Elevated formation of collagen type III and VI after ablation reflects recurrence of atrial fibrillation

Introduction Catheter ablation treatment for atrial fibrillation (AF) induces controlled myocardial injury to the pulmonary veins. This targeted injury initiates a wound-healing response involving fibroblast activation and extracellular matrix (ECM) remodelling. Remodelling of collagen type III and VI may indicate a persistent wound-healing response rather than physiological scar formation. Purpose In this study, we investigated changes in circulating biomarkers of collagen III and collagen VI formation in individuals with AF that underwent ablation to characterize the ECM remodelling response and explore their potential as indicators of post-procedural fibrosis. Methods Levels of collagen type III formation (PRO-C3) and collagen type VI turnover (PRO-C6) were quantified with enzyme-linked immunosorbent assays in serum samples of 276 individuals diagnosed with AF that underwent catheter ablation. Differences in serum levels of the biomarkers preoperative and 12 months post-ablation between paroxysmal and persistent AF and in individuals with and without heart failure, ischemic heart disease, hypertension, and diabetes were assessed using the Wilcoxon signed-rank test. Biomarker changes from baseline to follow-up were compared between individuals with and without AF recurrence using linear mixed models. To assess the biomarker associations with AF recurrence during the first year after ablation unadjusted and adjusted logistic regression models were used. Results Levels of circulating PRO-C3 and PRO-C6 increased significantly post-ablation (p<0.001, for both markers). Individuals who experienced AF recurrence had higher increase in post-ablation PRO-C3 and PRO-C6 levels from baseline compared to those without AF recurrence (p=0.003 and p=0.008, respectively). PRO-C3 levels were more elevated in individuals with persistent AF (p=0.018). PRO-C6 levels were more elevated in individuals with hypertension (p=0.04) and diabetes mellitus (p=0.03). Baseline levels of the markers were not associated with risk of AF recurrence, while post-ablation levels of PRO-C3 and PRO-C6 were associated to AF recurrence (OR 3.0, [1.4-6.7], p=0.006 and OR 2.6 [1.1-6.0], p=0.026, respectively). After adjustment for age and sex, only PRO-C3 levels remained associated to AF recurrence (OR 2.8 [1.3-6.4], p=0.012). Conclusion The association between AF recurrence and higher levels of circulating PRO-C3 and PRO-C6 12 months post-ablation, and the greater post-ablation increase from baseline of these biomarkers in individuals who suffered AF recurrence, suggest that these biomarkers may reflect excessive activation of fibroblasts following the ablation scarring procedure. Although physiological scarring is necessary for successful ablation procedure, AF recurrence might be driven by overactive fibrosis. Measuring PRO-C3 and PRO-C6 may help identify patients who develop excessive scarring and could benefit from antifibrotic treatment after ablation.