Atrium-Specific Kir3.x Determines Inducibility, Dynamics and Termination of Fibrillation by Regulating Restitution-Driven Alternans

Background—Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (IK,ACh-c) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how IK,ACh-c contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of IK,ACh-c blockade and Kir3.x downregulation on atrial fibrillation. Methods and Results—Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3- or Kcnj5-specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0...