Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes

Author:

Lachaud Quentin1ORCID,Aziz Muhamad Hifzhudin Noor23ORCID,Burton Francis L1ORCID,Macquaide Niall14ORCID,Myles Rachel C1ORCID,Simitev Radostin D2ORCID,Smith Godfrey L1ORCID

Affiliation:

1. Institute of Cardiovascular and Medical Sciences, University of Glasgow , Glasgow , UK

2. School of Mathematics and Statistics, University of Glasgow , Glasgow , UK

3. Institute of Mathematical Sciences, Faculty of Science, University of Malaya , Kuala Lumpur , Malaysia

4. School of Health and Life Sciences, Glasgow Caledonian University , Glasgow , UK

Abstract

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.

Funder

UK Engineering and Physical Sciences Research Council

Wellcome Trust

BHF

BHF PhD Studentship

Ministry of Higher Education Malaysia and University of Malaya via a SLAB scholarship awarded to M.H.N.A

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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