FGF23/FGFR4-mediated left ventricular hypertrophy is reversible

Abstract

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that directly targets cardiac myocytes via FGF receptor (FGFR) 4 thereby inducing hypertrophic myocyte growth and the development of left ventricular hypertrophy (LVH) in rodents. Serum FGF23 levels are highly elevated in patients with chronic kidney disease (CKD), and it is likely that FGF23 directly contributes to the high rates of LVH and cardiac death in CKD. It is currently unknown if the cardiac effects of FGF23 are solely pathological, or if they potentially can be reversed. Here, we report that FGF23-induced cardiac hypertrophy is reversible in vitro and in vivo upon removal of the hypertrophic stimulus. Specific blockade of FGFR4 attenuates established LVH in the 5/6 nephrectomy rat model of CKD. Since CKD mimics a form of accelerated cardiovascular aging, we also studied age-related cardiac remodeling. We show that aging mice lacking FGFR4 are protected from LVH. Finally, FGF23 increases cardiac contractility via FGFR4, while known effects of FGF23 on aortic relaxation do not require FGFR4. Taken together, our data highlight a role of FGF23/FGFR4 signaling in the regulation of cardiac remodeling and function, and indicate that pharmacological interference with cardiac FGF23/FGFR4 signaling might protect from CKD- and age-related LVH.

Fibroblast Growth Factor‐23 and Heart Failure With Reduced Versus Preserved Ejection Fraction: MESA

“…In experimental models, administration of recombinant FGF‐23 to mice affects cardiac myocytes directly and induces LVH 18, 29. FGF‐23 exerts a direct stimulatory effect on the renin‐angiotensin‐aldosterone system through suppression of angiotensin‐converting enzyme‐2,30 which suggests an alternative mechanism of the negative cardiovascular outcomes associated with FGF‐23.…”

Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

“…In humans, high FGF23 concentrations contribute to the pathogenesis of mineral and bone disorders in CKD and are associated with ventricular hypertrophy, cardiovascular events, and premature death. [4][5][6][7][8][9][10][11][12] Despite intense investigation, central elements of FGF23 regulation remain unknown. The primary role of FGF23 in phosphate homeostasis suggests regulation by serum phosphate concentrations; however, experimental studies have not detected direct actions of serum phosphate on FGF23.…”

High Fibroblast Growth Factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes

“…Future therapies should therefore focus on decreasing FGF23 concentrations or selectively block this effect of FGF23 on cardiomyocyte function in patients with CKD (Grabner et al. ) to reduce the risk of heart failure, even before the occurrence of LVH and cardiac dysfunction, and possibly also before the onset of overt hyperphosphatemia.…”

“…This disturbed calcium handling induced by high FGF23 concentrations might therefore explain part of the increased incidence of heart failure and cardiac mortality in CKD patients. Future therapies should therefore focus on decreasing FGF23 concentrations or selectively block this effect of FGF23 on cardiomyocyte function in patients with CKD (Grabner et al 2017) to reduce the risk of heart failure, even before the occurrence of LVH and cardiac dysfunction, and possibly also before the onset of overt hyperphosphatemia.…”