Dual effects of the small-conductance Ca ^{2 1} -activated K ¹ current on human atrial electrophysiology and Ca ^{2 1} -driven arrhythmogenesis: an in silico study

By sensing changes in intracellular Ca ^{2 +} , small-conductance Ca ^{2 +} -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 versus 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 _SK) 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 _SK have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) versus normal sinus rhythm (nSR) patient samples. Here, we use our multiscale modeling framework to obtain mechanistic insights into the contribution of I _SK in human atrial cardiomyocyte electrophysiology. We simulate several protocols to quantify how I _SK modulation affects the regulation of AP duration (APD), Ca ^{2 +} transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that I _SK activation shortens the APD and atrial effective refractory period, limits Ca ^{2 +} cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing I _SK counteracts DAD development by enhancing the repolarization force that opposes the Ca ^{2 +} -dependent depolarization. Taken together, our results suggest that increasing I _SK in human atrial cardiomyocytes could promote reentry while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, I _SK inhibition may thus be a beneficial or detrimental anti-AF strategy.