The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk

Abstract

High circulating fibroblast growth factor 23 (FGF23) levels are probably a major risk factor for cardiovascular disease in chronic kidney disease. FGF23 interacts with the receptor FGFR4 in cardiomyocytes inducing left ventricular hypertrophy. Moreover, in the liver FGF23 via FGFR4 increases the risk of inflammation which is also found in chronic kidney disease. In contrast, X-linked hypophosphatemia is characterized by high FGF23 circulating levels due to loss of function mutations of the phosphate-regulating gene with homologies to an endopeptidase on the X chromosome (PHEX), but is not characterized by high cardiovascular morbidity. Here we used a novel murine X-linked hypophosphatemia model, the Phex mouse line, bearing an amino acid substitution (p.Cys733Arg) to test whether high circulating FGF23 in the absence of renal injury would trigger cardiovascular disease. As X-linked hypophosphatemia patient mimics, these mice show high FGF23 levels, hypophosphatemia, normocalcemia, and low/normal vitamin D levels. Moreover, these mice show hyperparathyroidism and low circulating soluble αKlotho levels. At the age of 27 weeks we found no left ventricular hypertrophy and no alteration of cardiac function as assessed by echocardiography. These mice also showed no activation of the calcineurin/NFAT pathway in heart and liver and no tissue and systemic signs of inflammation. Importantly, blood pressure, glomerular filtration rate and urea clearance were similar between genotypes. Thus, the presence of high circulating FGF23 levels alone in the absence of renal impairment and normal/high phosphate levels is not sufficient to cause cardiovascular disease.

Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME‐CHF trial

“…Our data are in line with recent experimental findings also challenging FGF23's role in myocardial disease, e.g. primary elevations of FGF23 were found to be innocent and harmless to the rodent heart . Such data call into question the direction of causality and underline speculations that actually heart disease per se contributes to elevated FGF23 levels (pointing towards reverse causality) .…”

Strength of Fibroblast Growth Factor 23 as a Cardiovascular Risk Predictor in Chronic Kidney Disease Weaken by ProBNP Adjustment

“…Despite this early enthusiasm for such novel therapeutic interventions, certain caveats have recently arisen: Experimentally, independent study groups did not unanimously confirm a cardiotoxic effect of FGF23 [15][16][17][18][19], and latest rodent studies have implied that FGF23 may be a consequence rather than a cause of myocardial disease [20]. Epidemiologically, the majority of cohort studies that suggested an independent role of plasma FGF23 to predict adverse cardiovascular outcome dates back several years [3][4][5]7], when our understanding of FGF23 regulation was less comprehensive.…”

FGF23 effects on the heart—levels, time, source, and context matter

“…To address the first of these 2 questions, Pastor-Arroyo and colleagues 8 analyzed the cardiac phenotype in a mouse model of X-linked hypophosphatemia (XLH). As the most common form of inherited rickets, XLH is caused by mutations in the phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX), which causes an increase in the production and secretion of intact FGF23 from bone, which in turn decreases renal phosphate reabsorption resulting in hypophosphatemia.…”

“…4,5 However, these mice also show hypertension and an approximately 20-fold elevation of serum FGF23 levels, which is different from Phex C733R mice that are normotensive and have FGF23 elevations of about 10-fold. 8 Surprisingly, a recent phenotypic analysis of the Hyp mouse model revealed the absence of cardiac hypertrophy. 11 However, because this study does not report serum FGF23 levels and mice were normotensive, it is difficult to compare its outcome with findings from previous studies.…”