Bone marrow and plasma FGF‐23 in heart failure patients: novel insights into the heart–bone axis

Abstract

Aims Fibroblast growth factor 23 (FGF‐23) is known to be elevated in patients with congestive heart failure (CHF). As FGF‐23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF‐23 in CHF remains unclear. It is also unclear if FGF‐23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF‐23 levels measured in bone marrow plasma (FGF‐23‐BM) and in peripheral blood (FGF‐23‐P) in CHF patients to gain further insights into the heart–bone axis of FGF‐23 expression. We also investigated possible associations between FGF‐23‐BM as well as FGF‐23‐P and outcome in CHF patients. Methods and results We determined FGF‐23‐P and FGF‐23‐BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF‐23‐BM and FGF‐23‐P with all‐cause mortality in CHF patients, 32 events, median follow‐up 1673 days, interquartile range [923, 1828]. FGF‐23‐P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF‐23‐BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF‐23‐BM levels were significantly higher than FGF‐23‐P levels in both CHF patients and in healthy controls ( P < 0.001). FGF‐23‐P and FGF‐23‐BM correlated significantly with LVEF ( r = −0.37 and r = −0.33, respectively), N terminal pro brain natriuretic peptide levels ( r = 0.57 and r = 0.6, respectively), New York Heart Association status ( r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate ( r = −0.43 and r = −0.41, respectively) ( P for all <0.001) and were independently associated with all‐cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18–6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19–6.57], P = 0.018, respectively. Conclusions In CHF patients, FGF‐23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all‐cause mortality. The failing heart seems to interact via FGF‐23 within a heart–bone axis.

Estimating the distribution of a novel clinical biomarker (FGF-23) in the US population using findings from a regional research registry

“…The fact that the association between estimated NHANES FGF-23 values and CV and all-cause mortality was similar to what was observed by Haring and colleagues provides some support for the external validity of their equation. It is also interesting to note that the estimated FGF-23 levels for NHANES patients with CHF (not included in the Haring equation) were more than twice as high as among those without CHF, consistent with findings from other studies [36]. Nevertheless, the strength of our results hinge upon the strength of the assumption that the Haring equation can be validly extended to the broader NHANES population, an assumption that could best be tested were directly measured FGF-23 to be included as part of a future wave of NHANES.…”

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

“…Fibroblast growth factor 23 (FGF‐23), a bone‐derived hormone regulating renal phosphate homeostasis and vitamin D metabolism, has a direct action on the cardiovascular system and has been recently related to adverse cardiovascular events in chronic HF and implicated in cardiac remodelling 6–9 . Several recent studies suggested that higher FGF‐23 levels were associated with left ventricular hypertrophy 10 and worse prognosis, particularly among patients with chronic kidney disease (CKD) 11,12 but also in stable ischaemic cardiomyopathy 13 and HF with reduced ejection fraction (HFrEF) 6–8,14–16 . FGF‐23 has also been identified as a biomarker significantly related to atrial fibrillation 17 …”

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

“…Nevertheless, the meta-analysis by Marthi et al (2018) did not find a trend across different levels of kidney function in the association between high FGF-23 and HF. From a cardiac functional point of view, many studies have correlated high plasma levels of FGF-23 with a reduced left ventricular ejected fraction (LVEF; <40%), which indicates that high FGF-23 levels are directly linked to systolic dysfunction (Seiler et al, 2011;Shibata et al, 2013;Agarwal et al, 2014;Poelzl et al, 2014;von Jeinsen et al, 2019;Song et al, 2021). Furthermore, high plasma levels of FGF-23 are also associated with albuminuria in CKD which is strongly associated with Heart Failure with reduced Ejection Fraction (HFrEF), but not with Heart Failure with preserved Ejection Fraction (HFpEF) (Nayor et al, 2017).…”

“…FGF-23 is an early and complementary predictor of adverse cardiac events and could be suitable for improving risk assessment in vulnerable patients with HF or reduced ejection fraction ( Koller et al, 2015 ). FGF-23 is positively correlated with but does not directly depend on the classical biomarkers of cardiac damage, such as N-terminal-pro-B-type natriuretic peptide (NT-proBNP) ( Seiler et al, 2011 ; Shibata et al, 2013 ; Kestenbaum et al, 2014 ; Poelzl et al, 2014 ; Koller et al, 2015 ; Masson et al, 2015 ; Panwar et al, 2015 ; Speer et al, 2015 ; Wohlfahrt et al, 2015 ; Ter Maaten et al, 2018 ; von Jeinsen et al, 2019 ; Song et al, 2021 ), high-sensitive cardiac troponin T (hs-cTnT) ( Kestenbaum et al, 2014 ; Masson et al, 2015 ; Song et al, 2021 ) and C-reactive protein (CRP) ( Parker et al, 2010 ; Seiler et al, 2011 ; Ix et al, 2012 ; Lutsey et al, 2014 ; Panwar et al, 2015 ; Speer et al, 2015 ; Reindl et al, 2017 ; Song et al, 2021 ). Furthermore, it has already been demonstrated that the predictive value of the combination of these biomarkers on cardiovascular risk assessment is significantly greater than any of them alone ( Wohlfahrt et al, 2015 ).…”

“…FGF-23 is a hormone mainly synthesised by osteocytes and osteoblasts in long bones, although it can also be produced and secreted by different tissues, such as liver or even heart tissue under stress conditions ( Hu et al, 2013 ). FGF-23 is involved in phosphate homeostasis and promotes renal phosphate excretion ( Wolf, 2012 ; Mace et al, 2015 ), downregulation of 1,25-dihydroxyvitamin D (vitamin D) synthesis ( Krajisnik et al, 2007 ; Mace et al, 2015 ; Navarro-García et al, 2018 ) and a decrease in parathyroid hormone (PTH) secretion ( Navarro-García et al, 2018 ; von Jeinsen et al, 2019 ). FGF-23 is a 32 kDa protein encoded by the gene fgf23 located in chromosome 12 and belongs to the FGF subfamily FGF19, which corresponds to the endocrine FGFs ( Hu et al, 2013 ).…”