Cell-to-cell heterogeneity in ion channel conductance impacts substrate vulnerability to arrhythmia.

Determining whether an ectopic depolarization will lead to a self-perpetuating arrhythmia is of critical importance in determining arrhythmia risk, so it is necessary to understand what factors impact substrate vulnerability. This study sought to explore the impact of cell-to-cell heterogeneity in ion channel conductance on substrate vulnerability to arrhythmia by measuring the duration of the vulnerable window in computational models of one-dimensional cables of ventricular cardiomyocytes. We began by using a population of uniform cable models to determine the mechanisms underlying the vulnerable window phenomenon. We found that in addition to the known importance of GNa, the conductances GCa,L and GKr also play a minor role in determining the vulnerable window duration. We also found that a steeper slope of the repolarizing action potential during the vulnerable window correlated with a shorter vulnerable window duration in uniform cables. We applied our understanding from these initial simulations to an investigation of the vulnerable window in heterogeneous cable models. The heterogeneous cables displayed a great deal of intra-cable variation in vulnerable window duration, highly sensitive to the cardiomyocytes in the local environment of the ectopic stimulus. Coupling strength modulated not only the magnitude of the vulnerable window duration but also the extent of intra-tissue variability in vulnerable window duration.NEW & NOTEWORTHY We investigate the impact of cell-to-cell heterogeneity in ion channel conductance on substrate vulnerability to arrhythmia by measuring the vulnerable window duration in computational cardiomyocyte cable models. We demonstrate a wide range of intra-cable variability in vulnerable window duration (VWD) and show how this is changed by ion channel block and coupling strength perturbations.