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

Abstract

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 (P for 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 (P for 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.

Fibroblast‐growth‐factor‐23 in heart failure with preserved ejection fraction: relation to exercise capacity and outcomes

“…Moreover, as in the present report, the previous study found FGF23 levels to be associated with risk of all-cause death or HF hospitalization. While our study did not find association with ECV in contrast to the previous report, 24 we suggest there are consistent observations in the two studies, with differences in the characteristics of the populations, in imaging techniques, and in parameters considered in multivariate analyses, all likely to contribute to variation in the strength of observed associations. Importantly, to the association with adverse prognosis, we report an additional association for FGF23 with reduced exercise capacity in HFpEF.…”

Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome

“…As shown in Figure 3I , we noted a synergistic effect rather than an additive effect between MI and FGF23 overexpression, suggesting a positive feedback may exist between cardiac dysfunction and circulatory FGF23 levels. Our previous study showed that FGF23 overexpression could worsen heart failure [ 28 ], while high levels of FGF23 were significantly associated with the severity of heart failure [ 38 ]. Although both heart and kidney can produce FGF23, our results demonstrated that renal FGF23 gene was not changed in response to chronic MI or myocardial overexpression of FGF23, supporting that the heart is critical for FGF23 production in type 2 CRS.…”

FGF-23 correlates with endocrine and metabolism dysregulation, worse cardiac and renal function, inflammation level, stenosis degree, and independently predicts in-stent restenosis risk in coronary heart disease patients underwent drug-eluting-stent PCI

“…FGF-23 is a bone-derived hormone in response to the increment of circulating phosphate and calcitriol levels, and its implication in the pathogenesis of CKD has been revealed that increased FGF-23 disrupts the bone-kidney-parathyroid hormone balance, which promotes the generation of hyperphosphatemia with the progression of CKD [ 18 ]. Recently, several clinical studies suggest that FGF-23, as a pro-inflammatory role, is involved in several aspects of cardiovascular diseases [ 8 , 10 , 19 , 20 ]. For example, FGF-23 is reported to be an independent factor for increased stage of peripheral vascular calcified atherosclerotic plaque and carotid artery intima-media thickness, and is responsible for the development and progression of atherosclerosis [ 21 ].…”

“…(3) Thirdly, FGF-23 was reported to decrease active vitamin D synthesis via decreasing 1α-hydroxylase expression, resulting in low level of anti-inflammation calcitriol in serum, meanwhile, high level of FGF-23 presented enhancing effect on inflammatory mediators and signaling (NF-κB signaling), which both amplifying inflammation [ 8 ]. (4) Fourthly, previous study indicated that FGF-23 might trigger adverse cardiovascular remodeling and induce cardiac injury via interplaying with PTH and renin–angiotensin–aldosterone system, thereby leading to high cTnl, NT-proBNP level but low LVEF level [ 9 , 18 , 19 ]. In addition, considering these prominent contributing factors of stenosis including inflammation, cardiac injury and lipid disorder, FGF-23 was therefore correlated with stenosis degree of target lesion in CHD patients underwent PCI with DES.…”