PATHOGENESIS AND PREVENTION OF VALVE CALCIFICATION

瓣膜钙化的发病机制及预防

• 批准号: 3359689
• 负责人: HIROAKI HARASAKI
• 金额: $ 19.78万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3359689
• 关键词: aldehydes; calcification inhibitor; calcium channel; cell membrane; cow; diltiazem; dosage; electron probe spectrometry; erythrocytes; extracellular matrix; glutarates; laboratory rat; membrane permeability; phosphorus; platelets; prosthetic heart valve; tissue /cell culture

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.

营养不良性钙化是失败的最常见原因 生物瓣膜。 该并发症的发病机制不 已知且尚无有效且临床安全的预防措施 减轻或抑制钙化的措施。 其机制为 生物瓣膜钙化及其预防将是 本拟议研究的主题。一种特殊的钙进入阻滞剂， 地尔硫卓，建议在预防钙化方面进行试验 在小牛体内原位植入生物瓣膜。 来自我们的 大鼠模型中瓣膜组织植入的结果 据报道，地尔硫卓可有效预防钙化 动脉粥样硬化，我们假设 (1) 钙进入阻滞剂会发生反应 与死细胞以及活细胞的质膜成分 兴奋性细胞，以及（2）钙进入阻滞剂可预防营养不良 死者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 钙进入阻滞剂对钙和磷吸收的影响 降解细胞和细胞外基质蛋白的过程。 这 评估将严重依赖定量电子探针X射线 微量分析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 大鼠皮下植入阻断剂对瓣膜钙化的影响 获得剂量反应关系，并最终获得原位瓣膜 犊牛的替代品。 戊二醛的重要性 生物瓣膜钙化加速剂目前仍存在争议。 由于戊二醛处理和未处理的材料都用于 在这个程序中，戊二醛在钙化中的作用也将被 在体外和体内实验中进行了研究。 钙摄入量 尚未对阻滞剂用于预防假肢的目的进行研究 瓣膜钙化。 根据我们的初步研究结果，我们 预计钙进入阻滞剂也会抑制钙化 原位植入生物瓣膜。 如果这被证明是正确的，在防止钙化o 心血管植入物，钙进入阻滞剂将是药物 选择，可以长期安全给药，无需 显着的副作用。