Purpose: Mechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch.
Methods: Atrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n = 28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3 μM).
Results: On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3 μM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3 μM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138 ± 26 ms vs 95 ± 9 ms; p < 0.01), ventricular refractoriness (155 ± 18 ms vs 124 ± 16 ms; p < 0.01) and increments in spectral concentration (23 ± 5% vs 17 ± 2%; p < 0.01), the fifth percentile of ventricular activation intervals (46 ± 8 ms vs 31 ± 3 ms; p < 0.05), and wavelength of ventricular fibrillation (2.5 ±0.5 cm vs 1.7 ± 0.3 cm; p < 0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control = 38%, 0.03 μM = 33%, 0.1 μM = 33%, 0.3 μM = 14%; p < 0.01) and the stretch-induced increments in arrhythmia complexity index (control = 62%, 0.03μM = 41%, 0.1 μM = 32%, 0.3 μM = 16%; p < 0.05) progressively decreased on increasing the GS967 concentration.
Conclusions: GS967 attenuates stretch-induced changes in cardiac electrophysiology.
Keywords: Activation mapping of arrhythmias; GS967; Late sodium current; Mechanoelectric feedback; Myocardial stretch; Ventricular fibrillation.