Atrial reverse remodeling following rhythm control therapy in a translational large-animal model of atrial fibrillation

Background: Atrial fibrillation is a growing global health burden, yet current treatment options remain limited. On the pathophysiological level, disorganized atrial activity both results from and contributes to atrial electrical and structural remodeling. Benefits of early rhythm control therapy have been widely discussed in recent years, however the reversibility of atrial fibrillation-associated remodeling remains unstudied. Here, we investigated atrial reverse remodeling both on the electrophysiological and structural levels to identify foundations for more effective treatment strategies in atrial fibrillation. 

Methods: We conducted a comprehensive large-animal study involving three study groups: sinus rhythm (SR), atrial fibrillation (AF), and rhythm control (RC). Following atrioventricular node ablation and dual-chamber pacemaker implantation, AF was induced by atrial burst pacing and maintained for 4 or 8 weeks in the AF group. In the RC group, pigs were electrically cardioverted after 4 or 8 weeks of AF and recovered in SR for an equivalent period. To assess atrial remodeling, we combined clinical electrophysiological studies and echocardiography with cellular and molecular investigations, including patch-clamp recordings, histological analyses, and RNA sequencing. 

Results: Electrophysiologically, AF pigs showed significantly shortened atrial effective refractory periods (AERPs) compared to SR controls. In the RC group, AERPs fully restored to baseline values following the recovery period. On the cellular level, we found a significant shortening of the action potential duration at 90% repolarization (APD₉₀) in atrial cardiomyocytes obtained from AF compared to SR pigs, associated with a relevantly increased TASK-1 potassium current density. However, the AF-related changes in APD₉₀ and TASK-1 current density were not significantly reversed in the RC group. 

Structurally, left atrial diameters were significantly enlarged in AF animals compared to SR controls. This atrial dilatation remained stable in the RC group, without relevant progression. On the histological level, we observed a significant increase in left atrial fibrosis in AF pigs, which was relevantly reduced in the RC group. Transcriptomic analysis revealed an upregulation of gene sets related to fibrosis, inflammation, complement activation, and coagulation in left atrial tissue obtained from AF pigs compared to SR controls, all of which showed reversibility after RC therapy.

Conclusion: Our large-animal model of AF demonstrated characteristic remodeling of atrial properties, including AERP and APD₉₀ shortening, TASK-1 current upregulation, left atrial dilatation, fibrosis, and altered transcriptomic profiles. While AERPs, atrial fibrosis, and related gene expression changes were reversible following rhythm control therapy, APD₉₀ values, TASK-1 current densities, and atrial diameters remained unchanged within the study period. Further molecular investigations will help to identify new targets to promote the reversibility of atrial inflammation and fibrosis, and clarify a potential direct link between fibrotic burden and AERPs.