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Fibroblast growth factor (FGF)-23 induces ventricular arrhytmogenesis through Ca2+ handling dysregulation

AuthorsNavarro-García, Jose A.; Delgado, Carmen CSIC ORCID ; Fernández-Velasco, María CSIC ORCID; Val-Blasco, Almudena; Rodríguez‑Sánchez, E.; Aceves‑Ripoll, Jennifer; Hernández, Eduardo; Bada-Bosch, Teresa; Arribas, Fernando; Salguero, Rafael; Solís, Jorge; Praga, Manuel; Bueno, Héctor; Ruilope, Luis M.; Ruiz-Hurtado, Gema
Issue Date2017
CitationEuropean Society of Cardiology Congress (2017)
Abstract[Introduction] Fibroblast growth factor (FGF)-23 is a hormone synthesized in bones in response of an increase in circulating phosphate levels. It is known that patients with chronic kidney disease (CKD) show high serum levels of FGF-23 and this increment is gradual as CKD progresses. Despite of FGF-23 has been classically associated to renal dysfunction, during the last years is also considered as a non-conventional risk factor of cardiovascular (CV) disease. However, it is completely unknown whether FGF-23 might alter cardiac contractile function, especially in advanced stages of renal disease in which circulating FGF-23 levels are strongly increased.
[Purpose] 1) Analyze whether FGF-23 impairs calcium (Ca2+) handling, a key regulator of contractile function and consequently the ventricular rhythm. 2) Analyze the circulating levels of FGF-23 in dialysis patients and its relationship with the ventricular rhythm.
[Methods] Enzymatically isolated adult rat ventricular myocytes (n=9) were perfused firstly with a vehicle solution and subsequently with a FGF-23 solution (100 ng/mL). L-type Ca2+ current (ICaL) was recorded by the whole-cell patch-clamp technique. Ca2+ handling and contractile function were analyzed using confocal microscopy. To determinate FGF-23-dependent pathways, cardiomyocytes were pre-incubated with the FGF-receptors inhibitor PD173074 (10 μmol/mL) or soluble klotho (s-klotho) (100 ng/mL). In addition, FGF-23 serum levels were measured by the FGF-23 (C-term) ELISA-kit in samples from patients under dialysis (n=52).
[Results] FGF-23 induced a significant decline of ICaL (p<0.001), an important decrease in the intracellular Ca2+ transients amplitude (p<0.01) and in the sarcoplasmic reticulum Ca2+ load (p<0.01). All these alterations were functionally translated to a significant deterioration of cellular contraction values (p<0.01). Additionally, a considerable increase in diastolic Ca2+ sparks and waves (p<0.01) and therefore in the ryanodine receptors activity were observed during FGF-23 exposure. Interestingly, during FGF-23 perfusion cardiomyocytes showed a pro-arrhythmogenic phenotype when they were electrically stimulated. These effects induced by FGF-23 were blocked when cardiomyocytes were pretreated with PD173074 or s-klotho. On the other hand, serum levels of FGF-23 were strongly increased in dialysis patients, even reaching >1000 RU/mL of FGF-23 in 68% of total dialysis patients.
[Conclusion] Our study uncovers FGF-23 as new target in the intracellular Ca2+ handling, able to impair contractile function and induce a pro-arrhythmogenic phenotype in adult cardiomyocytes.
[Future perspectives] Alterations evoked by FGF-23 in cardiomyocytes could explain the CV events observed in patients with CKD, especially those in dialysis. The next step will be to analyze in CKD patients whether high FGF-23 levels impair cardiac function and heart rhythm.
DescriptionResumen del trabajo presentado al European Society of Cardiology (ESC) Congress, celebrado en Barcelona (España) del 26 al 30 de agosto de 2017.
Appears in Collections:(IIBM) Comunicaciones congresos
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