Introduction: Atrial fibrillation (AF) induces progressive atrial remodeling characterized by electrophysiological dysfunction, chamber dilation, and interstitial fibrosis. Fibrotic remodeling is a key contributor to the persistence of arrhythmogenic substrates; however, the dynamics of its reversibility following rhythm restoration remain incompletely understood. In a preclinical large-animal model, time-dependent alterations in electrophysiological parameters, atrial dilation, and fibrotic remodeling processes were investigated, with a particular focus on the temporal dynamics of functional and structural remodeling.
Methods: In a porcine model (n=31), AF was induced by right atrial burst pacing using dual-chamber pacemakers. Atrioventricular node ablation was performed to prevent tachycardia-induced heart failure. Animals were assigned to sustained AF groups (2, 4, or 8 weeks) with or without subsequent electrical cardioversion and sinus rhythm maintenance (RE groups: 2w, 4w, 8w follow-up). Atrial dimensions, effective refractory periods (AERP), and fibrosis levels were assessed by echocardiography, electrophysiological studies (EPS), and quantitative histomorphometry using Lillie’s trichrome staining and automated color deconvolution-based image analysis.
Results: Fibrosis quantification in the left atrium revealed progressive accumulation under sustained AF (8w AF: 11.3 % ± 5.5 %). Following cardioversion, a biphasic pattern emerged: while a significant increase was observed in the 4w RE group, fibrosis levels declined in the 8w RE group (8w RE: 9.3 % ± 4.9 % vs. 4w RE: 18.3 % ± 8.7 %; p = 0.01), indicating delayed partial regression. Right atrial fibrosis remained stable across all groups, underscoring the lateralized susceptibility of the left atrium. Left atrial dilation progressed with prolonged AF duration (8w AF: 6.96 ± 1.45 cm vs. baseline: 3.71 ± 0.61 cm; p = 0.01). Correspondingly, AERP shortening (AERP500: 8w AF: 133 ms ± 38 ms vs. baseline: 197 ms ± 76.1 ms; p = 0.12; AERP400: 8w AF: 120.7 ms ± 30.6 ms vs. baseline: 182.8 ms ± 46.8 ms; p = 0.01; AERP300: 8w AF: 100 ms ± 29.2 ms vs. baseline: 170.7 ms ± 37 ms; p = 0.03) was most pronounced in the 8w AF group and showed reversibility following sinus rhythm restoration (AERP500: 8w AF: 133.3 ms ± 38 ms vs. 8w RE: 230 ms ± 22.9 ms; p = 0.03; 4w AF: 109 ms ± 51.9 ms vs. 8w RE: 230 ms ± 22.9 ms; p = 0.04). Other electrophysiological parameters (SNRT, RVRP) showed no group-specific differences.
Conclusion: This porcine model reveals that fibrotic remodeling in the left atrium during AF follows a time- and intervention-dependent trajectory. Our results support fibrosis as a potential marker to guide therapy and underscore the importance of early rhythm restoration to prevent irreversible atrial remodeling.
