Liver status and secretome profiles define risk and outcomes in HFpEF

Background Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a systemic, multisystemic disorder with strong metabolic and hepatic components. Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in HFpEF and may contribute to its pathogenesis and progression, yet the mechanistic and prognostic relevance of hepatic dysfunction in HFpEF remains poorly defined. Objective To investigate the relationship between liver status, circulating liver-derived proteins, and both the incidence and outcomes of HFpEF in the UK Biobank cohort. Methods Liver status was assessed in UK Biobank participants using MRI-derived proton density fat fraction (PDFF) and corrected T1 (cT1), alongside serum-based indices of steatosis (FLI, HSI, DSI) and fibroinflammation (FIB4, NFS, Liver Risk Score). These measures were compared between HFpEF patients and matched controls and analyzed for their association with mortality. Plasma proteomic data for 673 liver-enriched proteins were analyzed using generalized linear models with PDFF or cT1 as predictors, adjusting for age, sex, HbA1c, waist-to-height ratio, triglycerides, and alcohol intake. Significant liver–protein associations were defined by FDR-adjusted p<0.05, local false sign rate <0.1, and high model variance explained. Proteins linked to both MRI and serum-derived hepatic metrics were further analyzed for associations with HFpEF using deconfounding models and multivariable logistic regression, followed by Cox models for mortality. Results HFpEF patients exhibited a markedly adverse hepatic phenotype compared with controls across all MRI- and score-based indices. Markers of hepatic fibroinflammation (cT1, FIB4, NFS, LRS), but not steatosis, were independently associated with higher mortality within the HFpEF group. Out of 673 liver-secreted proteins, 163 correlated their plasma level with liver phenotype, and 60 remained independently associated with HFpEF after deconfounding. Twenty-four proteins retained significance in multivariable models for HFpEF presence, and eight of them were independently associated with adverse prognosis. These proteins included mediators of extracellular matrix remodeling, oxidative stress, and hepatokine signaling. Conclusions HFpEF is characterized by a distinct hepatic phenotype in which liver fibroinflammation, more than steatosis, contributes to adverse outcomes. A subset of liver-secreted proteins reflects both hepatic status and HFpEF risk, offering mechanistic insight and potential biomarkers for HFpEF risk stratification and prognosis in MASLD and cardiometabolic disease.