Variable electrophysiology before and after block of the two delayed rectifier potassium channels in groups of...

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.

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.

The median APD₉₀ 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 APD₃₀ vs. APD₉₀ = 0.78 ± 0.06). Forty-four in silico models recreated the variability in APD₉₀, AP shape and response to inhibition of I_Kr and I_Ks by employing widely varying but interrelated values of maximal conductance values.

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.