Electrophysiologic effects of a new class III antiarrhythmic agent, E-4031, on atrial flutter, atrial refractoriness, and conduction delay in a canine sterile pericarditis model

Numerous studies have shown that E-4031 generally prolongs the atrial effective refractory period (AERP) without affecting cardiac conduction. The effects of E-4031 on AERP and cardiac conduction at short cycle lengths (CLs) close to the AERP were measured in 12 dogs with sterile pericarditis. Three pairs of electrodes were sutured at three sites in the atria 4 days after the model was created. We measured AERP and maximum conduction delay (MCD) after 8 beats train at CLs of 400, 300, 200 and 150 ms before and during continuous infusion of E-4031 (0.1 μg/kg/min) that followed an initial dose of 10 μg/kg/min/5 min. E-4031 interrupted sustained atrial flutter (AF) (≥10 min) in 4 of 5 episodes and atrial fibrillation (≥10 min) in 4 of 4. The CL of AF defined as a rapid atrial rhythm (rate ≥240 beats/min) in five episodes studied in the sterile pericarditis model was significantly (p < 0.005) prolonged from 120 ± 8 to 160 ± 17 ms. There were significant (p < 0.005) increases in AERP at each CL, and prolongation of AERP was 39 ± 18, 31 ± 14, 23 ± 14, and 16 ± 14 ms at CL 400, 300, 200, and 150 ms, respectively. E-4031 produced less prolongation of AERP at short pacing CLs and had no effect on conduction time during atrial rapid pacing at CLs > 150 ms. E-4031 did not prolong MCD at CL 400 ms, but did prolong MCD at CLs of 300, 200, and 150 ms, despite prolongation of AERP. Thus, at short pacing CLs close to that of AF1, the increase in prolongation of AERP was less, whereas the increase in atrial conduction delay was greater. These results demonstrate that (a) E-4031 prolongs AF1 CLs and effectively converts AF and atrial fibrillation to normal sinus rhythm in the pericarditis model; (b) at short CLs close to the CL of AF, prolongation of the AERP after E-4031 treatment was less than that observed at longer CLs; and (c) at short CLs close to the CL of AF, the increase in atrial conduction delay after E-4031 was greater than that observed at longer CLs.