Fibroblast Growth Factor 23 (FGF23) Induces Ventricular Arrhythmias and Prolongs QTc Interval in Mice in an FGF Receptor 4-Dependent Manner

Am J Physiol Heart Circ Physiol. 2021 Apr 30. doi: 10.1152/ajpheart.00798.2020. Online ahead of print.ABSTRACTFibroblast growth factor 23 (FGF23) is a phosphate regulating protein hormone released by osteocytes. FGF23 becomes markedly elevated in chronic kidney disease (CKD), for which the leading cause of death is cardiovascular disease, particularly sudden cardiac death. Previously, we found that FGF23 increases intracellular Ca2+ in cardiomyocytes and alters contractility in mouse ventricles ex vivo via FGF-receptor 4 (FGFR4). In the present study, we demonstrate that FGF23 induces cardiac arrhythmias and prolongs QTc interval in mice, and we tested whether these effects are mediated through FGFR4. In isolated Langendorff perfused hearts, FGF23 perfusion increased mechanical arrhythmias in the form of premature ventricular beats (PVBs), and induced runs of ventricular tachycardia in six of 11 animals, which were attenuated with pretreatment of an anti-FGFR4 blocking antibody. Ex vivo ECG analysis of isolated intact hearts showed increased ventricular arrhythmias and QTc prolongation after FGF23 infusion compared to vehicle. In vivo, injection of FGF23 into the jugular vein led to the emergence of premature ventricular contractions (PVCs) in 5 out of 11 experiments. FGF23 also produced a significant lengthening effect upon QTc interval in vivo. In vivo FGFR4 blockade ameliorated the arrhythmogenic and QTc prolonging effects of FGF23. Finally, FGF23 increased cardiomyocyte C...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Source Type: research

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