Variable electrophysiology before and after block of the two delayed rectifier potassium channels in groups of isolated rabbit ventricular cells

Background and Purpose Between‐cell differences in ventricular cardiomyocyte action potential duration (APD) and responses to ion channel block may contribute to pro‐arrhythmic dispersion of myocardial repolarisation. This study quantifies between‐cell physiological and pharmacological variability in the rabbit left ventricle (LV) and uses these data to calibrate populations of in silico models to suggest a mechanistic basis for variability. Experimental Approach Voltage‐sensitive dye was used to record APs from rabbit cardiomyocytes (2‐Hz stimulation, 37°C) before and after incubation with inhibitors of rapidly‐ or slowly‐activating delayed rectifier potassium currents ( I Kr or I Ks ). Using two published in silico single cell electrophysiological models, 10,000 versions of each model were created through randomised variation of eight key ion‐channel/exchanger conductances. Groups of models matching the experimental APD distribution, AP shape and responses to ion channel inhibition were extracted. Key Results The median APD 90 was 244 ± 25 ms (mean ± standard deviation, 19 hearts, >70 cardiomyocytes per heart) with a mean interquartile range (IQR) of 50 ± 13 ms and a narrow range of AP shapes (mean slope of APD 30 vs. APD 90 = 0.78 ± 0.06). Forty‐four in silico models recreated the variability in APD 90 , AP shape and response to inhibition of I Kr and I Ks by employing widely varying but interrelated values of maximal conductance values. Conclusions and Implications Ventricular cell electrophysiology and responses to channel blocking drugs are highly variable and reproduced by large between‐cell differences in maximal conductance values but preserved interrelationships. Cellular heterogeneity may contribute to drug‐induced increased spatial dispersion of repolarisation and pro‐arrhythmia in the intact heart.