Effects of Intermittent Heparin Administration on Cardiac Tissue in Uremic Rats

Background: CKD-MBD plays a key role in CKD-associated myocardial hypertrophy (MH). Hyperphosphatemia, hyperparathyroidism and elevated fibroblast growth factor 23 (FGF23) are associated with MH in preclinical and clinical studies. Recently, it was shown that heparin mediates the binding of FGF23 to its receptor FGFR4, promoting MH in a adenine model of CKD in mice. However, this has never been tested in other experimental models or species. In this study, we tested whether intermittent unfractioned heparin (UFHep) or low molecular heparin (LMWHep) administration induces MH in rats submitted to 5/6 nephrectomy (Nx). Methods: Male Wistar rats (n=50) were submitted to 5/6 Nx, or were sham operated. After a recovery period of one week, we divided the groups as follows, according to the administration: Sham (saline 0.9%), Nx (saline 0.9%), Nx+UFHep (125UI/Kg of UFHep) and Nx+LMWHep (1mg/Kg of LMWHep; enoxaparin). All groups received a standard rodent chow. Infusions were given subcutaneously, 3 times/ week. Tail cuff pressure and weight were measured weekly. After 2 months, serum and 24 hour-urine were collected, and myocardial histology was analyzed Results: Initial and final body weight did not differ among the groups. Initial tail cuff pressure values were similar among all groups. However, all Nx rats developed hypertension, with no differences among them. Uremia and albuminuria were found in Nx animals (Table). Although no differences were found in serum calcium or phosphate among the groups, Nx rats had higher PTH. Also, Nx and Nx+UFHep rats had slightly higher FGF 23 levels than Sham animals. MH and cardiac fibrosis were found in all Nx groups, with no differences among them. Higher FGFR1 expression was seen in Nx+UFHep and Nx+LMWHep. However, no differences were seen in FGFR4 or TGFBeta expression. Conclusion: Our data suggests that heparin is not able to worse MH in the absence of severe hyperparathyroidism or highly elevated FGF23. Whether this finding could be translated to clinical practice deserves future investigation. Funding: Government Support – Non-U.S.