Abstract 17138: Eleclazine, a Novel and Selective Late Sodium Current Inhibitor, Suppresses Ventricular Arrhythmias Induced by Acute Global Low-Flow Ischemia

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Introduction: An increase in late sodium current (INa,L) associated with myocardial ischemia is prone to trigger life-threatening ventricular arrhythmias (VAs).

Hypothesis: Eleclazine (GS-6615), a novel and selective INa,L inhibitor, was hypothesized to suppress VAs induced by acute global low-flow ischemia.

Methods: Hearts from New Zealand female rabbits were perfused with modified Krebs-Henseleit (K-H) solution in Langendorff mode at a rate of 20 mL/min. Continuous ventricular septal pacing (1HZ) was induced after themo-ablated of the AV nodal. Electrical signals form multiple channel monophasic action potentials (MAP), pseudo 12-lead electrocardiograms and 64-electrode epicardial ventricular mapping were recorded simultaneously. After a minimum of 15min normal perfusion, acute low-flow ischemia was induced by perfusion of 5ml/min.

Results: Low-flow ischemia was associated with shortening of epicardial (Epi-) MAPD90 and QT interval from 183±4 and 270±7 ms to 162±4 and 249±6 ms, and prolongation of intraventricular conduction time (CT) and postrepolarization refractoriness (PRR) from 23±3 and -12± 3 ms to 30±4 and 8±3 ms, respectively (n=29, P<0.05). Flecainide (FLEC, 0.4-2μM) and ranolazine (RAN, 2-10μM) prolonged the Epi-MAPD90, PRR and CT by 21±5% and 22±5%, 287±15% and 186±11%, and 22±5% and 23±4%, respectively (n=7 and 6, P<0.05). Lidocaine (LIDO, 2.1-21μM) and eleclazine (ELEC, 0.1-10μM) prolonged PRR by 264±13 and 98±7% (n=6 and 8, P<0.05). LIDO but not ELEC increased CT by 20±4% (P<0.05). VAs occurred in 18/29 (62.1%) of hearts studied. FLEC increased the incidence of VAs from 57.1% to 100% (n=7). In contrast, RAN, LIDO and ELEC decreased the incidence of VAs from 62.5%, 66.7% and 62.5% to 37.5%, 33.3% and 25% (n=6-8).

Conclusion: Inhibition of INa,L is effective in reducing global ischemia-induced VAs. Eleclazine has advantage of the absence of prolonging PRR but not MAPD90, CT and QT interval.

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