The bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH) in experimental models and it is associated with LVH in patients with and without chronic kidney disease (CKD). FGF23 is further expressed by cardiac myocytes and recent studies demonstrate that its expression is increased in cardiac and kidney injury, suggesting that cardiotoxicity of FGF23 may be at least partly due to the paracrine effects of heart-derived FGF23. Whether elevated cardiac FGF23 per se causes LVH in otherwise healthy subjects or a further challenge such as high phosphate is required for FGF23 to tackle the heart is controversially discussed.
We generated a mouse model with cardiac myocyte specific overexpression of FGF23 via myocardial gene transfer using adeno-associated virus (AAV-Fgf23) in order to elucidate the cardiotoxic properties of elevated FGF23. Administration of AAV-Fgf23 in unchallenged C57BL/6 wildtype mice caused 5,500-fold increased cardiac-specific overexpression of Fgf23 and induced intact Fgf23 (iFgf23) protein synthesis. Although AAV-Fgf23 did not enhance Fgf23 synthesis in bone, plasma levels of iFgf23 increased by 3-fold in AAV-Fgf23 mice compared to Ctrl, suggesting a cardiac origin. To investigate bioactivity of enhanced cardiac Fgf23, cultured isolated neonatal rat ventricular myocytes (NRVM) were treated with 2% serum of AAV-Fgf23 (sAAV-Fgf23) or Ctrl (sCtrl) mice for 48 hours. sAAV-Fgf23 stimulated hypertrophic growth of NRVM and induced pro-hypertrophic NFAT target genes ANP and BNPcompared to sCtrl, suggesting that AAV-Fgf23 driven iFgf23 protein is biologically active and induces corresponding downstream signaling pathways.
Despite four months overexpression of biologically active cardiac Fgf23, AAV-Fgf23 mice showed no changes in LV mass, heart function or geometry as analyzed by echocardiography and cardiac magnetic resonance imaging. Cross-sections of cardiac mid-chamber and cardiac myocyte size revealed no hypertrophic cell growth in AAV-Fgf23 compared to Ctrl. On molecular level, no differences in BNP, bMHC, Rcan1 and Trpc6 expression were observed, all of which normally associated with FGF23-induced pathological cardiac hypertrophy, and picrosirius red staining revealed no LV fibrosis.

To test whether chronic oral phosphate loading promotes the cardiotoxic effects of FGF23, AAV-Fgf23 and Ctrl mice were fed with a 2% high phosphate diet (HPD) or 0.8% normal phosphate control diet (NPD) for six months. The heart weight to tibia length ratio was unaffected in Ctrl, but increased in AAV-Fgf23 on HPD compared to Ctrl on HPD. Echocardiography showed impaired cardiac function in AAV-Fgf23 on HPD, while no significantly changes were detected in Ctrl on HPD. ESV and EDV were increased in AAV-Fgf23 on HPD compared to its NPD group and Ctrl on HPD. Systolic and diastolic LV diameters as well as respective LV inner diameters were enlarged in AAV-Fgf23 on HPD compared to NPD and Ctrl on HPD. Pressure-volume analysis using Millar catheter showed higher end-systolic and end-diastolic blood pressure in AAV-Fgf23 mice on HPD compared to NPD.
In conclusion, the combination of enhanced intra-cardiac synthesis of iFgf23 and chronic oral phosphate loading synergistically promotes cardiotoxicity of Fgf23 resulting in hypertension and LV dilation. In view of the increased dietary intake of phosphate in the Western world, this can pose a significant health problem for the general population.