Background Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF (LS-PAF) we tested the hypothesis that the rate of electrical and/or structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Methods and Results Self-sustained AF was induced by atrial tachypacing. Seven sheep were sacrificed 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm (SR); 7 sheep were sacrificed after 341.3±16.7 days of LS-PAF. Seven sham-operated animals were in SR for 1 year. DF was monitored continuously in each group. RT-PCR, western blotting, patch-clamping and histological analyses were used to determine changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase (dDF/dt) correlated strongly with the time to persistent AF. Significant action potential duration (APD) abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5 and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for one-year follow up. Conclusions In the sheep model of LS-PAF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in APD and densities of sodium, L-type calcium and inward rectifier currents.

Background Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF) and left-to-right atrial (LA-to-RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in-vivo the time-course in atrial DF values from paroxysmal to persistent AF in sheep, and test the hypothesis that a LA-to-RA DF difference is associated with LA drivers in persistent AF. Methods and Results AF was induced using RA tachypacing (N=8). Electrograms were obtained weekly from a RA lead and a loop recorder (ILR) implanted near the LA. DFs were determined for 5-sec-long electrograms (QRST subtracted) during AF in-vivo and in ex-vivo optical mapping. Underlying structural changes were compared to weight-matched controls (N=4). Following the first AF episode, DF increased gradually over a 2-week period (7±0.21 to 9.92±0.31 Hz, N=6, p<0.05). During 9–24 weeks of AF the DF values on the ILR were higher than the RA (10.6±0.08 vs. 9.3±0.1 Hz, respectively; N=7, p<0.0001). Subsequent optical mapping confirmed a DF gradient from posterior LA-to-RA (9.1±1.0 to 6.9±0.9 Hz. p<0.05) and demonstrated patterns of activation compatible with drifting rotors in the posterior LA (PLA). Persistent AF sheep showed significant enlargement of the PLA compared to controls. Conclusions In the sheep transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in-vivo together with enlargement of the PLA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.