Background: In electrophysiology studies of patients with persistent atrial fibrillation (AF), Isoproterenol increases the slope of action potential duration restitution (APDR) to >1 and promotes fibrillation. However, the mechanism by which Isoproterenol steepens APDR is unclear. Using computational modeling, we set out to determine if Isoproterenol directly steepens APDR by altering ion channel currents or by shortening the functional refractory period (FRP). Methods: Realistic cell and tissue models of the left atria were developed for control and persistent AF conditions. Ion channel remodeling during AF was modeled based on slot-blot data. Beta-Adrenergic stimulation by 0.01-1.0µM Isoproterenol was simulated by increasing ICaL, Iup, IKs, and IKur up to 200%, 200%, 150%, and 250%, respectively. APDR curves were generated by pacing each model at a baseline cycle length of 400ms, followed by premature stimuli coupled initially at 380ms, then decreasing the coupling by 10ms until effective refractory period was reached. APDR slopes and FRPs were validated with data from 10 persistent AF patients. Results: In single cells, alterations in ion channel currents by Isoproterenol did not increase APDR slope above 1 (0.5 to 0.8). In tissue models, Isoproterenol reduced FRP by up to 40ms, which further steepened APDR and resulted in slopes >1 (0.7 to 1.5). Similarly, in AF patients administered Isoproterenol APDR slope increased from 0.55±0.29 to 1.81±0.88 with a mean FRP shortening of 33ms. Conclusions: Both alterations in ion channels and FRP shortening are necessary to explain APDR slopes > 1 in the left atria of persistent AF patients. Future studies should determine the mechanisms by which FRP is altered in AF patients and whether strategies for lengthening FRP would be effective for managing AF during increased Beta-adrenergic stimulation.