Abstract 13310: Selective Inhibition of the Late Sodium Current to Prevent Ventricular Fibrillation
Background: An emerging new strategy to suppress early afterdepolarization (EAD)- and delayed afterdepolarizations (DADs)-mediated triggered activity and VT/VF is to eliminate the increased late inward Na current (INa-L). The new triazolopyridine derivative, GS-967 (Gilead Science Inc.) is shown to selectively and potently (IC50=0.45 μM) inhibit INa-L.
Hypothesis: GS-967 suppresses and prevents VT/VF in fibrotic aged hearts exposed to hydrogen peroxide (H2O2) and local LV injection of aconitine by inhibiting EADs and DADs that trigger the VT/VF.
Methods: VT/VF were induced by arterial perfusion of 0.1 mM H2O2 in aged rats (24-26 months, N=18), or local aconitine injection (50 μg) in the LV muscle of adult (3-4 months) rats (N=14). All isolated hearts were perfused in Langendorff setting; the activation of the LV epicardium was optically mapped along with simultaneous ECG and single cell action potential (AP) recordings with microelectrode near the aconitine site.
Results: Optical mapping showed the sudden emergence of rapid focal triggered activity at CLs of 80±12 ms on the LV surface 10 min after H2O2 and 1 min after aconitine. The focal activity was caused by EADs in the H2O2 and combined EAD/DAD in the aconitine model. The VT degenerated to mixed focal-reentrant VF that becomes sustained by mixed focal and incomplete reentrant mechanisms in both models. In the H2O2 model, perfusion with 1 μM GS-967 suppressed the VF in 5 out 8 hearts and prevented (when perfused 15 min prior to H2O2) its emergence in 4 out of 6 hearts (P<0.05). In the aconitine groups, GS-967 (1 μM) suppressed the VT/VF in 6 out of 8 and prevented its initiation in 2 out of 2 hearts. GS-967 shortened the AP duration (APD) and flattened the slope of the dynamic APD restitution curve in both age groups (N=4 in each group) and prevented the maintenance of rapid pacing-induced VT/VF in the aged hearts (N=4). GS-967 did not promote VT/VF (proarrhythmia) in the adult hearts (N=6) during rapid pacing.
Conclusions: The selective INa-L blocker GS-967 effectively suppresses and prevents mixed focal-reentrant VT/VF induced by H2O2 and aconitine. In addition to the suppression of the EAD and DAD, triggers of the VT/VF, GS-967 flattens the APD restitution curve suppresses wavebreak and prevents the maintenance of VF.
- © 2013 by American Heart Association, Inc.