Atrial fibrillation in HFpEF and HFmrEF Is linked to a distinct systemic proteomic phenotype
J Vogel, S Jura, S Settelmeier, T Lerchner, F Buehning, L Yahsaly, A Carpinteiro, C Reinhardt, S Mathew, T Rassaf, L MichelAbstract
Background
In heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF), atrial fibrillation (AF) is common and prognostically relevant. Beyond electrical instability, AF is linked to structural atrial remodelling and adverse outcomes. Emerging evidence suggests that atrial remodelling in HFpEF/HFmrEF is driven not only by hemodynamic stress but also by systemic processes such as inflammation, metabolic dysregulation, and vascular dysfunction. High-dimensional circulating proteomics enables integrated assessment of these pathways and may elucidate molecular mechanisms linking systemic disease biology to atrial remodelling.
Methods
Serum samples from 86 HFpEF/HFmrEF patients (54 with AF) were analysed using the Olink® Explore HT platform (>5,400 proteins). Associations between protein expression and AF were assessed using multivariable linear regression adjusted for clinical covariates. Significant proteins were evaluated by pathway enrichment, protein–protein interaction networks, and disease mapping. Correlations with echocardiographic and clinical parameters were explored.
Results
A total of 126 circulating proteins were associated with AF, defining a distinct proteomic profile. Network analyses revealed interconnected modules related to extracellular matrix turnover, thrombo-inflammatory signalling, oxidative stress, and metabolic pathways, with enrichment of coagulation and matrisome processes. Several AF-associated proteins correlated with structural remodelling: COL4A1 and ACE2 with left atrial enlargement (LAVI), MYOZ2 and WIPI2 with increased LV mass. Proteins inversely associated with renal function (FGF18, CCDC77, TRIM27) strongly correlated with reduced eGFR. Additional associations were observed with impaired right ventricular function (TAPSE), suggesting a proteomic signature of advanced atrial, ventricular, and cardiorenal remodelling.
Conclusions
In HFpEF/HFmrEF, AF is linked to a distinct circulating proteomic signature reflecting systemic inflammatory, metabolic, and vascular pathways associated with cardiac remodelling. These findings support the concept of AF as a manifestation of advanced disease biology rather than an isolated electrical disorder and may improve phenotyping and risk stratification in this heterogeneous population.Volcano