Targeting atrioventricular differences in ion channel properties for terminating acute atrial fibrillation in pigs

Abstract

Aims: The goal was to terminate atrial fibrillation (AF) by targeting atrioventricular differences in ionic properties. Methods and results: Optical mapping was used to record electrical activity during carbachol (0.25-0.5 μM)-induced AF in pig hearts. The atrial-specific current, IKur, was blocked with 100 μM 4-aminopyridine (4-AP) or with 0.5 μM DPO-1. Hearts in AF and ventricular fibrillation (VF) were also subjected to increasing levels of extracellular K+ ([K+]o: 6-12 mM), compared with controls (4 mM). We hypothesized that due to the more negative steady-state half inactivation voltage for the atrial Na+ current, INa, compared with the ventricle, AF would terminate before VF in hyperkalaemia. Mathematical models were used to interpret experimental findings. The IKur block did not terminate AF in a majority of experiments (6/9 with 4-AP and 3/4 with DPO-1). AF terminated in mild hyperkalaemia ([K +]o ≤ 10.0 mM; N = 8). In contrast, only two of five VF episodes terminated at the maximum ([K+]o: 12 mM [K +]o). The IKur block did not terminate a simulated rotor in cholinergic AF because its contribution to repolarization was dwarfed by the large magnitude of the acetylcholine-activated K+ current (IK,ACh). Simulations showed that the lower availability of the atrial Na+ current at depolarized potentials, and a smaller atrial tissue size compared with the ventricle, could partly explain the earlier termination of AF compared with VF during hyperkalaemia. Conclusion: I Kur is an ineffective anti-arrhythmic drug target in cholinergic AF. Manipulating Na+ current 'availability' might represent a viable anti-arrhythmic strategy in AF. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010.