Dual effects of the small-conductance Ca²⁺-activated K⁺current on human atrial electrophysiology and Ca²⁺-driven arrhythmogenesis: anin silicostudy

Abstract 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 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 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) vs. normal sinus rhythm (nSR) patient samples. Here, we use our multi-scale modeling framework to obtain mechanistic insights into the contribution of I SK in human atrial myocyte 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 reducing the coupling between transmembrane potential and intracellular Ca 2+ . Taken together, our results suggest that increasing I SK in human atrial myocytes 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.