PATHOGENESIS AND PREVENTION OF VALVE CALCIFICATION

营养不良的钙化是导致失禁的最常见原因 生物假体瓣膜。这种并发症的发病机制并不是 清楚地知道并且没有有效和临床安全的预防措施 减轻或抑制钙化的措施。它的作用机制 生物瓣膜钙化及其预防将成为 这项拟议研究的主题。一种特殊的钙离子进入阻滞剂， 地尔硫卓，被建议在预防钙化方面进行试验 小牛原位植入生物瓣膜。从我们的 在大鼠模型上植入瓣膜组织的结果 地尔硫卓预防儿童牙周炎钙化的疗效观察 动脉粥样硬化，我们假设(1)钙通道阻滞剂反应 与死亡细胞的质膜成分以及活细胞 兴奋性细胞，以及(2)钙内流阻滞剂防止营养不良 死亡动物质膜成分中发生的钙化 细胞及其亚细胞成分。 本项目的具体目标是：(1)体外研究 钙通道阻滞剂对钙磷吸收的影响 通过降解的细胞和细胞外基质蛋白进行加工。这个 评估将在很大程度上依赖于定量电子探针X射线 微量分析以阐明营养不良的这些关键步骤 钙化；(2)研究钙离子进入的体内效应 阻滞剂对大鼠心脏瓣膜钙化的影响 获得剂量-反应关系，并在最终的原位瓣膜 小牛的替补。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都用于 本程序中，戊二醛在钙化中的作用也将被 在体外和体内实验中都进行了研究。钙离子进入 阻滞剂还没有被用于预防假体的研究 瓣膜钙化。从我们的初步研究结果来看，我们 预期钙离子进入阻滞剂也会抑制钙化 原位植入的生物瓣膜。 如果这被证明是真的，在预防钙化方面 心血管植入物，钙通道阻滞剂将是 选择，可以长期安全地服用，而不需要 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.