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Abstract: PO2158

Fibroblast Growth Factor 23 Induces Ventricular Arrhythmias and Prolongs QTc Interval in Mice In Vivo Mediated Through FGF Receptor 4

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Vallejo, Julian, Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States
  • Wang, Derek, Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States
  • Graves, Jonah M., Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States
  • Faul, Christian, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Wacker, Michael J., Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States
Background

Sudden cardiac death and arrhythmias are leading causes of mortality in those with compromised renal function, such as in chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone released by osteocytes, which becomes markedly elevated in CKD. Previously, we found that FGF23 increases intracellular Ca2+ in cardiomyocytes and alters contractility in mouse ventricles ex vivo via stimulation of FGF receptor 4 (FGFR4). Since FGF23 could disrupt Ca2+ homeostasis, we hypothesized that FGF23 at pathological levels would alter depolarization/repolarization of the heart and induce arrhythmias in vivo via a mechanism involving FGFR4.

Methods

To asses our hypothesis, CD-1 male mice (3 months old) were anesthetized and electrocardiogram (ECG) needle electrodes were inserted into the limbs. The jugular vein was cannulated for infusion of vehicle or FGF23 (9ng/ml total blood volume) with and without pretreatment with an FGFR4-specific blocking antibody (anti-FGFR4; U3 Pharma). Lead II ECG and arrhythmias were monitored at baseline and then for 30 minutes post injection.

Results

FGF23 induced premature ventricular contractions (PVCs) in 5 out of 11 mice (P=0.038 vs vehicle) with an average maximal rate of PVCs in these 5 mice of 10.2 ± 5.2 PVC/minute (P<0.01 vs vehicle). Vehicle (n=9) and FGF23+anti-FGFR4 treated (n=8) mice did not exhibit PVCs. Treatment with Isoproterenol (0.1mg/kg) after FGF23 further augmented arrhythmias to a maximal rate of 28.0 ± 21.1 PVC/minute (P<0.05 vs vehicle) and 2 out of 8 mice displayed ventricular tachycardia. Upon examination of ECG intervals, FGF23 prolonged QTc within 30 minutes (P<0.05, n=8) compared to vehicle treatment (n=9), whereas no effect was found for PR interval or QRS duration. FGFR4 blockade abrogated the QTc prolonging effects of FGF23 (n=8).

Conclusion


We conclude that FGF23/FGFR4 signaling in the heart may contribute to ventricular arrhythmogenesis and repolarization disturbances commonly observed in patients with CKD and may be an important therapeutic target to reduce cardiac mortality in CKD.