Hyperphosphatemia is Required for Initiation, but Not Propagation, of Uraemia-Induced Calcific Aortic Valve Disease - The 65th Annual Conference of the Israel Heart Society & The Israel Society of Cardiothoracic Surgery, 24-25 April 2018

Suzan Abedat Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Mony Shuvy Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Ran Eliaz Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Israa Abu-Rmeileh Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Asmahan Asmahan Abu-Snieneh Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Iddo Z. Ben-Dov Department of Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Karen Meir Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel David Pereg Department of Cardiology, Meir Medical Center, Jerusalem, Israel Ronen Beeri Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Chaim Lotan Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Aims: High serum levels of phosphate are associated with uraemia-induced calcific aortic valve disease. However, it is not clear whether hyperphosphataemia is required in all phases of the process. Our aim was to determine the effects of phosphate and phosphate depletion at different phases of valve disease.

Methods and results: The experimental design consisted of administering a uraemia-inducing diet, with or without phosphate enrichment, to rats for 7 weeks. Forty-two Sprague-Dawley rats were fed with a phosphate-enriched uraemic regimen that caused renal insufficiency and hyperphosphataemia. Another 42 rats were fed with a phosphate-depleted uraemic regimen, which induces similar severity of renal insufficiency, but without its related mineral disorder. Aortic valves were evaluated at several points during the course of CAVD. In the second part of the study, 54 rats were fed a phosphate-enriched diet for various time periods and then were switched to a phosphate-depleted diet to complete 7 weeks of uraemic diet. Aortic valves were examined by histology, Western blot, and immunofluorescence.

Osteoblast transformation. inflammation and eventually valve calcification were observed only in rats that were fed with a phosphate-enriched regimen. Diet switch from a phosphate-enriched to a phosphate-depleted regimen resulted in gradual normalisation of serum phosphate and parathyroid hormone levels. Significant valve calcification was observed only in rats that were fed a phosphate-enriched diet for at least 4 weeks. Osteoblast markers as well as macrophages, did not appear earlier than 3 weeks into the consumption of the phosphate-enriched diet. Valve calcification was observed only when the switch to a phosphate-depleted regimen occurred after osteoblast markers had already been found in the valve.

Conclusions: Phosphate is essential for the initiation of the calcification process, which includes macrophage accumulation and osteoblast phenotype. However, when osteoblast markers are already expressed in valve tissue, phosphate depletion will not halt the disease.