Can inhibition of IKur promote atrial fibrillation?

Abstract

Background: Block of ultrarapid delayed rectified potassium current (I(Kur)), present in atria but not in ventricles, is thought to be a promising approach for atrial-specific therapy of atrial fibrillation (AF). However, it has been shown that I(Kur) block may abbreviate atrial repolarization and that loss-of-function mutations in KCNA5, which encodes K(v) 1.5 channels responsible for I(Kur), is associated with familial AF.

Objective: Our objective in this study was to use low concentrations of 4-aminopyridine (4-AP, 10 to 50 microM), known to selectively block I(Kur), to assess the proarrhythmic and antiarrhythmic effects of I(Kur) block in healthy and remodeled atria.

Methods: Isolated canine coronary-perfused right atrial preparations were used. Acetylcholine or ischemia/reperfusion was used to acutely remodel the atria. Transmembrane action potentials and a pseudo-electrocardiogram were simultaneously recorded.

Results: Normal (healthy) atria typically displayed action potentials (AP) with a prominent plateau, whereas remodeled atria displayed triangular-shaped APs (remodeled). In healthy atria, in which AF could not be induced with programmed stimulation, 4-AP abbreviated action potential measured at 90% repolarization (APD(90)) and effective refractory period (ERP), permitting the induction of AF in 4 of 12 preparations (33%). In remodeled atria, 4-AP produced little (50 microM) to no (10 to 25 microM) prolongation of APD(90) or ERP and was either ineffective or poorly effective in terminating AF or preventing its induction.

Conclusion: Our findings suggest that block of I(Kur) can provide the substrate for development of AF in healthy canine atria, presumably via abbreviation of APD and ERP.

Figure 1

Inhibition of I_Kur using low concentrations of 4-aminopyridne (4-AP) abbreviates APD₉₀ and ERP in “healthy” atrial preparations. Shown are superimposed action potentials recorded from the crista terminalis (CT) under control conditions (C) and after the addition of 4-AP (A). Graphs plot summary data of APD₉₀ (B) and ERP (C) recorded from CT and pectinate muscle (PM) sites as a function of 4-AP concentration. CL = 500 ms. n=7–12. * − p<0.05 vs. respective control. Note that atrial ERP corresponds to the level of APD₇₅.

Figure 2

Non-sustained AF induced by a single premature beat (S₁–S₂ = 115 ms) in the presence of 25 µM 4-AP in a “healthy” atrial preparation.

Figure 3

Effects of 4-AP on APD₉₀ and ERP in “acutely remodeled” atrial preparations. Shown are superimposed action potentials obtained from atria pre-treated with acetylcholine (ACh, A) and from atria exposed to ischemia and reperfusion + isoproterenol (Isch/Rep/Iso, B) before and after addition of 4-AP. C–D: Summary APD₉₀ and ERP data from pectinate muscle. n=7–12. CL = 500 ms. * − p<0.05 vs. respective control.

Figure 4

Concentrations of 4-AP that selectively block I_Kur fail to prevent or terminate atrial fibrillation in “remodeled” atria. Shown are simultaneously recorded ECG and AP traces. A: 25 µM 4-AP fails to terminate persistent AF induced in the presence of acetylcholine (ACh, 0.5 µM). B: 25 µM 4-AP fails to prevent the induction of non-sustained AF by a single premature beat (S₁–S₂ = 85 ms, which is ERP) in ischemia/reperfusion+isoproterenol AF model (Isch/Rep/Iso). C: An increase of 4-AP concentration to 100 µM prolongs ERP and prevents the initiation of the arrhythmia by premature stimulation (S₁–S₂ = 110 ms, which is ERP).