Multi-omics profiling identifies inflammation metabolism fibrosis crosstalk as a defining feature of HFpEF distinct from HFrEF

Background Heart failure with preserved ejection fraction (HFpEF) represents an entity distinct from heart failure with reduced ejection fraction (HFrEF), driven by highly heterogeneous and systemic pathophysiological mechanisms. Conventional biomarkers such as NT-proBNP primarily indicate hemodynamic stress and remain inadequate to elucidate the diverse, multi-organ network underlying HFpEF. Purpose We hypothesized that an integrated multi-omics approach combining targeted plasma proteomics and circulating miRNA sequencing would identify HFpEF-specific molecular signatures distinct from HFrEF, providing insight into its unique systemic mechanisms. Methods Plasma samples were collected from patients with HFpEF (n=14), HFrEF (n=14), and healthy controls (n=12). A targeted panel of 100 plasma proteins was quantified using aptamer-based proteomics. The panel interrogated five domains: established biomarkers, inflammation, metabolism and cellular stress, muscle biology, and myokines. Differentially expressed proteins were identified using log2 fold-change >=0.5 and p <=0.05. Plasma miRNA profiling by next-generation sequencing was performed. HFpEF-specific miRNAs were defined as differentially expressed against both Normal and HFrEF. Results Proteomic profiling identified a distinct HFpEF signature characterized by significant dysregulation (p < 0.05) across five interconnected axes. Unlike the MMP-9 driven degradation pattern in HFrEF, HFpEF exhibited accumulation-type fibrosis (elevated TIMP-1) and cytoskeletal remodeling (increased CFL2, decreased MYH14). Concurrently, HFpEF was driven by microvascular anti-angiogenesis (upregulated COL18A1 and ANGPTL3, downregulated Apelin), Th17-mediated chronic inflammation (elevated IL-23 and CD14, preserved CRP), and metabolic insulin resistance (increased IGFBP1, IGFBP2, and FABP). Transcriptomic sequencing isolated a unique panel of five HFpEF-specific miRNAs (log2 fold-change >= 0.5, p < 0.05; hsa-miR-30c-2-3p, hsa-miR-3200-3p, hsa-miR-340-3p, hsa-miR-144-5p, hsa-miR-2278). In silico network analysis demonstrated that these miRNAs mechanistically target the dysregulated proteomic markers identified above, including APLN, MYH14, and COL18A1. Conclusion HFpEF is a chronic, multi-organ systemic disease driven by inflammation, metabolism, fibrosis, and vascular dysfunction crosstalk, distinct from the acute injury paradigm of HFrEF. The convergence of HFpEF-specific miRNAs with proteomic alterations provides a coherent molecular framework. These findings provide a mechanistic rationale for targeted pharmacological interventions addressing these specific metabolic and inflammatory pathways.