Abstract 16790: Anti-Arrhythmic Properties of a Novel Cardiac Late Na+ Current Inhibitor, GS-6615, in a Mouse Model of Long QT Type 3
Background: Congenital Long QT syndrome type 3 (LQT3) is caused by mutations in the gene SCN5A resulting in enhanced late Na+ current (INa). Enhanced late INa leads to early-afterdepolarizations (EADs) and triggered activity (TA), spatiotemporal differences in repolarization time which promote reentrant electrical activity. This study was designed to investigate whether selective inhibition of late INa by GS-6615 (dihydrobenzoxazepinone) could effectively suppress ventricular arrhythmias in a transgenic mouse model of LQT3.
Methods: The effects of GS-6615 on late INa and action potential duration (APD) in ventricular myocytes isolated from a transgenic mouse model of LQT3 (N1325S) were determined using whole-cell patch-clamp technique.
Results: Compared to a transgenic WT mouse, the amplitude of late INa, APD to 50 and 90% repolarization (APD50 and APD90, respectively) and beat-to-beat variability of APD (BVR, Figure 1a and e) were significantly increased in N1325S ventricular myocytes. In addition, spontaneous EADs and TA were observed in N1325S ventricular myocytes. Application of GS-6615 (0.3 and 1 μM, n=4 each, Fig. 1b, c and e) reduced late INa, shortened APD50 and APD90, abolished, BVR, spontaneous EADs and TA.
Conclusion: Taken together, these results suggest that the novel and highly potent cardiac late INa inhibitor GS-6615 may be effective in the termination of ventricular arrhythmias by suppressing arrhythmogenic markers, afterpotentials and BVR.
Figure 1. Effects of GS-6615 on Beat-to-beat Variability in APD in Myocytes Expressing the Human LQT3 Mutation, N1325S
Author Disclosures: S. Rajamani: Employment; Significant; Gilead Sciences. Ownership Interest; Modest; Gilead Sciences. N. El-Bizri: Employment; Significant; Gilead Sciences. Ownership Interest; Modest; Gilead Sciences. G. Liu: Employment; Significant; Gilead Sciences. Ownership Interest; Modest; Gilead Sciences. L. Belardinelli: Employment; Significant; Gilead Sciences. Ownership Interest; Modest; Gilead Sciences.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.