Background:Atrial fibrillation (AF) is common in heart failure patients with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) and contributes to adverse outcomes through complex structural, metabolic, and inflammatory mechanisms. Large-scale proteomic profiling enables the identification of molecular disease signatures beyond conventional biomarkers.
Aim:To characterise the serum proteomic landscape of AF in HFpEF/HFmrEF and to explore clinical, structural, and molecular differences between patients with and without AF, thereby identifying key pathways linking AF to remodelling, inflammation, and metabolic dysregulation.
Methods:In this retrospective study, serum samples from 86 patients with HFpEF or HFmrEF enrolled at the West German Amyloidosis Center were analyzed, including 54 (63%) with AF. Proteomic profiling was conducted using the Olink® Explore platform, quantifying more than 5400 proteins. Associations between circulating proteins and the presence of AF were assessed using multivariable linear regression. Functional enrichment, protein–protein interaction network, and disease association analyses were performed using STRING, Metascape, and DisGeNET. The study was approved by the local ethics committee (24-12241-BO).
Results:The median age was 79 years, and 82.6% were male. Median LVEF was 55%, and mean eGFR was 59 mL/min/1.73 m². Patients with AF showed larger left atrial volumes (LAVI 53.6 vs. 37 mL/m², p = 0.008) and lower right ventricular function (TAPSE 19.9 vs. 21.1 mm, p = 0.045) compared to those in sinus rhythm. A total of 126 proteins were significantly associated with AF (p < 0.05), including a distinct upregulation of proteins involved in extracellular matrix remodelling, oxidative stress, and inflammatory pathways. The STRING network identified several highly connected clusters, which grouped into four major biological themes: Cardiac and extracellular remodelling, Vascular and thrombo-inflammatory signalling, Metabolic and oxidative dysregulation, and Neurohumoral and cellular signalling. Enrichment analyses (GO/WikiPathways) confirmed the involvement of processes related to blood coagulation, lipid catabolism, and JNK/Wnt signalling, while DisGeNET linked the proteomic signature to vascular and thrombotic diseases (e.g., cerebral venous sinus thrombosis, atherogenesis, chronic kidney disease, amyloidosis). In the clinical correlation heatmap, AF-associated proteins correlated positively with markers of atrial and ventricular remodelling (LAVI, LVMM) and inversely with renal function (eGFR) and right ventricular performance (TAPSE).
Conclusions:Comprehensive serum proteomics revealed a distinct molecular signature of AF, characterised by intertwined pathways of structural remodelling, vascular inflammation, and metabolic dysregulation. These proteomic alterations parallel echocardiographic markers of atrial and ventricular remodelling and impaired renal function in AF patients. These findings underscore the systemic nature of AF-related remodelling and may guide the development of novel biomarkers and therapeutic targets in heart failure with preserved ejection fraction. Our AF proteomic dataset provides a translational foundation for future studies linking molecular alterations to clinical outcomes and therapeutic response.
