Dual effects of the small-conductance Ca2+-activated K+ current on human atrial electrophysiology and Ca2+-driven arrhythmogenesis: an in silico study

By sensing changes in intracellular Ca , small-conductance Ca -activated K (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria vs. ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF), the most common cardiac arrhythmia. However, the precise contribution of SK current (I ) to atrial arrhythmogenesis is poorly understood, and may potentially involve different mechanisms that depend on species, heart rates, and degree of AF-induced atrial remodeling. Both reduced and enhanced I have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) vs. normal sinus rhythm (nSR) patient samples. Here, we use our multi-scale modeling framework to obtain mechanistic insights into the contribution of I in human atrial cardiomyocyte electrophysiology. We simulate several protocols to quantify how I modulation affects the regulation of AP duration (APD), Ca transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that I activation shortens the APD and atrial effective refractory period, limits Ca cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing I counteracts DAD development by enhancing the repolarization force that opposes the Ca -dependent depolarization. Taken together, our results suggest that increasing I in human atrial cardiomyocytes could promote reentry, while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, I inhibition may thus be a beneficial or detrimental anti-AF strategy.