POTENTIAL FOR DRONEDARONE TO CONTROL ATRIAL FIBRILLATION IN DOGS

Abstract

The present study was hypothesized that dronedarone changed electrophysiological properties of atria resulted in prevention of atrial fibrillation (AF) without adverse effects on inotropy and lusitropy in dog model of sustained AF. In order to test the hypothesis, this study was divided into 3 parts. The aim of part 1 was to determine the acute effects of escalating concentrations of dronedarone (0.5, 1.0 and 2.5 mg/kg, 15 min for each dose) on electrocardiograms (ECG), hemodynamics and cardiac mechanics in healthy anesthetized dogs. All parameters in vehicle-treated dogs were unaltered. Dronedarone at 2.5 mg/kg significantly lengthened PQ interval (P<0.01), reduced cardiac output (CO) (P<0.01) and increased systemic vascular resistance (P<0.01). Dronedarone also produced negative inotropy and negative lusitropy. Then, the intravenous doses were extrapolated to the oral doses. Part 2 was designed to evaluate the chronic effects of oral dronedarone (20 mg/kg, BID) on cardiac inotropy and lusitropy, blood pressure (BP), and ECG in conscious, healthy dogs instrumented with telemetry units and sono-micrometry crystals to obtain left ventricular pressure-volume relationship, BP and ECG. The results showed that dronedarone had no effect on inotropy and lusitropy while it significantly lengthened PQ interval (P<0.001) and lowered MBP (P<0.05). Part 3 was intended to assess efficacy of dronedarone on attenuation AF duration in a canine model of sustained AF induced by rapid right atrial pacing (20 V, 40 Hz) simultaneously with infusion of phenylephrine (2µg/kg/min, intravenously) for 20 min. The duration of sustained AF was recorded and the animals were allowed to recover. Dronedarone was given at a dose of 20 mg/kg, BID, PO for 7 days. On the last day, dogs were anesthetized again to record action potential duration (APD) of atrium and atrial effective refractory period (AERP). Then, the AF was induced with the similar procedure. After dronedarone administration, the AERP was significantly lengthened more than APD’s, developing a post-repolarization refractoriness (PRR). The duration of sustained AF was also significantly attenuated after receiving dronedarone (P<0.05). In conclusion, short-term oral dronedarone administration (20 mg/kg, BID, 7 days) produced negative dromotropy and induced hypotension in conscious dogs while the highest dose of intravenous dronedarone induced negative inotropy and lusitropy. Furthermore, short-term oral dronedarone effectively attenuates duration of AF supported by PRR mechanism.