Biomarkers in atrial fibrillation: insights from the ACaSA study

Abstract Background Continuous rhythm monitoring by pacemakers enables precise quantification of atrial fibrillation (AF) occurrence and burden. Circulating biomarkers reflecting endothelial dysfunction, fibrosis, and inflammation may help identify patients at increased risk, but few have been validated in continuously monitored cohorts. Purpose To investigate associations between biomarkers representing distinct pathophysiological pathways and device-detected AF (DDAF) incidence and burden in a prospective pacemaker population. Methods Patients without permanent AF at baseline were enrolled in a prospective observational study with continuous pacemaker monitoring. Baseline plasma concentrations of NT-proBNP, fibroblast growth factor-23 (FGF-23), angiopoietin-2 (ANGPT2), tumour necrosis factor-related apoptosis-inducing ligand receptor-2 (TRAIL-R2), bone morphogenetic protein-10 (BMP-10) and growth differentiation factor-15 (GDF-15) were quantified by ELISA. Two endpoints were analysed after a 30-day blanking period: (1) DDAF incidence (time to first episode ≥ 6 min) using Cox regression, and (2) total DDAF burden, categorised by interquartile range (< 25%, 25–75%, > 75%), using multinomial logistic regression. Biomarker levels were log2-transformed and standardised; models were adjusted for age, sex, heart failure, diabetes, and prior myocardial infarction. Results Among 210 patients (median age 75 years, 38 % women), higher ANGPT2 levels were significantly associated with incident DDAF (hazard ratio per 1 SD 1.28, 95 % CI 1.05–1.55; p = 0.013). In burden analysis, ANGPT2 showed a strong graded relationship, with a fourfold higher odds of belonging to the highest burden category (> 75%) (odds ratio 4.44, 95 % CI 1.96–10.09; p < 0.001). GDF-15 was not related to incidence but was associated with both medium (OR 1.91, 95 % CI 1.08–3.35; p = 0.025) and high (OR 2.12, 95 % CI 1.04–4.31; p = 0.038) DDAF burden. NT-proBNP showed a non-significant trend towards higher burden (OR 2.02, p = 0.061). FGF-23, TRAIL-R2 and BMP-10 were not significantly associated with either endpoint. Conclusions In continuously monitored pacemaker patients, angiopoietin-2—an endothelial activation marker—was independently associated with both AF onset and burden, while GDF-15, a stress and fibrosis marker, related specifically to AF burden. These findings highlight endothelial dysfunction and systemic stress signalling as key biological pathways underlying the initiation and maintenance of AF and suggest that endothelial biomarkers may offer incremental prognostic value beyond traditional cardiac load markers. Larger multicentre studies are warranted to confirm these results.Graphical Abstract