The development of atrial fibrillation (AF) is associated with electrical and structural remodeling. The aim of this study was to assess the contribution of electrical and structural remodeling to the development of AF in a rapid atrially paced ovine model with and without His bundle ablation and to determine the role of the angiotensin pathway and matrix metalloproteinases in this process. Thirty-five sheep were rapidly paced in the atrium and were randomized to undergo His bundle ablation (HBA) (21 sheep; HBA sheep) or not (14 sheep; non-HBA sheep). After HBA the ventricles were paced at 80 bpm. Both groups were subdivided to receive active treatment (quinapril+losartan) or placebo. Sheep were followed for 15 weeks. Inducible AF was defined as a rapid irregular atrial rhythm lasting >1 min. Inducible AF was considered to be persistent if during further follow-up no sinus rhythm (SR) was documented anymore. The inducibility of AF with atrial tachypacing was not different between the 4 groups. On the other hand, non-HBA sheep developed persistent AF significantly earlier than HBA sheep (p=0.028). They had elevated ventricular rates, diminished atrial MMP-2, increased TIMP-2 expression, and more extensive atrial fibrosis. Active treatment in these sheep significantly lowered AT-II (p=0.018), prevented atrial fibrogenesis (p<0.001) and slowed the development of persistent AF (p=0.049). Electrical remodeling is sufficient to induce AF, while structural changes are needed for persistent AF. Fibrosis development in our model is the result of an increased expression of AT-II in combination with changes in MMP expression. Inhibition of the angiotensin pathway suppresses atrial fibrosis and the development of persistent AF.