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 atrial TASK ‐1 currents was described in patients suffering from atrial fibrillation ( AF ). We therefore hypothesized that TASK ‐1 channels represent an ideal target for antiarrhythmic therapy of AF . In the present study, we tested the antiarrhythmic effects of the high‐affinity TASK ‐1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF . Methods and Results Heterologously expressed human and porcine TASK ‐1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK ‐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. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF 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 surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK ‐1 currents exerts antiarrhythmic effects in vivo as well as in silico , resulting in acute cardioversion of paroxysmal AF . Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.

Natural bioactive compounds are of general interest for pharmaceutical research because they may serve as leads in drug development campaigns. Among them, microginins are linear peptides known to inhibit various exopeptidases. The crystal structure of microginin FR1 from Microcystis sp. bound to bovine lens leucine aminopeptidase was established at 1.73 Å resolution. The observed binding structure could be beneficial for the design of potent aminopeptidase inhibitors.

Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an increase in mortality and stroke incidences. While stroke risk can be significantly reduced through anticoagulant therapy, adequate treatment of other AF related symptoms remains an unmet medical need in many cases. Two main treatment strategies are available: rate control that modulates ventricular heart rate and prevents tachymyopathy as well as rhythm control that aims to restore and sustain sinus rhythm. Rate control can be achieved through drugs or ablation of the atrioventricular node, rendering the patient pacemaker-dependent. For rhythm control electrical cardioversion and pharmacological cardioversion can be used. While electrical cardioversion requires fasting and sedation of the patient, antiarrhythmic drugs have other limitations. Most antiarrhythmic drugs carry a risk for pro-arrhythmic effects and are contraindicated in patients with structural heart diseases. Furthermore, catheter ablation of pulmonary veins can be performed with its risk of intraprocedural complications and varying success. In recent years TASK-1 has been introduced as a new target for AF therapy. Upregulation of TASK-1 in AF patients contributes to prolongation of the action potential duration. In a porcine model of AF, TASK-1 inhibition by gene therapy or pharmacological compounds induced cardioversion to sinus rhythm. The DOxapram Conversion TO Sinus rhythm (DOCTOS)-Trial will reveal whether doxapram, a potent TASK-1 inhibitor, can be used for acute cardioversion of persistent and paroxysmal AF in patients, potentially leading to a new treatment option for AF.