Proteomics to improve phenotyping in obese patients with heart failure with preserved ejection fraction

Aims: Recent evidence points towards a distinct obese phenotype among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes.

Methods and results: From the LIFE-Heart study, 999 patients with HFpEF and 999 patients without heart failure (no-HF) were selected and 92 circulating serum biomarkers were measured using a proximity extension assay. Elevation of identified biomarkers was validated in 220 patients from the Aldo-DHF trial with diagnosed HFpEF. HFpEF patients were older and had more comorbidities including coronary artery disease and type 2 diabetes as compared to no-HF patients (P < 0.05 for all). After adjusting for covariates, adrenomedullin (ADM), galectin-9 (Gal-9), thrombospondin-2 (THBS-2), CD4, and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) were significantly higher in obese HFpEF patients [body mass index (BMI) ≥30 kg/m² , n = 464] as compared to lean HFpEF (BMI <30 kg/m² , n = 535) and obese no-HF patients (BMI ≥30 kg/m² , n = 387) (P < 0.001 for both); these findings were verified in the Aldo-DHF validation cohort (P < 0.001). Except for CD4 these proteins were associated with increased estimates of left atrial pressure in a linear fashion. Importantly, ADM and CD4 were associated with increased mortality in obese HFpEF patients after adjusting for covariates.

Conclusion: Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS-2) and systemic inflammation (Gal-9, CD4) compared to obese non-HFpEF or lean HFpEF patients. These findings support the clinical definition of a distinct obese HFpEF phenotype and might merit further investigation.