Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes

Lachaud, Q., Aziz, M. H. N., Burton, F. L., Macquaide, N. , Myles, R. C. , Simitev, R. D. and Smith, G. L. (2022) Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes. Cardiovascular Research, 118(15), pp. 3112-3125. (doi: 10.1093/cvr/cvab375) (PMID:35020837) (PMCID:PMC9732512)

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Aims: Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells. Methods and results: APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK. Conclusion: Modelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.

Item Type:Articles
Additional Information:R.S. was supported by the UK Engineering and Physical Sciences Research Council [grant numbers EP/N014642/1 and EP/S030875/1]. R.C.M. was supported by the Wellcome Trust (105907/Z/14/Z). N.M. was supported by the BHF (FS/13/7/30054). The experimental work was supported by a BHF PhD Studentship (FS/16/55/32731) to Q.L. The computational modelling was supported by the Ministry of Higher Education Malaysia and University of Malaya via a SLAB scholarship awarded to M.H.N.A.
Glasgow Author(s) Enlighten ID:Burton, Dr Francis and Noor Aziz, Dr Muhamad Hifzhud and Lachaud, Dr Quentin and Simitev, Professor Radostin and Myles, Dr Rachel and Smith, Professor Godfrey and MacQuaide, Dr Niall
Authors: Lachaud, Q., Aziz, M. H. N., Burton, F. L., Macquaide, N., Myles, R. C., Simitev, R. D., 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:Cardiovascular Research
Publisher:Oxford University Press
ISSN (Online):1755-3245
Published Online:10 January 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cardiovascular Research 118(15): 3112-3125
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172141EPSRC Centre for Multiscale soft tissue mechanics with application to heart & cancerRaymond OgdenEngineering and Physical Sciences Research Council (EPSRC)EP/N014642/1M&S - Mathematics
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
171105Heterogeneity of sympathetic stimulation as a mechanism of ventricular arrhythmia following myocardial infarctionRachel MylesWellcome Trust (WELLCOTR)105907/Z/14/ZInstitute of Cardiovascular & Medical Sciences
167805The role of RyR cluster morphology in Ca2+ homeostasisGodfrey SmithBritish Heart Foundation (BHF)FS/13/7/30054Institute of Cardiovascular & Medical Sciences
173470BHF 4-Year PhD Studentship (4th intake 2016 of 3rd Scheme)Rhian TouyzBritish Heart Foundation (BHF)FS/16/55/32731Institute of Cardiovascular & Medical Sciences