Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation

Inward rectifier potassium currents I-K1 and acetylcholine activated I-K,I-ACh are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), I-K,I-ACh develops a receptor-independent, constitutively active component that together with increased I-K1 is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial I-K1 and I-K,I-ACh in patients with and without cAF. I-K1 and I-K,I-ACh were measured with voltage clamp technique in atrial myocytes from 58 sinus rhythm (SR) and 35 cAF patients. The M-receptor agonist carbachol (CCh; 2 A mu M) was employed to activate I-K,I-ACh. In SR, basal current was not affected by either drug indicating no effect of these compounds on I-K1. In contrast, all tested drugs inhibited CCh-activated I-K,I-ACh in a concentration-dependent manner. In cAF, basal current was confirmed to be larger than in SR (at -80 mV, -15.2 A +/- 1.2 pA/pF, n = 88/35 vs. -6.5 A +/- 0.4 pA/pF, n = 194/58 [myocytes/patients]; P < 0.05), whereas CCh-activated I-K,I-ACh was smaller (-4.1 A +/- 0.5 pA/pF vs. -9.5 A +/- 0.6 pA/pF; P < 0.05). In cAF, receptor-independent constitutive I-K,I-ACh contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active I-K,I-ACh channels. In cAF, all tested drugs reduced CCh-activated I-K,I-ACh. We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active I-K,I-ACh, suggesting that they may block I-K,I-ACh channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of I-K,I-ACh.