Computational modelling of the pro- and antiarrhythmic effects of atrial high rate-dependent trafficking of small-conductance calcium-activated potassium channels.

Small-conductance calcium-activated potassium (SK) channels are promising targets for atrial-specific antiarrhythmic therapies, with evidence suggesting tachycardia-dependent SK-channel upregulation. However, the dynamics of SK-channel gating and trafficking in human atrial electrophysiology remain unclear because of experimental limitations, including the availability of human cardiomyocytes and long patch clamp experiments. Although computational models help explore these mechanisms, none integrate SK-channel trafficking. In the present study, we expanded our K11.1 trafficking model to simulate rate-dependent SK-channel trafficking in a human atrial cardiomyocyte model. Calibrated against experimental data, our model replicates time- and rate-dependent SK-channel function, allowing simulations of SK-channel trafficking and its effects on action potentials. Tachypacing at 5 Hz increased SK-channel density, enhancing SK current and shortening action potential duration, with or without calcium buffering. Two-dimensional tissue simulations with physiological calcium handling showed that tachycardia increased re-entry duration and ectopic activity. SK-channel inhibition reduced re-entry duration but promoted ectopic activity, suggesting a reduction in atrial fibrillation burden rather than complete elimination. Our novel computational model highlights SK channels' role in re-entry-promoting effects of short atrial tachycardia episodes, offering insights into early atrial fibrillation progression and potential antiarrhythmic strategies. KEY POINTS: Small-conductance calcium-activated potassium (SK) channels have emerged as potential targets for atrial-specific antiarrhythmic therapies, especially in atrial fibrillation (AF). Emerging evidence suggests that tachycardia-induced SK-channel trafficking can regulate cardiac cellular electrophysiology over minutes, but investigating its impact on arrhythmogenesis in humans is experimentally challenging. We adapted our recent in silico K11.1 trafficking model to simulate SK-channel trafficking and incorporated it into a human atrial cardiomyocyte model, which was calibrated based on experimental results. Tachypacing at 5 Hz led to a substantial increase in SK channel-density at the membrane, resulting in enhanced SK current and a reduction in action potential duration. 2-D tissue simulations demonstrated that rapid pacing promoted both re-entry and ectopic (triggered) activity. Blocking SK channels reduced re-entry duration but increased ectopic activity, suggesting that SK channel inhibition could decrease AF burden, but may not eliminate AF per se.