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Cardiac remodeling is frequently observed in patients with sickle cell disease (SCD), and contributes to cardiac dysfunction and premature death. Cardiac dysfunction in SCD has been related to chronic anemia and low oxygen saturation. However, the mechanisms whereby they induce cardiac dysfunction are not completely understood and additional factors still have to be identified; a potential candidate is the fibroblast growth factor 23 (FGF23). FGF23 is secreted by bone cells and controls calcitriol and serum phosphate concentrations by acting on the kidney, which is its main physiological target. The intact form of FGF23 (iFGF23) is the only form that circulates under physiological conditions and mediates its physiological effects. iFGF23 can be cleaved in an Nand a C-terminal fragment and it is not certain whether these fragments have any biological effects. Two different immunoassays can be used to measure iFGF23 or C-terminal FGF23 fragment (cFGF23) concentrations. In patients with chronic kidney disease (CKD), plasma FGF23 concentration progressively increases when glomerular filtration rate (GFR) declines. Elevated FGF23 concentration has been associated with cardiac hypertrophy and mortality in CKD patients and in the general population. Injection of iFGF23 in the heart of rats induces cardiac hypertrophy. In 5 of 6 nephrectomized rats (which have elevated iFGF23 plasma concentrations), treatment with an FGF receptor (FGFR) antagonist attenuated cardiac hypertrophy. The mechanism whereby iFGF23 can induce heart hypertrophy is still not completely understood but does not require the expression of the FGF23 co-receptor aKlotho. To determine whether FGF23 could contribute to cardiac remodeling in SCD patients, we measured plasma iFGF23 and cFGF23 concentrations in 77 young adult SCD patients and 172 healthy control subjects of the same ethnic background. A local ethic committee approved the study protocol (Comité de Protection des Personnes Ile de France II number: 2011531-RCEB). The main characteristics of the SCD patients and the control subjects are presented in Online Supplementary Table S1. Among the SCD patients, 53 had hemoglobin SS genotype (HbSS), 15 had hemoglobin SC (HbSC), 8 had sickle cell hemoglobin S-β thalassemia (HbS β), and one had hemoglobin SD (HbSD). Patients with SCD were younger, had lower body mass index (BMI), lower blood pressure, higher estimated GFR and lower hemoglobin concentration than controls. SCD patients had significantly higher cFGF23 plasma concentration than controls whatever their phenotypes (SS or non-SS) (Figure 1A). Fifty-eight (75.3%) SCD patients versus 18 (10.5%) controls had values above normal (150 RU/mL) (P<10). Patients with SS genotype had significantly higher cFGF23 concentration than non-SS patients (Figure 1A). Forty-five of the SS patients (86.5%) and 13 of the non-SS patients (52%) had cFGF23 concentration above the upper normal value (P=0.0013). We also measured FGF23 concentration with an assay that measures only iFGF23 in 50 SCD patients (33 with SS genotype and 17 with non-SS genotype). In this subgroup, cFGF23 concentration was above normal values in 39 patients (78%). By contrast, iFGF23 concentration was normal (<50 pg/mL) in all but 5 of these 50 SCD patients. Furthermore, in SCD patients, at variance with our observations in non-SCD subjects, iFGF23 and cFGF23 levels were not correlated (Online Supplementary Figure S1) suggesting that mainly cleaved FGF23 was present in the plasma of SCD patients. cFGF23 concentration correlated negatively with hemoglobin levels in SCD patients (r=0.187, P<0.0001). We observed a negative correlation between hemoglobin levels and GFR (r=0.062, P=0.0293) and a positive correlation between cFGF23 and GFR (r=0.058, P=0.0343). There was no difference in

Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease