Abstract 11401: Electrophysiological Basis for Atrial Arrhythmia in a Long QT Syndrome Mouse Model
Introduction: Long-QT syndromes (LQTSs) are known to cause ventricular tachyarrhythmias, but increasing evidence indicates they can also cause atrial fibrillation. Although atrial early afterdepolarizations (EADs) are a plausible cause, there are no published studies of cellular arrhythmia mechanisms at the atrial level in models of congenital LQTS. We therefore studied atrial-cellular electrophysiology in mice with an LQTS-3 SCN5A inactivation-impairing mutation (ΔKPQ) and matched littermate controls (WT).
Methods: Late Na+ current (INaL) was measured with whole-cell patch-clamp. Transmembrane action potentials (APs) were recorded with floating microelectrodes from the epicardial side of the isolated left atrium, paced at 6 frequencies between 0.5 and 10 Hz, at 35°C (pH 7.4). Ranolazine (10 μM) was used as an INaL-blocker.
Results: As expected, INaL was increased in atrial myocytes of ΔKPQ mice (Figure A). APs in ΔKPQ-mice were significantly prolonged over all frequencies. AP-duration (APD) prolongation was most marked at lower frequencies (e.g. APD90 at 0.5 Hz: 188±20 ms, vs WT 74±9 ms, p=0.0005). However, significant prolongation was also seen at the fastest pacing frequencies (e.g. at 10 Hz: 23.6±0.7 ms, vs WT 19.0±0.9 ms, p=0.0005). EADs and triggered activity occurred at 0.5 Hz in 10/18 ΔKPQ (56%) vs 1/10 WT (10%) atria (p=0.041). Ranolazine reduced APD in ΔKPQ (e.g. APD90 at 0.5 Hz to 125±17 ms), without significantly changing APD in WT, and prevented EAD-occurrence (to 1/9, 11%, P=0.042; Figure B).
Conclusions: This study implicates INaL in excessive atrial APD-prolongation and arrhythmic EAD-occurrence in a congenital LQT3 mouse model. Our observations provide the first insights into cellular mechanisms of atrial arrhythmogenesis in an animal model of congenital LQTS, and have potential implications for therapeutic approaches.
- © 2010 by American Heart Association, Inc.