Abstract 10620: Potential Role of Ca2+-Dependent K+ Channels in Atrial Fibrillation
Background: Atrial fibrillation (AF) is often initiated by ectopy from the pulmonary veins (PVs). Recently, SNPs in Ca2+-dependent K+-channels (encoded by SK subunits) have been implicated in AF risk. Here, we assessed potential differences between left atrial (LA) and PV SK-channels in control (CTL) dogs and dogs with an AF substrate induced by 1-wk atrial tachypacing (AT-P).
Methods: Action potential duration (APD) and SK-channel current (ISK, identified by highly selective blockers apamin and NS8593) were recorded with perforated and tight-seal patch-clamp techniques respectively in isolated canine LA and PV cells. SK mRNA and protein were quantified by qPCR and immunoblot.
Results: NS8593 specifically blocked ISK with an IC50 of ~5 µM, without affecting IK1, IKr, or ICa. In CTL dogs, NS8593 and apamin (classical ISK blocker) increased PV APD, with small or absent effects in LA (Figure A). ISK was significantly larger in PV vs LA cells, e.g. at -110 mV -2.5±0.4 vs -1.2±0.2 pA/pF (P<0.001, Figure Ba). AT-P upregulated ISK (Figure Bb) and reduced APD in both PV and LA. ISK-block significantly increased APD in both PV and LA-cells after AT-P, with larger effects in PV (Figure A). SK1 mRNA and protein expression were more abundant in PV than LA in CTL dogs (Figure C), whereas BKCa, SK2, SK3 and SK4 expression were similar. AT-P significantly increased SK2 mRNA and protein expression in both PV and LA, without significantly affecting SK1 expression (Figure C).
Conclusions: 1. SK subunits are more abundantly expressed in canine PV vs LA, leading to larger ISK in PV. 2. AT-P increases SK mRNA and protein expression and current, contributing to APD decreases. 3) ISK inhibition increases APD, with effects enhanced in the AT-P induced AF substrate. These data help to explain the arrhythmogenic properties of PVs, shed light on the potential functional role of SK-channel SNPs in predisposition to AF, and position SK-blockers as potentially useful antiarrhythmic agents.
- © 2011 by American Heart Association, Inc.