Our results highlight the contribution of Cx43 to the pathophysiology of AF and demonstrate the viability of gene therapy for prevention of atrial arrhythmias.

Knockdown of caspase 3 by atrial Ad-siRNA-Cas3 gene transfer suppresses or delays the onset of persistent AF by reduction in apoptosis and prevention of intra-atrial conduction delay in a porcine model. These results highlight the significance of apoptosis in the pathophysiology of AF and demonstrate short-term efficacy of gene therapy for suppression of AF.

BACKGROUND AND PURPOSE Human K2P3.1 (TASK1) channels represent potential targets for pharmacological management of atrial fibrillation. K2P channels control excitability by stabilizing membrane potential and by expediting repolarization. In the heart, inhibition of K2P currents by class III antiarrhythmic drugs results in action potential prolongation and suppression of electrical automaticity. Carvedilol exerts antiarrhythmic activity and suppresses atrial fibrillation following cardiac surgery or cardioversion. The objective of this study was to investigate acute effects of carvedilol on human K2P3.1 (hK2P3.1) channels. EXPERIMENTAL APPROACH Two‐electrode voltage clamp and whole‐cell patch clamp electrophysiology was used to record hK2P3.1 currents from Xenopus oocytes, Chinese hamster ovary (CHO) cells and human pulmonary artery smooth muscle cells (hPASMC). KEY RESULTS Carvedilol concentration‐dependently inhibited hK2P3.1 currents in Xenopus oocytes (IC50= 3.8 µM) and in mammalian CHO cells (IC50= 0.83 µM). In addition, carvedilol sensitivity of native IK2P3.1 was demonstrated in hPASMC. Channels were blocked in open and closed states in frequency‐dependent fashion, resulting in resting membrane potential depolarization by 7.7 mV. Carvedilol shifted the current–voltage (I–V) relationship by −6.9 mV towards hyperpolarized potentials. Open rectification, characteristic of K2P currents, was not affected. CONCLUSIONS AND IMPLICATIONS The antiarrhythmic drug carvedilol targets hK2P3.1 background channels. We propose that cardiac hK2P3.1 current blockade may suppress electrical automaticity, prolong atrial refractoriness and contribute to the class III antiarrhythmic action in patients treated with the drug.