Potassium Channel Blockade Enhances Atrial Fibrillation-Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade
Background—A lack of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K+-channel blockade (KCB) improves the atrial-selective electrophysiological profile and anti-AF effects of optimized Na+-channel blockers (NCBos).
Methods and Results—Realistic cardiomyocyte, tissue and state-dependent Na+-channel block mathematical models, optical mapping and action potential recording were used to study the effect of Na+-current (INa) blockade with or without concomitant inhibition of the rapid or ultra-rapid delayed rectifier K+-currents (IKr, IKur, respectively). In the mathematical model, maximal AF-selectivity was obtained with an inactivated-state Na+-channel blocker. Combining NCBo with IKr block increased rate-dependent and atrial selective peak INa reduction, increased AF-selectivity and more effectively terminated AF compared to NCBo alone. Combining NCBo with IKur block had similar effects but without IKr block-induced ventricular action potential prolongation. Consistent with the mathematical model, in coronary-perfused canine hearts the addition of dofetilide (selective IKr blocker; DOF) to pilsicainide (selective INa blocker; PIL) produced enhanced atrial-selective effects on maximal phase-0 upstroke and conduction velocity. Furthermore, PIL+DOF had higher AF termination efficacy than PIL alone. PIL alone had no statistically significant effect on AF inducibility while PIL+DOF rendered AF non-inducible.
Conclusions—K+-channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na+-channel blockade. Combining optimized Na+-channel block with blockade of atrial K+-currents is a potentially valuable AF-selective antiarrhythmic drug strategy.
- Sodium channel blockers
- Potassium channel blockers
- Combination therapy
- antiarrhythmic drug
- atrial fibrillation
- Received June 15, 2015.
- Revision received August 20, 2015.
- Accepted September 10, 2015.