Abstract 13905: Na+ Channel Blockade Determines Propensity for Arrhythmias During Calcium Overload
Introduction: Andersen-Tawil syndrome (ATS1) associated ventricular arrhythmias are initiated by frequent, hypokalemia-exacerbated, premature ventricular activity (PVA). We previously demonstrated that a guinea pig model of drug induced ATS1 (DI-ATS1) evidenced increased arrhythmias that were associated with regional functional NCX expression. Specifically, increasing global NCX dominance via SERCA2a inhibition increased arrhythmia incidence, while direct NCX blockade significantly reduced such events suggesting a role not only for Ca2+ but also for Na+ in ATS1-associated arrhythmogenesis. The purpose of this study was to determine whether decreased cytosolic Na+ entry, either through cardiac or tetrodotoxin (TTX)-sensitive Na+ channels during DI-ATS1 can ameliorate arrhythmia burden.
Methods: DI-ATS1 was induced with 10μ M BaCl2 and 2mM [K+]o. Ca2+ transients and conduction velocity (CV) were optically mapped with indo-1 and di-4-ANEPPS respectively from Langendorff perfused guinea pig ventricles.
Results: Na+ channel blockade with 1µM flecainide during DI-ATS1 slowed both transverse and longitudinal CV in the left ventricle (LV, 13.2±0.6 v.s 15.3±0.1 cm/sec and 39.2±1.6 vs. 46.4±0.6 cm/sec, respectively, p<0.05, n=5), decreased Ca2+ transient amplitude (CaA) by 13.9±4.8% (p<0.05, n=5) and abolished the incidence of rapid paced induced ventricular tachycardia (VT, n=10) while decreasing the incidence of PVA (2.1±0.6 vs. 5.5±1.0 PVA/10min, p<0.05, n=10) relative to DI-ATS1 alone. On the other hand, 100nM TTX did not alter either transverse or longitudinal LV CV (15.4±0.4 vs. 15.7±0.4 cm/sec and 45.9±0.6 v.s 47.0±0.6 cm/sec, respectively, n=6); however, it did decrease CaA by 23.4±3.2% (p<0.05, n=4), PVA (2.2±0.7 vs. 6.5±1.3 PVA/10min, p<0.05, n=10) and rapid paced induced VT incidence (10% vs. 100%, n=10) relative to DI-ATS1.
Conclusions: These data suggest that cytosolic Na+ entry is necessary for arrhythmogenesis. During loss of IK1 function, not only NCX dominance but Na+ flux may determine arrhythmia incidence. Therefore, inhibiting cytosolic Na+ influx may offer a potential therapeutic target to alleviate arrhythmia burden during states of Ca2+ overload secondary to loss of IK1 function.
- © 2011 by American Heart Association, Inc.