Abstract 15303: GS-458967, a Selective Late Sodium Current Inhibitor, Prohibits Torsades de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog Model
Introduction: GS-458967 (GS) is a novel selective and highly potent late sodium current (INaL) inhibitor.
Hypothesis: GS was investigated 1) in-vivo in sinus rhythm (SR) dogs and 2) to suppress Torsades de Pointes (TdP) in the chronic atrioventricular block (cAVB) dog and Early After Depolarizations (EADs) in isolated canine myocytes.
Methods: In SR dogs (n=10), monophasic action potentials (MAP) from left and right ventricles (LV and RV MAP duration) along with ECG intervals were recorded after GS 0.1 mg/kg/5’. In cAVB dogs (n=8) GS (0.1 mg/kg/5’) was administered after TdP was reproducibly induced by dofetilide (D: 25 μg/kg/5’). Electrical parameters and incidence of TdP were continuously recorded, arrhythmic score was determined as the average of the 3 most severe arrhythmic endpoints; being single or multiple ectopic beats (sEBs and mEBs), TdPs (as >5 EBs) and defibrillations. In isolated LV and RV myocytes from both SR and cAVB dogs, the 1) INaL, 2) IC50 for the block of INaL by GS, concentration-dependent effects of GS (30-100-300-1000 nM) on 3) baseline APD, and 4) EADs in the presence of D (1 μM) were determined.
Results: In SR dogs, plasma concentration of GS was 787±265 nM and repolarization parameters were reduced after GS, including QTc (307±9 to 297±9 ms, *p<0.05) and interventricular dispersion: ΔMAPD as LV - MAPD (15±13 to 11±14* ms). In cAVB dogs, GS terminated TdP (6/8 vs. 0/8*) and reduced arrhythmic score (39.9±31.3 to 1.9±0.7*). mEBS were abolished but sEBs remained in 6/8 dogs, while GS reduced repolarization parameters such as QT interval and ΔMAPD (134±49 to 86±69 ms), but did not reach significance. In-vitro, INaL was 1) most prominent in LV vs. RV of SR cells (0.30±0.10 vs. 0.21±0.10* pA/pF), 2) reduced in LV cells of cAVB vs. SR (0.18±0.05 vs. 0.30±0.10* pA/pF) and the IC50 values were 189±20 and 187±23 nM, for LV and RV SR respectively. Cellular APDs were shortened by GS (100 nM: 399±97 to 299±79* ms) and EADs were suppressed concentration-dependently in SR and cAVB cells (0/7, 2/8, 9/14* at 100, 300 and 1000 nM).
Conclusions: This study demonstrates that selective blockade of INaL 1) shortens repolarization 2) is very effective in terminating D-induced TdP in cAVB dogs, but 3) the underlying mechanism seems less dependent on EAD suppression as on decrease in ΔMAPD.
Author Disclosures: A. Bossu: Research Grant; Modest; Gilead Sciences, Inc.. R. Varkevisser: None. M.J. Houtman: Research Grant; Modest; Gilead Sciences, Inc.. J.D. Beekman: None. M.A. van der Heyden: None. T.R. Stams: None. M.B. Rook: None. T.P. de Boer: None. H. Takanari: None. G. Antoons: None. N. Mollova: Employment; Significant; Gilead Sciences, Inc. S. Rajamani: Employment; Significant; Gilead Sciences, Inc. L. Belardinelli: Employment; Significant; Gilead Sciences, Inc.. M.A. Vos: None.
- © 2014 by American Heart Association, Inc.