Abstract 12877: Investigation of the Role of Fgf23 in the Pathogenesis of Post-Splenectomy Cardiovascular Dysfunction

Abstract

Introduction: Splenectomy is a relatively common surgical procedure in hematologic disorders, such as thalassemia, to improve anemia. However, splenectomy is clinically indicated as a strong risk factor for the development of post-splenectomy cardiovascular dysfunction. The underlying mechanisms have not been well established. We have found elevated levels of circulating FGF23 in thalassemia mice. As a hormone mainly expressed by osteocytes in bone, FGF23 has been shown to be an independent marker for cardiovascular risk in various patient populations. In this study we sought to investigate the role of FGF23 in the pathogenesis of post-splenectomy cardiovascular dysfunction. Methods: Splenectomy was performed in thalassemia ( Hbb th-3 ) mice at 4 weeks of age and cardiovascular functions were evaluated at 10 weeks post-splenectomy. Right ventricular maximum systolic pressure (RVSP) was measured using a closed chest right heart catheterization approach. Cardiac structure and functions were evaluated using echocardiography. Realtime RT-PCR and immunostaining were used to determine FGF23 expression in mouse tissues. Hepatocyte specific FGF23 KO thalassemia mice were generated by cross breeding albumin-Cre, Flox-Fgf23 and thalassemia mice. Results: Using a thalassemia mouse model ( Hbb th-3 ), we found that Hbb th-3 mice with surgical splenectomy developed significant cardiovascular dysfunction including biventricular cardiac hypertrophy, impaired diastolic function as well as pulmonary hypertension. We also found circulating levels of intact FGF23 were dramatically elevated in splenectomised Hbb th-3 mice, along with significantly upregulated FGF23 expression in liver and bone tissues. However, FGF23 levels in plasma were not normalized in hepatocyte specific FGF23 KO mice, suggesting bone-derived FGF23 is most likely the major source account for elevated FGF23 in circulation. Conclusions: Our findings suggest bone-derived FGF23 may contribute to the development of post-splenectomy cardiovascular dysfunction in thalassemia. The role of FGF23 in post-splenectomy pathogenesis will be further investigated using global FGF23 KO and osteocyte specific FGF23 KO mouse models.