Can inhibition of IKur promote atrial fibrillation?

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 mu M), 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-etectrocardiogram 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 mu M) to no (10 to 25 mu M) 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 APO and ERP.