Synergistic anti-arrhythmic effects of combined blockade of sodium and ultra-rapid delayed rectifier potassium channels in human atria

Atrial fibrillation (AF) is the commonest cardiac arrhythmia. Developing effective and safe anti-AF drugs remains unmet. Atrial-selective blocking the ultra-rapid delayed rectifier potassium current (I
_Kur
) and sodium channel (I
_Na
) was recently reported to be potentially effective in the treatment of AF. We used computational models of human atria to assess the antiarrhythmic effects of IKur and INa blocks on human atria. A mathematical model of IKur channel block was developed to describe the blocking effects of acacetin, an IKur-selective blocker. INa blockade was simulated using the guarded-receptor model. The effects of these channel blocks were simulated using mathematical models of human atrial myocytes and tissue. Applying acacetin rendered significant APD prolongation (by 29.3 ms at 1 Hz). The I
_Na
blocker significantly reduced peak I
_Na
at fast pacing rates, but produced no effect at 1 Hz in both atria and ventricles. Combined actions of the two drugs further decreased peak INa and prolonged APD at a fast pacing rate. These effects were also demonstrated in two-dimensional simulations, where combined blockers showed reduced the life span of re-entrant excitation waves, exerting synergistic antiarrhythmic effects in the human atria, indicating that combined blocks of IKur and I
_Na
may be a valuable strategy for the treatment of AF.