Structural in addition to electrical remodeling may be induced by persistent atrial fibrillation per se and make atrial fibrillation refractory to antiarrhythmic drug therapy. Matrix metalloproteinases (MMPs) contribute to structural remodeling in the interstitial space. Amiodarone is effective in treating persistent atrial fibrillation compared with other antiarrhythmic drugs. In mongrel dogs, right atrial pacing at 540 beats/min (bpm) was performed along with ventricular pacing at 100 bpm for 6 weeks after atrioventricular node ablation. Right atrial pacing at 400 bpm was continued for 4 weeks with (n=5) or without (n=5) oral amiodarone (30 mg/kg/day). In sham dogs, only ventricular pacing was done with (n=4) or without (n=6) amiodarone. In atrial pacing without amiodarone group, electrical remodeling characterized by monophasic action potential duration shortening, loss of action potential duration-rate adaptation and depressed conduction velocity and structural remodeling characterized by slightly but significantly increased interstitial fibrosis and enhanced MMP-2 activity compared with sham group were observed, and sustained atrial fibrillation was easily induced. In atrial pacing with amiodarone group, both electrical and structural remodeling were reversed and sustained atrial fibrillation was not induced. In sham group with amiodarone, action potential duration prolongation and depressed conduction velocity compared with sham without amiodarone were observed, but either increased fibrosis or enhanced MMP-2 activity was not observed. Not only electrical but structural remodeling were induced in a canine persistent atrial fibrillation model. Amiodarone reversed both of them, which may be related to its high efficacy in preventing recurrence of persistent atrial fibrillation.