An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

Abstract

Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.

Keywords: FGF-23; FGFR; LVH; heart; heart failure – pharmacological treatment – systolic dysfunction.

FIGURE 1

Relationship between high plasma levels of FGF-23, mineral bone metabolism components and cardiac damage. (1) Parathyroid stimulates the release of phosphate and calcium from large calcium stores in the bones into the bloodstream. (2) High plasma levels of phosphate promote FGF-23 synthesis in bone marrow. (3) FGF-23 enhances the excretion of phosphate in kidneys. (4) High circulating FGF-23 levels are associated with several forms as cardiac damage including hypertrophy and HF. (5) FGF-23 reduces circulating 1,25(OH)2D, active form of vitamin D, and deficiency of vitamin D is associated with cardiac damage. (6) Low levels of Klotho are linked to both high plasma levels of FGF-23 and cardiac damage.

FIGURE 2

FGF-23-FGFR signalling. FGF-23 binds to the extracellular domain of its receptor, causing autophosphorylation. In cardiomyocytes, this change leads to phosphorylate calcium regulatory proteins, such as CAMKII, which promotes Ca²⁺ mishandling and cardiac dysfunction. In addition, FGF-23/FGFR4 triggers calcium cascade and the activation of calcineurin, which dephosphorylate NFAT inducing transcription of pro-hypertrophic genes such as β-MHC, BNP, or Rcan1. In fibroblasts, FGF-23 promotes fibrosis through activation of β-catenin.