Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model

Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K+ channel (TASK‐1;hK 2P 3.1) two‐pore–domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart,TASK ‐1 channels are specifically expressed in the atria. Furthermore, upregulation of atrialTASK ‐1 currents was described in patients suffering from atrial fibrillation (AF ). We therefore hypothesized thatTASK ‐1 channels represent an ideal target for antiarrhythmic therapy ofAF . In the present study, we tested the antiarrhythmic effects of the high‐affinityTASK ‐1 inhibitor A293 on cardioversion in a porcine model of paroxysmalAF .Methods and Results Heterologously expressed human and porcineTASK ‐1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparableTASK ‐1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. ParoxysmalAF was induced by right atrial burst stimulation. After induction ofAF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surfaceECG parameters and the ventricular effective refractory period lengths remained unchanged.Conclusions Pharmacological inhibition of atrialTASK ‐1 currents exerts antiarrhythmic effects in vivo as well as in silico, resulting in acute cardioversion of paroxysmalAF . Taken together, these experiments indicate the therapeutic potential of A293 forAF treatment.