Circulating Proteomics and Risk of Atrial Fibrillation: A Systematic Review of Cohort Studies.

Atrial fibrillation (AF) is a common arrhythmia associated with significant morbidity and adverse outcomes. High-throughput proteomics offers a promising approach for identifying circulating biomarkers to improve AF risk stratification. This systematic review evaluated cohort studies published from 2010 to 2024 that employed proteomic approaches to investigate associations between circulating proteins and AF incidence. Studies were screened using predefined criteria, and proteins significantly associated with AF in fully adjusted models were extracted. Bioinformatics analyses, including pathway enrichment and protein-protein interaction (PPI) network mapping, were conducted to characterise the implicated biological processes. Proteins reproducibly associated with AF across studies were further evaluated through drug target annotation and assessed for potential causal relationships using Mendelian randomisation (MR). In total, 111 proteins were identified across nine cohorts, with significant enrichment in pathways related to extracellular matrix organisation and cell adhesion. PPI analysis identified interleukin-6, matrix metalloproteinase-2 and C-reactive protein as central network hubs. Thirteen proteins were reproducible across at least two studies, with NT-proBNP consistently reported in eight cohorts, supporting its role as a robust and reliable biomarker of AF risk. Drug target analysis showed that four proteins-ANGPT-2, adrenomedullin, GDF15 and PLAUR-are currently under clinical investigation. MR analysis did not confirm causal associations between these proteins and AF, suggesting they may reflect disease-related processes rather than directly drive AF onset. This review highlights reproducible proteomic biomarkers and their functional networks in AF, providing a foundation for future studies focused on biomarker-guided prevention and therapeutic development. Trial Registration: PROSPERO number: CRD420251063038.