Abstract 2692: Bepridil Destabilizes Spiral-Wave Reentry and Facilitates Its Early Termination in Cardiac Muscle Through an Increase of Intercellular Coupling
Backgrounds: Recent clinical studies have shown that bepridil is effective in cardioversion of atrial fibrillation as well as in treatment of drug-refractory ventricular arrhythmias. The underlying mechanisms remain unclear. In a preliminary study, we observed that bepridil increased conduction velocity (CV) despite its INa blocking effect. We hypothesized that bepridil increases gap-junctional conductance, and investigated changes of spiral-wave dynamics by bepridil in terms of cell-to-cell electrical coupling.
Methods: A 2-dimensional epicardial muscle layer was prepared by endocardial cryoablation of rabbit ventricles, and action potential signals were recorded by a high-resolution optical mapping system. Intercellular electrical coupling was estimated by the space constant (λ) and the curvature effect on local CV. λwas calculated from the distance-decay of subthreshold depolarization. The relation between the curvature (κ) and local CV was analyzed during centrifugal propagation. Ventricular tachycardia (VT) resulting from spiral-wave reentry (SWR) was induced by burst pacing.
Results: By application of bepridil (1 μM), λ along and across the fiber orientation (λL and λT) were both increased from control (λL: 1.29±0.09 vs. 1.08±0.19 mm, λT: 1.12±0.21 vs. 0.84±0.13 mm, n=5, p<0.05). In both control and with bepridil, there was an inverse linear relation between κ and CV; CV=CV0-Dκ (D: diffusion coefficient, CV0: CV at κ=0) as expected from a model of excitable media (Zykov and Morozova, 1979). Bepridil increased D and CV0 from control (D: 0.43±0.03, vs 0.25±0.03 cm2/s, CV0: 60.6±4.0 vs. 51.1±3.3 cm/s, n=5, p<0.01), resulting in an increase of CV at κ<20 cm−1 and a decrease of CV at κ>40 cm−1. SWR in the presence of bepridil was characterized by decremental conduction near the rotation center, giving rise to a prominent drift of the circuit and often self-termination by collision with anatomical boundaries. The incidence of sustained VTs (>300 s) after bepridil decreased from control (4/33 vs. 40/52, n=5, p<0.01).
Conclusions: Bepridil increases intercellular electrical coupling of cardiac muscle, and compromises propagation of wavefront with high curvature as in the rotation center of SWR, which may favors early self-termination of SWR.