Every myocyte in the ventricle is different

Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes

Quentin Lachaud, Muhamad Hifzhudin Noor Aziz, Francis L Burton, Niall Macquaide, Rachel C Myles, Radostin D Simitev, Godfrey L Smith

Researchers from the cardiac theme in collaboration with a group from Mathematics have recently published that that single myocytes from the same region of a heart have highly variable electrophysiology and different responses to ion-channel blocking drugs because of even higher inter-cell variation in ion-channel activity.

The data demonstrate that it is the relative activity of a single ion channel compared to others that determines electrophysiological stability in the heart. Therefore, predisposition to arrhythmias from genetic or environmental causes is not due to up-or downregulation of single ion-channels, but instead disrupted patterns of co-expression. An alternative treatment strategy therefore is to manipulate other ion-channels in the network to restore a stable co-expression pattern.

Full article available here: https://academic.oup.com/

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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First published: 19 January 2022