Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model

Abstract

Aims Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied atrial cardiomyocyte electrophysiology in mice with an LQTS3 SCN5A inactivation-impairing mutation (ΔKPQ heterozygotes). Methods and resultsPeak and late Na current (INaP and INaL) were measured with whole-cell patch clamp in left atrial (LA) cardiomyocytes. APs were recorded in multicellular LA preparations with floating microelectrodes. INaL was increased by 110 in LA cardiomyocytes of ΔKPQ mice, whereas INaP was unchanged. AP duration (APD) was prolonged over all frequencies in ΔKPQ mice, but particularly at lower frequencies [e.g. APD90 at 0.5 Hz: 197 ± 8 ms vs. wild-type (WT) 82 ± 2 ms, P< 0.001]. EADs occurred at 0.5 Hz in 10/18 ΔKPQ (56) vs. 1/10 WT (10) atria (P< 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited INaL (50 inhibitory concentration: 12.5 vs. 151.8 M for INaP) in ΔKPQ myocytes. At 10 M, ranolazine shortened APD (e.g. APD90 at 0.5 Hz to 122 ± 4 ms, P 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11, P< 0.05). ConclusionThis study implicates increased INaL in excessive atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have potential clinically-relevant mechanistic and therapeutic implications. © 2011 The Author.