Increased aldosterone-dependent Kv1.5 recycling predisposes to pacing-induced atrial fibrillation in Kcne3-/- mice

Hyperaldosteronism is associated with an increased prevalence of atrial fibrillation (AF).Mutations in KCNE3 have been associated with AF, and Kcne32/2 mice exhibit hyperaldosteronism. In this study, we used recently developed Kcne32/2 mice to study atrial electrophysiology with respect to development of aldosterone- dependentAF. In invasive electrophysiology studies,Kcne32/2 mice displayeda reduced atrial effective refractory period (AERP) and inducible episodes of paroxysmal AF. The cellular arrhythmogenic correlate for AF pre- dispositionwas a significant increase in atrialKvcurrents generatedbythemicromolar 4-aminopyridine-sensitive Kv current encoded by Kv1.5. Electrophysiological alterations in Kcne32/2 mice were aldosterone dependent and were associated with increased Rab4, -5, and -9-dependent recycling of Kv1.5 channels to the Z-disc/T-tubulus region and lateral membrane via activation of the Akt/AS160 pathway. Treatment with spironolactone inhibited Akt/AS160 phosphorylation, reduced Rab-dependent Kv1.5 recycling, normalized AERP and atrial Kv currents to the wild-type level, and reduced arrhythmia induction in Kcne32/2 mice. Kcne3 deletion inmicepredisposes toAF by a heretofore unrecognized mechanism—namely, increased aldosterone-dependent Kv1.5 recycling via Rab GTPases.The findingsuncoverdetailedmolecularmechanismsunderpinninga channelopathy-linkedformofAF and emphasize the inevitability of considering extracardiac mechanisms in genetic arrhythmia syndromes.— Lisewski, U., Koehncke, C., Wilck, N., Buschmeyer, B., Pieske, B.,Roepke, T. K. Increased aldosterone-dependent Kv1.5 recycling predisposes to pacing-induced atrial fibrillation in Kcne32/2 mice.