Phenomenological analysis of simple ion channel block in large populations of uncoupled cardiomyocytes

Simitev, R. D. , Al dawoud, A., Aziz, M. H.N., Myles, R. and Smith, G. L. (2023) Phenomenological analysis of simple ion channel block in large populations of uncoupled cardiomyocytes. Mathematical Medicine and Biology, 40(2), pp. 175-198. (doi: 10.1093/imammb/dqad001) (PMID:36689769)

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Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a multiplicative factor to an effective ion conductance, a closed form asymptotic expression for APD is derived and inverted to determine model parameters as functions of APD and ΔAPD (drug-induced change in APD) for each myocyte. Two free protocol-related quantities are calibrated to experiment using an adaptive-domain procedure based on an original assumption of optimal excitability. The explicit APD expression and the resulting set of model parameter values allow (a) direct evaluation of conditions necessary to maintain fixed APD or ΔAPD, (b) predictions of the proportion of cells remaining excitable after drug application, (c) predictions of stimulus period dependency and (d) predictions of dose-response curves, the latter being in agreement with additional experimental data.

Item Type:Articles
Additional Information:This work was supported by the UK Engineering and Physical Sciences Research Council [grant numbers EP/S030875/1 and EP/T017899/1].
Glasgow Author(s) Enlighten ID:Simitev, Professor Radostin and Myles, Dr Rachel and Smith, Professor Godfrey and Al dawoud, Antesar Mohammed A
Authors: Simitev, R. D., Al dawoud, A., Aziz, M. H.N., Myles, R., and Smith, G. L.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Science and Engineering > School of Mathematics and Statistics > Mathematics
Journal Name:Mathematical Medicine and Biology
Publisher:Oxford University Press
ISSN (Online):1477-8602
Published Online:23 January 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Mathematical Medicine and Biology 40(2):175-198
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303232EPSRC Centre for Multiscale soft tissue mechanics with MIT and POLIMI (SofTMech-MP)Xiaoyu LuoEngineering and Physical Sciences Research Council (EPSRC)EP/S030875/1M&S - Mathematics
308255The SofTMech Statistical Emulation and Translation HubDirk HusmeierEngineering and Physical Sciences Research Council (EPSRC)EP/T017899/1M&S - Statistics