Abstract 1365: Role of Kv1.5 in Atrial Fibrillation: KCNA5-Deficient Mice Do Not Have Enhanced Arrhythmia Susceptibility
Background: A loss-of-function mutation in KCNA5, the gene that encodes the voltage-gated K+ channel Kv1.5 (IKur) in human atria, has been reported in an AF case ( Hum Mol Genet. 2006;15:2185). Kv1.5 encodes K+ currents in mouse atria and ventricles, and inhibition of Kv1.5 with 4-AP delays mouse cardiac repolarization. We examined the role of Kv1.5 in atrial arrhythmogenesis using KCNA5 KO mice.
Methods: Electrophysiologic features were studied with standard EP protocols in anesthetized, adult WT (n=18) and Kv1.5 −/− KO (n=23) mice using a right atrial 2F octapolar catheter. AF induction was performed in the absence and presence of isoproterenol (iso 5 μg, IP) with triple extra stimulation and burst pacing (20 –50 Hz). AF was considered inducible if ≥1 bursts or triple extra stimulation evoked an AF episode ≥0.1 sec. Action potentials (APs) were recorded from isolated WT (n=5) and KO (n=8) left atrium at 1 Hz in the absence and presence of 1μM iso using standard microelectrodes.
Results: Taqman did not detect any Kv1.5 mRNA in KO heart, and there were no differences in Kv1.4, Kv2.1 and Kv4.2 mRNAs between WT and KO mice. Mean±SEM atrial ERP, HR and SNRT were not significantly different between KO and WT mice. No spontaneous atrial or ventricular arrhythmias were observed in KO or WT mice. Burst pacing induced AF in 2 of 10 KO and 1 of 8 WT mice without iso, and in 4 of 10 KO and 5 of 8 WT mice with iso, with no statistical difference among groups. Iso increased AF duration (AFD) in both WT and KO, but AFD under iso was longer in WT versus KO mice. There was no difference in AV node function (PR, AVN-ERP and Wenckebach CL) between KO and WT mice. APD90 was prolonged in KO (45±5 vs 39±2, P=0.06) but other AP indices were unchanged. Iso induced more EAD, DAD and atrial tachycardia-like activity in WT (5/5) than in KO (3/8, P<0.05).
Conclusions: This study, the first to examine the role of Kv1.5 in AF using a KO approach, indicates that loss of Kv1.5 does not enhance AF susceptibility and may in fact reduce it.