Atrial fibrillation (AF) is associated with an increased risk of adverse cardiovascular events, but the underlying biological mechanisms remain incompletely understood. Here we evaluated a panel of 12 circulating biomarkers representing diverse pathophysiological pathways in a cohort of 3,817 AF patients to assess their association with adverse cardiovascular outcomes. We identified 5 biomarkers—d-dimer, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTropT)—that were independently associated with cardiovascular death, stroke, myocardial infarction, and systemic embolism, significantly enhancing predictive accuracy. Additionally, GDF-15, insulin-like growth factor-binding protein-7 (IGFBP-7), NT-proBNP, and hsTropT were strong predictors of heart failure hospitalization, while GDF-15 and IL-6 were associated with major bleeding events. Incorporating IL-6, NT-proBNP, and hsTropT to the CHA₂DS₂-VASc score improved stroke risk prediction. Machine learning models incorporating these biomarkers demonstrated consistent improvements in risk stratification across all outcomes. Our results highlight the potential of integrating biomarkers related to myocardial injury, inflammation, oxidative stress, and coagulation into both conventional and machine learning-based models refine prognosis and guide clinical decision-making in AF patients.

P.B.M. received funding from the Swiss National Science Foundation outside the submitted work. S.A. received funding from the Swiss Heart Foundation and speaker fee from Roche Diagnostics outside of the submitted work. S.B. received funding from the Swiss National Science Foundation, the Mach-Gaensslen Foundation and the Bangerter-Rhyner Foundation outside the submitted work. T.R. reports research grants from the Swiss National Science Foundation, the Swiss Heart Foundation and the sitem insel support fund, all for work outside the submitted study. Speaker/consulting honoraria or travel support from Abbott/SJM, Astra Zeneca, Brahms, Bayer, Biosense-Webster, Biotronik, Boston-Scientific, Daiichi Sankyo, Medtronic, Pfizer-BMS and Roche, all for work outside the submitted study. Support for his institutions fellowship program from Abbott/SJM, Biosense-Webster, Biotronik, Boston-Scientific and Medtronic for work outside the submitted study. A.M. reports fellowship and training support from Biotronik, Boston Scientific, Medtronic, Abbott/St. Jude Medical, and Biosense Webster; speaker honoraria from Biosense Webster, Medtronic, Abbott/St. Jude Medical, AstraZeneca, Daiichi Sankyo, Biotronik, MicroPort, Novartis, and consultant honoraria for Biosense Webster, Medtronic, Abbott/St. Jude Medcal, and Biotronik. G.M. has received consultant fees for taking part to advisory boards from Novartis, Boehringer Ingelheim, Bayer, Astra Zeneca and Daiichi Sankyo, all outside of the current work. A.Z. is an employee of Roche Diagnostics, a commercial provider of diagnostic tests. M.K. reports personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Pfizer BMS, personal fees from Daiichi Sankyo, personal fees from Medtronic, personal fees from Biotronik, personal fees from Boston Scientific, personal fees from Johnson&Johnson, grants from Bayer, grants from Pfizer, grants from Boston Scientific, grants from BMS, grants from Biotronik. Grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Foundation for Cardiovascular Research Basel and the University of Basel. D.C. has received consultant fees from Roche Diagnostics and Trimedics, outside of the current work. The remaining authors have nothing to disclose.

This work was supported by grants of the Swiss National Science Foundation (grant numbers 33CS30_148474, 33CS30_177520, 32473B_176178, and 32003B_197524), the Swiss Heart Foundation, the Foundation for Cardiovascular Research Basel (FCVR), and the University of Basel. The BEAT-AF study was supported by the Swiss National Science Foundation (Grant number PP00P3_159322), the Swiss Heart Foundation, the University of Basel, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dome, Bayer, Daiichi-Sankyo and Pfizer/Bristol-Myers Squibb.

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