Estimating the probabilities of rare arrhythmic events in multiscale computational models of cardiac cells and tissue

Ectopic heartbeats can trigger reentrant arrhythmias, leading to ventricular fibrillation and sudden cardiac death. Such events have been attributed to perturbed Ca 2+ handling in cardiac myocytes leading to spontaneous Ca 2+ release and delayed afterdepolarizations (DADs). However, the ways in which perturbation of specific molecular mechanisms alters the probability of ectopic beats is not understood. We present a multiscale model of cardiac tissue incorporating a biophysically detailed three-dimensional model of the ventricular myocyte. This model reproduces realistic Ca 2+ waves and DADs driven by stochastic Ca 2+ release channel (RyR) gating and is used to study mechanisms of DAD variability. In agreement with previous experimental and modeling studies, key factors influencing the distribution of DAD amplitude and timing include cytosolic and sarcoplasmic reticulum Ca 2+ concentrations, inwardly rectifying potassium current (I K1 ) density, and gap junction conductance. The cardiac tissue model is used to investigate how random RyR gating gives rise to probabilistic triggered activity in a one-dimensional myocyte tissue model. A novel spatial-average filtering method for estimating the probability of extreme (i.e. rare, high-amplitude) stochastic events from a limited set of spontaneous Ca 2+ release profiles is presented. These events occur when randomly organized clusters of cells exhibit synchronized, high amplitude Ca 2+ release flux. It is shown how reduced I K1 density and gap junction coupling, as observed in heart failure, increase the probability of extreme DADs by multiple orders of magnitude. This method enables prediction of arrhythmia likelihood and its modulation by alterations of other cellular mechanisms.