Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes

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 similar to 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 APD(90) 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 APD(90) differences accounted for similar to 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 APD(90) distribution was generated from a larger population of models created by random variation of the maximum conductances (G(max)) 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 G(max) 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 G(max) 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.

Automated summary

The aim of this study is to assess intra-regional differences in the action potential waveform and quantify the contribution of specific ion channels to the action potential duration (APD) in rabbit ventricular cells. The results show that there is considerable inter-cell variation in channel/pump/exchanger activity in ventricular tissue, and specific interrelationships between ionic conductances are necessary for stable repolarization despite large inter-cell variation of individual conductances, which explains the variable sensitivity to ion channel block.