Abstract 14019: Electrophysiological Effects of the Late Sodium Current Inhibitor GS967 in Scn5a-1798insD Mouse and Human SCN5A-1795insD iPSC-derived Cardiomyocytes
Background and Aim: Selective inhibition of cardiac late sodium current (INa,L) is an emerging target in the treatment of ventricular arrhythmias. The electrophysiological effects of GS967, a potent INa,L inhibitor, were investigated in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from human SCN5A-1795insD induced pluripotent stem cells (iPSC-CMs) and mice carrying the homologous mutation Scn5a-1798insD.
Methods and Results: On patch-clamp analysis, isolated mouse Scn5a-1798insD cardiomyocytes and human SCN5A-1795insD iPSC-CMs showed decreased peak INa and action potential (AP) upstroke velocity (Vmax) and increased INa,L and AP duration at 90% repolarization (APD90) as compared to wild-type. GS967 (50-300 nM) significantly decreased APD90 in mouse Scn5a-1798insD cardiomyocytes by 8±2% (mean±SEM) at 50 nM (n=7), 13±3% at 100 nM (n=11) and 20±5% at 300 nM (n=6) (all p<0.01 vs. control), without affecting Vmax. GS967 (300 nM) selectively inhibited INaL in mouse Scn5a-1798insD cardiomyocytes (GS967-sensitive current of 0.7±0.1 pA/pF, n=6), but had no effect on peak INa. Furthermore, GS967 (100 nM) suppressed fast (5 Hz) pacing-induced afterpotentials and triggered activity. In human SCN5A-1795insD iPSC-CMs (n=6), GS967 (300 nM) significantly reduced APD90 without affecting the resting membrane potential or Vmax. In Langendorff-perfused, isolated mouse Scn5a-1798insD hearts (n=5), GS967 (300 nM) had no effect on ventricular activation time or conduction velocity (as assessed by epicardial mapping).
Conclusion: Selective inhibition of INaL by GS967 attenuated AP prolongation and prevented pro-arrhythmic activity in mouse Scn5a-1798insD cardiomyocytes and human SCN5A-1795insD iPSC-CMs, thus suppressing the gain-of-function features of this overlap syndrome mutation. Importantly, these beneficial actions of GS967 occurred in the absence of deleterious effects on sodium channel availability or cardiac conduction, despite a pre-existing decrease in peak INa. Thus, selective inhibition of INa,L constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced INaL, even in overlap syndromes whereby peak INa is decreased.
Author Disclosures: V. Portero: None. M. Hoekstra: None. A.O. Verkerk: None. I. Mengarelli: None. R.P. Davis: None. C. Freund: None. C.R. Bezzina: None. L. Belardinelli: Employment; Significant; Gilead Sciences. Ownership Interest; Significant; Gilead Sciences. S. Rajamani: Employment; Significant; Gilead Sciences. Ownership Interest; Significant; Gilead Sciences. M.W. Veldkamp: None. C. Remme: Research Grant; Significant; Gilead Sciences.
- © 2014 by American Heart Association, Inc.