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

• Published in: Cardiovascular research 2011-03, Vol.89 (4), p.843-851
• Main Authors: Pandit, Sandeep V, Zlochiver, Sharon, Filgueiras-Rama, David, Mironov, Sergey, Yamazaki, Masatoshi, Ennis, Steven R, Noujaim, Sami F, Workman, Antony J, Berenfeld, Omer, Kalifa, Jerome, Jalife, José
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine - pharmacology; Action Potentials - drug effects; Animals; Atrial Fibrillation - drug therapy; Computer Simulation; Hyperkalemia - physiopathology; Male; Original : Focus on the Molecular Basis of Atrial Fibrillation; Phosphines - pharmacology; Potassium - metabolism; Potassium Channel Blockers - therapeutic use; Swine
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvq359

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 μM)-induced AF in pig hearts. The atrial-specific current, I(Kur), 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, 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.