Meng Zhen, Li Zhe, Zhang Erli, Zhang Li, Liu Qingrong, Wu Yongjian
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Analytical Instrumentation Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Front Cardiovasc Med. 2021 Sep 29;8:740038. doi: 10.3389/fcvm.2021.740038. eCollection 2021.
Sevelamer hydrochloride is a phosphate binder used to treat hyperphosphatemia in chronic kidney disease (CKD) patients that can reduce valvular and vascular calcification. The aim of this study was to examine the effects of sevelamer treatment on calcification in bioprosthetic heart valves (BHVs). Wister rats were randomly divided into three groups according to sevelamer intake and implantation (sham-sham operation; implant-implantation and normal diet, implant+S implantation, and sevelamer diet). Two kinds of BHVs-bovine pericardium treated with glutaraldehyde (GLUT) or non-GLUT techniques-were implanted in rat dorsal subcutis at 4 weeks. After implantation, sevelamer was administered to the implant+S group. The animals were executed at days 0 (immediately after implantation), 7, 14, 28, and 56. Calcium levels were determined by atomic absorption spectroscopy and von Kossa staining. Serum biochemistry analysis, Western blotting, real-time quantitative polymerase chain reaction, alkaline phosphatase activity measurement, histopathologic analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were conducted to identify the anti-calcification mechanism of sevelamer. Non-GLUT crosslinking attenuates BHV calcification. Serum phosphate and calcium remained unreactive to sevelamer after a 14-day treatment. However, the mean calcium level in the implant+S group was significantly decreased after 56 days. In addition, the PTH level, inflammatory cell infiltration, system and local inflammation, and expression of Bmp2, Runx2, Alp, IL-1β, IL-6, and TNF-α were significantly reduced in the implant+S group. Sevelamer treatment significantly attenuated the calcification of BHVs and had anti-inflammation effects that were independent from serum calcium and phosphate regulation. Thus, sevelamer treatment might be helpful to improve the longevity of BHVs.
盐酸司维拉姆是一种用于治疗慢性肾脏病（CKD）患者高磷血症的磷结合剂，可减少瓣膜和血管钙化。本研究的目的是检验司维拉姆治疗对生物人工心脏瓣膜（BHV）钙化的影响。将Wistar大鼠根据司维拉姆摄入和植入情况随机分为三组（假手术组；植入组 - 植入且正常饮食，植入 + S组 - 植入并给予司维拉姆饮食）。4周时，将两种BHV（经戊二醛（GLUT）处理或非GLUT技术处理的牛心包）植入大鼠背部皮下。植入后，对植入 + S组给予司维拉姆。在第0天（植入后立即）、第7天、第14天、第28天和第56天处死动物。通过原子吸收光谱法和冯科萨染色测定钙水平。进行血清生化分析、蛋白质印迹法、实时定量聚合酶链反应、碱性磷酸酶活性测定、组织病理学分析、免疫组织化学和酶联免疫吸附测定以确定司维拉姆的抗钙化机制。非GLUT交联可减轻BHV钙化。14天治疗后，血清磷酸盐和钙对司维拉姆无反应。然而，56天后植入 + S组的平均钙水平显著降低。此外，植入 + S组的甲状旁腺激素水平、炎性细胞浸润、全身和局部炎症以及骨形态发生蛋白2（Bmp2）、Runx2、碱性磷酸酶（Alp）、白细胞介素 - 1β（IL - 1β）、白细胞介素 - 6（IL - 6）和肿瘤坏死因子 - α（TNF - α）的表达均显著降低。司维拉姆治疗可显著减轻BHV钙化，并具有独立于血清钙和磷酸盐调节的抗炎作用。因此，司维拉姆治疗可能有助于提高BHV的使用寿命。
