C-terminal FGF23 is a strong predictor of survival in systolic heart failure
Highlights
► Fibroblast growth factor 23 is an important of phosphate and calcium metabolism. ► C-terminal FGF23 is a 71 amino acids peptide. ► We have evaluated Ct-FGF23 in patients presenting systolic heart failure. ► Ct-FGF23 levels were markedly increased in HF patients. ► Ct-FGF23 is the strongest predictor of long term CV death.
Introduction
Heart failure (HF) is a highly prevalent disease associated to a worse prognosis and characterized by a strong neurohormonal activation playing a significant role in myocardial and multi-organ adaptations to the failing myocardium [12]. Neurohormones and biomarkers testing may contribute to the risk stratification and treatment selection of patients with HF.
Abnormalities of phosphorus homeostasis have been linked to cardiovascular risk in different populations. A greater risk of HF has been associated to increased serum phosphorus in a community-based study [2]. Several other studies have also linked phosphorus levels to cardiac hypertrophy and mortality in patients with chronic kidney disease (CKD) and in patients with coronary artery disease (CAD) [11], [21].
Fibroblast growth factor 23 (FGF23), a bone-derived protein, is an important regulator of the phosphorus homeostasis [15]. The amino-terminal portion of FGF23 (amino acids 1–24) may serve as a signal peptide allowing the secretion into the blood circulation and the carboxyl-terminal portion (aa 180–251) participates to its biological action. FGF23 levels are independently associated with left ventricular mass index and hypertrophy as well as mortality is patients with CKD [5], [10], [20]. Seiler et al. showed that FGF23 was associated with left ventricular dysfunction and atrial fibrillation in CAD subjects even in the absence of impaired renal function [19]. FGF23 levels have been studied in patients with stable CAD and were also independently associated with mortality and cardiovascular (CV) events [13]. More recently, Plischke et al. have reported an independent prognostic value of intact FGF23 for all-cause mortality in stable systolic HF [14].
The aim of our study was to determine the circulating levels of C-terminal FGF23 (Ct-FGF23) in heart failure patients with reduced left ventricular ejection fraction (HF-REF) and their predictive value of long term CV death. The relation of Ct-FGF23 with estimated glomerular filtration rate (eGFR), calcium, phosphorus, parathyroid hormone (PTH) and B-type natriuretic peptide (BNP) levels was also evaluated.
Section snippets
Patient population
Seventy-three consecutive HF patients with reduced left ventricular ejection fraction (defined as EF < 40%) referred to the Cliniques Universitaires Saint-Luc, an academic hospital of Brussels, Belgium, between March 30th 2004 and December 10th 2004 (the mean time of follow-up was 3.4 years and the maximum and minimum follow-up times were days and 6.5 years, respectively) and 68 healthy sex-matched controls were included in the study. Left ventricular ejection fraction (EF) was determined by
Circulating levels of Ct-FGF23 and other biomarkers in HF-REF patients compared to controls.
The baseline characteristics of the control and HF-REF groups are showed in Table 1. In HF-REF patients, the levels of Ct-FGF23 were much higher than in controls. There were significant differences in the phospho-calcic parameters between HF-REF patients and controls, as calcium was significantly lower and phosphorus significantly higher in HF-REF but remaining within the normal range. Mean intact PTH was about twice as high in HF-REF patients than in controls. Median eGFR levels were
Discussion
Our study shows that Ct-FGF23 circulating levels are significantly increased in HF-REF patients in comparison to healthy individuals and uncovers for the first time that Ct-FGF23 allows identifying HF-REF patients with high risk of CV death over a long-term follow-up. Our data also showed that in a multivariate analysis including age, EF, PTH, BNP, Ct-FGF23, calcium, phosphorus and eGFR levels, Ct-FGF23 was the strongest predictor of long term CV death in HF-REF patients.
In patients with CKD,
Disclosures
None.
Acknowledgement
The authors thank S. Goletti for her support to Ct-FGF23 testing.
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