Comparative Proteomics of Pericardial Fluid in Patients with Heart Failure and Normal Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome characterized by diastolic dysfunction, myocardial stiffness, and systemic inflammation despite normal systolic performance. Its diagnosis and management remain challenging due to heterogeneous pathophysiology and a lack of specific biomarkers. The pericardial fluid (PF), bathing the epicardial surface of the heart, reflects local biochemical changes and may offer a unique window into myocardial pathology. Comparative proteomic profiling of PF could uncover novel mechanisms and identify HFpEF-specific biomarkers distinct from systemic signatures. Methods and Results: In this study, PF samples were obtained from patients undergoing elective cardiac surgery, including those with clinical HFpEF and matched controls with normal cardiac function. High-resolution mass spectrometry combined with label-free quantification identified over 1,200 proteins, of which 132 were differentially expressed between groups. Key upregulated proteins in HFpEF included extracellular matrix modulators (periostin, fibulin-1), inflammatory mediators (complement C3, S100A8/9), and oxidative stress markers (glutathione peroxidase, peroxiredoxin-2). Downregulated proteins involved metabolic enzymes and mitochondrial transporters. Pathway enrichment revealed activation of TGF-β signaling, neutrophil degranulation, and impaired fatty acid oxidation. Several proteins, including galectin-3 and fibronectin, showed strong correlation with left atrial volume and diastolic filling pressures. Conclusion: Comparative proteomic analysis of pericardial fluid reveals a distinct biochemical signature in HFpEF, characterized by inflammation, fibrosis, and metabolic dysregulation. These findings highlight the diagnostic and pathophysiological relevance of pericardial biomarkers and support their integration into multi-marker panels for improved detection and phenotyping of HFpEF. This approach may pave the way for targeted therapies based on localized molecular insights.