested for proarrhythmic risk and in particular risk of Torsade de Pointes (TdP), as indicated by prolongation of the QT interval. Drugs that inhibit the rapid delayed rectifier current ( ) can prolong the action potential duration (APD) and thereby the QT interval, and so are routinely rejected. However, simultaneous inhibition of the L-type current ( ) can mitigate the effect of inhibition, so that including both effects can improve test specificity.
Introduction
The rapid delayed rectifier current ( ) is a major ionic current responsible for the repolarisation of ventricular cardiomyocytes [1]. Inhibition of prolongs the action potential (AP) duration (APD) and the QT interval [2]. Many drugs inhibiting have been shown to increase the risk of Torsade de Pointes (TdP), a potentially deadly arrhythmia [2,3]. Regulatory bodies established guidelines ICH S7B and ICH E14 to prevent the development of new compounds with unacceptable pro-arrhythmic risk [4,5].
Materials and method
4.1. Ex vivo action potential acquisition
4.1.1. Sharp electrode recording protocol for data acquisition.
Experimental AP data were produced by the AnaBios Corporation, following the methods previously described by Page et al. [34]. In brief, trabeculae were extracted from adult human hearts that were not suitable for transplantation, sharp electrodes were impaled in isolated cardiac muscle fibers, their electrophysiological activity was recorded at physiological temperature with vehicle or drugs added. Up to three trabeculae per heart were obtained from the inner endocardial wall of the left (78 trabeculae) and right (4 trabeculae) ventricles. 4 to 15 trabeculae were exposed to the same drug.
Results
2.1. Experimental change in from baseline with drug exposure
Experimental measured after 25 min of steady 1 Hz pacing are summarised in Table 1 for the 9 tested compounds. The standard error of the mean (SEM) is also reported in the Table
Discussion
3.1. Main findings
The performance of 11 literature AP models was evaluated against new ex vivo data from adult human ventricular trabeculae, which measured response to inhibition of and/or by 9 different drugs.
Acknowledgments
The authors thank Dr. Abi-Gerges (AnaBios Corporation) for his support with experimental oversight for ex vivo data analysis. The authors thank Dr. Bartolucci and Dr. Severi for their help in implementing the BPS model [16]. The authors thank Evgenia Gissinger and Fabian Häusermann (Dr. Polonchuk’s lab) for performing the patch-clamp experiments.
Citation: Barral Y-SHM, Polonchuk L, Clerx M, Gavaghan DJ, Mirams GR, Wang K (2025) Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings. PLoS Comput Biol 21(7): e1012913. https://doi.org/10.1371/journal.pcbi.1012913
Editor: Alain Nogaret, University of Bath, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
Received: February 24, 2025; Accepted: June 12, 2025; Published: July 7, 2025
Copyright: © 2025 Barral et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The data, models, and scripts used to generate the results in this paper are available at the GitHub repository at the address: https://github.com/CardiacModelling/APD90_ex_vivo_vs_in_silico. Zenodo (permanent archive of Github): https://doi.org/10.5281/zenodo.14791284.
Funding: This research was funded in part by the Wellcome Trust [212203/Z/18/Z]. GRM and MC acknowledge support from the Wellcome Trust via a Wellcome Trust Senior Research Fellowship to GRM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Authors YSHMB, KW, and LP were employees of F. Hoffmann-La Roche Ltd. at the time of the study and KW is a shareholder. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
