Atrium-Specific Kir3.x Determines Inducibility, Dynamics and Termination of Fibrillation by Regulating Restitution-Driven Alternans
Background—Atrial fibrillation (AF) is the most common cardiac arrhythmia. Ventricular pro-arrhythmia hinders pharmacological AF 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 AF induction, dynamics and termination. Therefore we investigated the effects of IK,ACh-c blockade and Kir3.x downregulation on AF.
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 short hairpin RNAs. 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 to 128.8±16.9ms,p<0.0001) in atrial cultures during reentry, indicating the presence of IK,ACh-c. Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0Hz,p<0.05) and complexity(6.6±7.7 to 0.6±0.8 phase singularities,p<0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of IK,ACh-c prevented/terminated reentry by prolonging APD and changing APD and conduction velocity (CV) restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole heart mapping experiments confirmed key findings (e.g. >50% reduction in AF inducibility after IK,ACh-c blockade).
Conclusions—Atrium-specific Kir3.x controls induction, dynamics and termination of fibrillation by modulating APD and APD/CV restitution slopes in atrial tissue with IK,ACh-c. This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.
- Received July 11, 2013.
- Revision received September 11, 2013.
- Accepted September 13, 2013.