PATHOGENESIS AND PREVENTION OF VALVE CALCIFICATION

营养不良性钙化是最常见的原因， 生物瓣膜 这种并发症的发病机制不是 明确已知，没有有效和临床安全的预防措施 缓解或抑制钙化的措施。 的机理 生物瓣膜的钙化及其预防将是 本研究的主题。一种特殊的钙离子进入阻滞剂， 地尔硫卓拟用于预防钙化， 原位植入小牛的生物瓣膜。 从我们 大鼠模型中瓣膜组织移植的结果， 报告了地尔硫卓在预防钙化方面的有效性， 动脉粥样硬化，我们假设（1）钙离子进入阻滞剂反应 死细胞和活细胞的质膜成分 兴奋性细胞，和（2）钙进入阻滞剂防止营养不良 钙化发生在死亡的质膜成分中， 细胞及其亚细胞成分。 本课题的具体目的是：（1）在体外研究 钙通道阻滞剂对钙磷吸收的影响 降解细胞和细胞外基质蛋白的过程。 的 评价将严重依赖于定量电子探针X射线 微分析来阐明营养不良的这些关键步骤， 钙化;（2）研究钙进入的体内效应 阻断剂对瓣膜钙化的抑制作用， 获得剂量-反应关系，并在最终的原位瓣膜中 替换小牛。 戊二醛作为一种 加速剂在生物瓣膜钙化中的作用仍存在争议。 由于戊二醛处理和未处理的材料均用于 本方案中，戊二醛在钙化中的作用也将 在体外和体内实验中研究。 钙进入 阻断剂尚未被研究用于预防假体 瓣膜钙化 根据初步研究结果， 预期钙进入阻滞剂也将抑制钙化 原位植入的生物瓣膜。 如果这一点被证实是正确的，那么在预防钙化方面， 心血管植入物，钙进入阻滞剂将是药物， 选择，可以长期安全地使用， 严重的副作用。

Dystrophic calcification is the most common cause of failure to bioprosthestic valves. The pathogenesis of this complication is not clearly known and there are no effective and clinically safe preventive measures to mitigate or inhibit calcification. The mechanism of calcification of bioprosthetic valves and its prevention will be the subject of this proposed study. One particular calcium entry blocker, Diltiazem, is proposed to be tested in prevention of calcification in orthotopically implanted bioprosthetic valves in calves. From our results with valve tissue implantations in a rat model together with reported effectiveness of Diltiazem in prevention of calcification in atherosclerosis, we hypothesize that (1) a calcium entry blocker reacts with the plasma membrane components of dead cells as well as viable excitatory cells, and (2) a calcium entry blocker prevents dystrophic calcification which occurs in the plasma membrane components of dead cells and their subcellular components. The specific aims of this project are: (1) to investigate in vitro the effects of a calcium entry blocker on the calcium and phosphorus uptake process by degraded cells and extracellular matrix proteins. The evaluation will rely heavily on quantitative electron probe X-ray microanalysis to elucidate these crucial steps in dystrophic calcification; (2) To investigate in vivo effects of a calcium entry blocker on valve calcification using rat subcutaneous implantation to obtain a dose-response relationship, and in eventual orthotopic valve replacement in calves. The importance of glutaraldehyde as an accelerator in bioprosthetic valve calcification is still controversial. Since both glutaraldehyde-treated and non-treated materials are used in this program, a role of glutaraldehyde in calcification will also be investigated in both in vitro and in vivo experiments. Calcium entry blockers have not been investigated for prevention purposes of prosthetic valve calcification. From the results of our preliminary studies we anticipate that a calcium entry blocker will also suppress calcification of orthotopically implanted bioprosthetic valves. If this is proved to be true, in preventing calcification o cardiovascular implants, calcium entry blockers would be the drug of choice, which can be administered safely for a long term without significant side effects.