Fibroblast growth factor-23 promotes rhythm alterations and contractile dysfunction in adult ventricular cardiomyocytes

Abstract

Background Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart. Whether FGF-23 modulates ventricular cardiac rhythm is unknown, prompting us to study its role on excitation–contraction (EC) coupling. Methods We examined FGF-23 in vitro actions on EC coupling in adult rat native ventricular cardiomyocytes using patch clamp and confocal microscopy and in vivo actions on cardiac rhythm using electrocardiogram. Results Compared with vehicle treatment, FGF-23 induced a significant decrease in rat cardiomyocyte contraction, L-type Ca2+ current, systolic Ca2+ transients and sarcoplasmic reticulum (SR) load and SR Ca2+-adenosine triphosphatase 2a pump activity. FGF-23 induced pro-arrhythmogenic activity in vitro and in vivo as automatic cardiomyocyte extracontractions and premature ventricular contractions. Diastolic spontaneous Ca2+ leak (sparks and waves) was significantly increased by FGF-23 via the calmodulin kinase type II (CaMKII)-dependent pathway related to hyperphosphorylation of ryanodine receptors at the CaMKII site Ser2814. Both contraction dysfunction and spontaneous pro-arrhythmic Ca2+ events induced by FGF-23 were blocked by soluble Klotho (sKlotho). Conclusions Our results show that FGF-23 reduces contractility and enhances arrhythmogenicity through intracellular Ca2+ mishandling. Blocking its actions on the heart by improving sKlotho bioavailability may enhance cardiac function and reduce arrhythmic events frequently observed in ESRD.

Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca2+ handling

“…First, our results show that decreased Klotho availability, together with the presence of pathologically elevated FGF‐23 levels, might be a warning sign for increased risk of developing arrhythmic events in patients with CKD. Supporting this idea, several studies have previously shown that FGF‐23 exposure alters cardiac contractility and Ca 2+ handling in isolated adult ventricular cardiomyocytes (Navarro‐García et al, 2019; Touchberry et al, 2013) and in HL‐1 atrial cells (Kao et al, 2014). These findings support the notion that systemic elevation of FGF‐23 is likely to have deleterious and direct effects on heart function in the complex pathological setting of uraemic cardiomyopathy (Faul, 2018).…”

“…Adult male mice (6–8‐week‐old +/+ or kl/kl , 14‐week‐old WT‐Sham, Nfx, Sham+rKL or Nfx+rKL, and Tg‐Kl‐ Sham or Tg‐Kl‐ Nfx, blindly selected) were anaesthetised with sodium pentobarbital‐heparin (100 mg/kg, i.p.). Mice were sacrificed, and hearts were rapidly removed and cannulated via the ascending aorta on a Langendorff perfusion system (Navarro‐García et al, 2019; Ruiz‐Hurtado et al, 2015). Hearts were retrogradely perfused with calcium‐free Tyrode's solution supplemented with EGTA (0.2 mmol·L −1 ) for 3 min followed by Tyrode's solution containing 0.1 mmol·L −1 of CaCl 2 , 1 mg·mL −1 of type II collagenase (Worthington, Lakewood, NY), and 1 mg·mL −1 of BSA for 3–4 min at room temperature.…”

Fibroblast growth factor 23 decreases PDE4 expression in heart increasing the risk of cardiac arrhythmia; Klotho opposes these effects

“…Our findings that FGF23 increases the number of SCWs in cardiomyocytes by acute β-AR stimulation due to increased SR Ca 2+ leak and higher RyR2-S2814 phosphorylation are in agreement with these observations. Recently Novarro-Garcia et al reported similar results [34]. They observed that FGF23 induced RyR phosphorylation at the CaMKII site resulting in an increase in Ca 2+ spark frequency that could trigger pro-arrhythmogenic events.…”

“…This effect was FGF receptor-dependent but independent of Klotho. It has been recently reported that FGF23 could favor spontaneous proarrhythmic Ca 2+ events and that sKlotho could block this effect [34]. While all these data support a direct role of FGF23 on heart, the effects of FGF23 beyond the cardiac hypertrophy, and the mechanisms by which high FGF23 concentration could favor ventricular arrhythmias and sudden death are however largely unknown.…”

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

“…Recent research provides evidence that a high plasma level of fibroblast growth factor-23 (FGF)-23 is a hallmark of cardiac damage resulting in deleterious remodelling and the induction of cardiac hypertrophy. In the last few years, FGF-23 has been identified as a new trigger of cardiac dysfunction (Seiler et al, 2011;Leifheit-Nestler et al, 2018b;Navarro-García et al, 2019). Therefore, it is essential to not only understand the mechanisms whereby FGF-23 signals are transduced but also the variables associated with the increase in FGF-23 so new therapeutic…”