Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction

Aims Besides regulating calcium-phosphate metabolism, fibroblast growth factor 23 (FGF-23) has been associated with incident heart failure (HF) and left ventricular hypertrophy. However, data about FGF-23 in HF and preserved ejection fraction (HFpEF) remain limited. The aim of this study was to assess the association between FGF-23 levels, clinical and imaging characteristics, particularly diffuse myocardial fibrosis, and prognosis in HFpEF patients. Methods and results We prospectively included 143 consecutive HFpEF patients (78 +/- 8 years, 61% female patients) and 31 controls of similar age and gender (75 +/- 6 years, 61% female patients). All subjects underwent a complete two-dimensional echocardiography and cardiac magnetic resonance with extracellular volume (ECV) assessment by T1 mapping. FGF-23 was measured at baseline. Among the patients, differences in clinical and imaging characteristics across tertiles of FGF-23 levels were analysed with a trend test across the ordered groups. Patients were followed over time for a primary endpoint of all-cause mortality and first HF hospitalization and a secondary endpoint of all-cause mortality. Median FGF-23 was significantly higher in HFpEF patients compared with controls of similar age and gender (247 [115; 548] RU/mL vs. 61 [51; 68] RU/mL,P < 0.001). Among HFpEF patients, higher FGF-23 levels were associated with female sex, higher incidence of atrial fibrillation, lower haemoglobin, worse renal function, and higher N terminal pro brain natriuretic peptide levels (Pfor trend < 0.05 for all). Regarding imaging characteristics, patients with higher FGF-23 levels had greater left atrial volumes, worse right ventricular systolic function, and more fibrosis estimated by ECV (Pfor trend < 0.05 for all). FGF-23 was moderately correlated with ECV (r = 0.46,P < 0.001). Over a mean follow-up of 30 +/- 8 months, 43 patients (31%) died and 69 patients (49%) were hospitalized for HF. A total of 87 patients (62%) reached the primary composite endpoint of all-cause mortality and/or first HF hospitalization. In multivariate Cox regression analysis for the primary endpoint, FGF-23 (HR: 3.44 [2.01; 5.90],P < 0.001) and E wave velocities (HR: 1.01 [1.00; 1.02],P = 0.034) were independent predictors of the primary composite endpoint. In multivariate Cox regression analysis for the secondary endpoint, ferritin (HR: 1.02 [1.01; 1.03],P < 0.001), FGF-23 (HR: 2.85 [1.26; 6.44],P = 0.012), and ECV (HR: 1.26 [1.03; 1.23],P = 0.008) were independent predictors of all-cause mortality. Conclusions Fibroblast growth factor 23 (FGF-23) levels were significantly higher in HFpEF patients compared with controls of similar age and gender. FGF-23 was correlated with fibrosis evaluated by ECV. High levels of FGF-23 were significantly associated with signs of disease severity such as worse renal function, larger left atrial volumes, and right ventricular dysfunction. Moreover, FGF-23 was a strong predictor of poor outcome (mortality and first HF hospitalization).