Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes (original) (raw)

Lachaud, Quentin, Aziz, Muhamad Hifzhudin Noor, Burton, Francis L., Macquaide, Niall ORCID: https://orcid.org/0000-0001-9026-0073, Myles, Rachel C. ORCID: https://orcid.org/0000-0003-4670-361X, Simitev, Radostin D. ORCID: https://orcid.org/0000-0002-2207-5789 and Smith, Godfrey L. ORCID: https://orcid.org/0000-0003-4821-9741(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)

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.

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Funder and Project Information

EPSRC Centre for Multiscale soft tissue mechanics with application to heart & cancer

Raymond Ogden

EP/N014642/1

M&S - Mathematics

EPSRC Centre for Multiscale soft tissue mechanics with MIT and POLIMI (SofTMech-MP)

Xiaoyu Luo

EP/S030875/1

M&S - Mathematics

Heterogeneity of sympathetic stimulation as a mechanism of ventricular arrhythmia following myocardial infarction

Rachel Myles

105907/Z/14/Z

Institute of Cardiovascular & Medical Sciences

The role of RyR cluster morphology in Ca2+ homeostasis

Godfrey Smith

FS/13/7/30054

Institute of Cardiovascular & Medical Sciences

BHF 4-Year PhD Studentship (4th intake 2016 of 3rd Scheme)

Rhian Touyz

FS/16/55/32731

Institute of Cardiovascular & Medical Sciences

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