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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Abstract
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 |
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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. |
Status: | Published |
Refereed: | Yes |
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: | 0008-6363 |
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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