Abstract 13752: Prolonged Exposure to Elevated FGF23 Does Not Cause Left Ventricular Hypertrophy in Aged Mice

Introduction:Elevated levels of FGF23 are associated with an increased risk of left ventricular hypertrophy (LVH) in chronic kidney disease and studies have reported that FGF23 directly induces LVH by a mechanism that involves FGF23 binding to FGFR4 in the heart. However, two recently published studies have challenged these findings using mouse models of X-linked hypophosphatemia, a disorder characterized by excess circulating FGF23; both studies found no evidence of LVH or altered cardiac function. Nevertheless, these studies only examined mice up to 30 weeks of age and only in the context of hypophosphatemia, so any effects developing after 30 weeks or requiring normal to high serum phosphate levels would have been missed.Methods and Results:To examine the effects of prolonged exposure to increased FGF23 on the heart, we studied mice with Fgfr1and Fgfr4conditionally deleted in the kidney (KCFgfr1-/-/Fgfr4-/-mice) by Pax3-Cre (expressed in the metanephric mesenchyme and neural crest cells) at 18-20 months of age along with age-matched controls (WT mice). Importantly, Fgfr1and Fgfr4are not deleted from the heart. Serum FGF23 and phosphate levels were significantly increased in KCFgfr1-/-/Fgfr4-/-compared to WT mice (FGF23: 9371 ? 1291 vs 400 ? 34 for males (M), 5050 ? 765 vs 339 ? 27 for females (F), pg/mL, p<0.05 for both; phosphate: 10.4 ? 0.4 vs 9.0 ? 0.3 for M, 9.1 ? 0.3 vs 7.5 ? 0.2 for F, mg/dL, p<0.05 for both), while serum calcium and urea were not significantly different (calcium: 9.1 ? 0.1 vs 9.0 ? 0.1 for M & F, mg/dL; urea: 49.5 ? 2.7 vs 49.0 ? 3.0 for M & F, mg/dL). Ejection fraction (by MRI) was essentially unchanged between the two groups (59.2 ? 3.2 vs 58.2 ? 2.8 for M, 67.9 ? 2.3 vs 66.0 ? 0.6 for F, %) and heart weight/tibial length (a measure of LVH) was also not significantly different (9.8 ? 0.9 vs 10.9 ? 0.7 for M, 6.7 ? 0.2 vs 7.3 ? 0.3 for F, mg/mm). Additionally, cardiac gene expression of Anp, Bnp, and ?-Mhc, markers of pathological hypertrophy, were not increased in the KCFgfr1-/-/Fgfr4-/-mice, indicating a lack of cardiac remodeling. All values are expressed as mean ? SEM. N = 6-9 for M, 9-14 for F.Conclusion:Prolonged exposure to elevated levels of FGF23 in mice with modestly elevated serum phosphate does not induce LVH or cause alterations in ejection fraction.