Fibroblast growth factor 23 (FGF23) induces ventricular arrhythmias and prolongs QTc interval in mice in an FGF receptor 4-dependent manner
| Autor: | Derek Wang, Christian Faul, Julian Vallejo, Chelsea S Hamill, Shaan Patel, Michael J. Wacker, Rohan Ahuja, Jonah M Graves |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cardiac function curve Fibroblast growth factor 23 medicine.medical_specialty Physiology Heart Ventricles 030204 cardiovascular system & hematology Ventricular tachycardia urologic and male genital diseases QT interval Sudden cardiac death 03 medical and health sciences Electrocardiography Mice 0302 clinical medicine Physiology (medical) Internal medicine Medicine Repolarization Animals Myocytes Cardiac Receptor Fibroblast Growth Factor Type 4 cardiovascular diseases Renal Insufficiency Chronic business.industry Myocardium Arrhythmias Cardiac Heart Isolated Heart Preparation Fibroblast growth factor receptor 4 medicine.disease Ventricular Premature Complexes Fibroblast Growth Factors stomatognathic diseases Fibroblast Growth Factor-23 Long QT Syndrome 030104 developmental biology Cardiology cardiovascular system Tachycardia Ventricular Calcium Cardiology and Cardiovascular Medicine business Ex vivo Signal Transduction Research Article |
| Zdroj: | Am J Physiol Heart Circ Physiol |
| ISSN: | 1522-1539 |
| Popis: | Fibroblast 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 Ca(2+) 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 6 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 with 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 Ca(2+) levels in intact left ventricular muscle which was inhibited by FGR4 blockade. We conclude that FGF23/FGFR4 signaling in the heart may contribute to ventricular arrhythmogenesis and repolarization disturbances commonly observed in patients with CKD via Ca(2+) overload and may be an important therapeutic target to reduce cardiac mortality in CKD. NEW & NOTEWORTHY Here we provide direct evidence that fibroblast growth factor 23 (FGF23), a phosphaturic hormone elevated in chronic kidney disease, is proarrhythmic. FGF23 acutely triggered ventricular arrhythmias and prolonged corrected QT interval (QTc) in isolated mouse hearts and in vivo. FGF23 also increased Ca(2+) levels in ventricular muscle tissue. Blockade of the FGF receptor 4 signaling pathway using a monoclonal antibody ameliorated ventricular arrhythmias, QTc prolongation, and elevated ventricular Ca(2+) induced by FGF23, and may represent a potential therapeutic target in chronic kidney disease. |
| Databáze: | OpenAIRE |
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