Repolarization variability mechanism and its relation with cardiac arrhythmogenesis

Enhanced temporal variability of ventricular repolarization has been related to increased ventricular arrhythmic risk. In this study, we investigate the influence of stochastic ion channel gating on the variability of four arrhythmic risk biomarkers: action potential (AP) duration (APD), AP triangulation and systolic and diastolic calcium levels. Different levels of white noise, representing different channel numbers, were introduced by means of a stochastic differential equation for the gating variables of the ten Tusscher-Panfilov human ventricular model (TP06). In single cells the rapid and slow delayed rectifier potassium currents (I_Kr and I_Ks) were the main contributors to biomarkers variability, which was shown to be increased at fast pacing frequencies, particularly for APD and diastolic calcium. At tissue level, electrotonic coupling masked the effects of stochastic gating on the variability of all the investigated biomarkers. In particular, a very notable reduction in variability was obtained for 2D and 3D tissue models, with 80% reduction with respect to 1D models, and more than 20 folds with respect to isolated cells under physiological conditions. This indicates that large variations in cellular AP are required in order to reproduce physiological variability levels measured in tissue.