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

The goal was to terminate atrial fibrillation (AF) by targeting atrioventricular differences in ionic properties.

Optical mapping was used to record electrical activity during carbachol (0.25-0.5 microM)-induced AF in pig hearts. The atrial-specific current, I(Kur), was blocked with 100 microM 4-aminopyridine (4-AP) or with 0.5 microM 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, I(Na), compared with the ventricle, AF would terminate before VF in hyperkalaemia. Mathematical models were used to interpret experimental findings. The I(Kur) 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 I(Kur) 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 (I(K,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.

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.