Abstract 17029: Selective Inhibition of Late Sodium Current Suppresses Arrhythmogenic Markers in Models of Long QT Syndrome
Introduction: Long QT syndrome (LQTs) is characterized by reduction of net repolarizing current, increased transmural dispersion of repolarization (TDR), prolongation of QT interval and polymorphic ventricular arrhythmias (Torsade de Pointes, TdP). Management of LQTs and TdP is still a challenge and an effective drug therapy has not been well established. This study tested the hypothesis that selective inhibition of late Na+ current (INaL) can stabilize cardiac repolarization and terminates ventricular arrhythmias. Towards this, GS-6615 (dihydrobenzoxazepinone), a potent and selective inhibitor of INaL that is currently in clinical development for the treatment of ventricular arrhythmias was used to determine its effect on arrhythmogenic markers in models mimicking LQT2 and 3 syndromes.
Methods: Transmembrane action potentials (APs) were simultaneously recorded from epicardium (Epi) and endocardium (Endo) along with a transmural electrocardiogram (ECG) at different basic cycle lengths (BCL; 500, 1000 and 2000 ms) in arterially perfused rabbit left ventricular wedge preparations. E-4031 (IKr blocker) and Anemonia sulcata toxin (ATX-II, late INa enhancer) were used to mimic LQT2/3, respectively.
Results: E-4031 (60 nM) and ATX-II (2 nM) caused early afterdepolarization (EADs, Fig. 1A), increased TDR (Fig 1B), prolonged QT (Fig 1C) and Tp-e intervals (Fig 1D), Tp-e/QT ratio, steeper QT-BCL and Tp-e-BCL slopes, R-on-T phenomenon (Fig. 1A) and TdP. GS-6615 (0.1 -1 μM, n=4) in the presence of E-4031 (Fig. 1A) or ATX-II caused a concentration-dependent decrease in all the above mentioned arrhythmogenic markers. Similarly, pretreatment of wedge preparations with GS-6615 (0.3 μM, n=4), abolished the pro-arrhythmic phenotypes of E-4031 and ATX-II.
Conclusions: Our results show that selective inhibition of late INa is effective in suppressing arrhythmogenic markers and ventricular arrhythmias associated with LQT2/3 syndromes.
Author Disclosures: D. Guo: None. G. Liu: None. S. Rajamani: None. L. Belardinelli: None.
- © 2014 by American Heart Association, Inc.