GAGs: Function and Fixation in Bioprosthetic Heart Valves

GAG：生物人工心脏瓣膜的功能和固定

• 批准号: 7683027
• 负责人: Michael S Sacks
• 金额: $ 36.71万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683027
• 关键词: Address; Alcohol consumption; Animals; Applications Grants; Biological; Biomechanics; Bioprosthesis device; Calcinosis; Carbodiimides; Cardiac Surgery procedures; Cattle; Chemicals; Chemistry; Clinical; Collagen; Coronary; Coupled; Crosslinker; Deterioration; Devices; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Ethanol; Exhibits; Extracellular Matrix; Failure; Family suidae; Fatigue; Fixatives; Generations; Glutaral; Glycosaminoglycans; Grant; Heart Valves; Human; In Vitro; Intervention; Life; Life Expectancy; Light; Living Wills; Mediating; Modeling; Muscle Rigidity; Neomycin; Operative Surgical Procedures; Patients; Performance; Play; Predisposition; Procedures; Property; Rattus; Role; Sheep; Technology; Testing; Time; Tissue Fixation; Tissues; aortic valve; base; calcification; crosslink; heart valve replacement; implantable device; implantation; improved; in vitro testing; in vivo; inhibitor/antagonist; innovation; meetings; mitral valve replacement; novel; pericardial sac; prevent; public health relevance; sample fixation; success; tissue processing

DESCRIPTION (provided by applicant): Bioprosthetic heart valves (BHVs) derived from glutaraldehyde-crosslinked porcine aortic valves are used annually in thousands of heart valve replacement surgeries. These devices often fail clinically due degeneration and pathologic calcification. Understanding degenerative failure of BHVs in the absence of calcification is rarely addressed. In the previous grant period, we showed that valvular glycosaminoglycans (GAGs) are lost during tissue fixation and after implantation. GAG-degrading enzymes either present in the valve tissue or infiltrated after in vivo implantation are a major cause of GAG degeneration. Loss of GAGs from BHVs leads to decreased tissue flexural rigidity, loss of hysteresis, and collagen structural deterioration. Maintaining the structural integrity of the extracellular matrix (ECM) in the processed tissues is essential for a durable BHV. We found that chemical fixatives alone are only partially effective in preventing GAG loss from BHVs. Our recent results show that addition of neomycin, an inhibitor of GAG-degrading enzymes, in combination with chemical GAG fixation by carbodiimide crosslinking prior to routine glutaraldehyde (GLUT) crosslinking leads to significantly better stabilization of valvular GAGs. The overall aim of this project is extend the durability of BHVs well beyond 20 years. We are proposing to study BHV durability for up to 800 million cycles (25 years of valve functional life). Such long-term fatigue damage study is unprecedented in the BHV field. Thus, we will test the following hypotheses.1) BHVs with improved extracellular matrix stabilization and ethanol pretreatment to prevent calcification will resist degeneration in vitro during extended flexural fatigue and after in vivo implantation. Our novel neomycin-based crosslinking procedure will be combined with clinically used ethanol anti-calcification pretreatment. a) GAG stability will be tested in vitro during storage and cyclic fatigue up to 800 million cycles (more than 25 years of functional life) and b) in vivo in a rat subdermal-implantation model. 2) BHVs with improved extracellular matrix stabilization and ethanol pretreatment for preventing calcification will have improved biomechanical function and enhanced long-term durability. The role of native GAGs in preserving the biomechanical performance of GLUT-crosslinked porcine aortic valve cusps will be studied in two major deformation modes associated with valve function: planar biaxial tension and flexure in presence or absence of GAGs. b) Cuspal biomechanical function during in vitro cyclic fatigue up to 800 million cycles (25 years of functional life) will be studied. 3) BHVs with improved extracellular matrix stabilization and ethanol pretreatment for preventing calcification will be endowed with improved biological durability. Degeneration and calcification of BHVs with GAG-targeted chemistry/GLUT/Ethanol will be compared with clinically used ethanol pretreated GLUT-fixed BHVs in a sheep mitral valve-replacement model. PUBLIC HEALTH RELEVANCE: About 175,000 patients need heart valve replacements due to damaged or dysfunctional valves. Bioprosthetic heart valves derived from chemically fixed pig heart valves are used frequently for this purpose. The majority of these valves fail after 5-15 years due to degeneration and calcification and need replacements again. This grant proposal is investigating new chemical fixatives that would improve functional life-time of these valves so that the valve could outlast the patient.

描述（由申请人提供）：由戊二醛交联猪主动脉瓣衍生的生物假心脏瓣膜（bhv）每年用于数千例心脏瓣膜置换手术。由于退变和病理性钙化，这些装置在临床上常常失效。在没有钙化的情况下，对bhv退行性衰竭的理解很少得到解决。在之前的研究中，我们发现瓣膜糖胺聚糖（GAGs）在组织固定和植入后丢失。GAG降解酶要么存在于瓣膜组织中，要么在体内植入后浸润，是导致GAG变性的主要原因。bhv中GAGs的丢失导致组织屈曲刚度降低、迟滞丧失和胶原结构恶化。在加工组织中保持细胞外基质（ECM）的结构完整性对于持久的BHV至关重要。我们发现单独使用化学固定剂在防止bhv造成的GAG损失方面仅部分有效。我们最近的研究结果表明，在常规戊二醛（GLUT）交联之前，添加新霉素（一种GAG降解酶抑制剂）与碳二亚胺交联的化学GAG固定相结合，可以显著改善瓣膜性GAG的稳定性。该项目的总体目标是将bhv的使用寿命延长到20年以上。我们建议研究BHV长达8亿次循环（25年的阀门功能寿命）的耐久性。这种长期的疲劳损伤研究在BHV领域是前所未有的。因此，我们将检验以下假设。1)增强细胞外基质稳定性和乙醇预处理以防止钙化的bhv在体外抗拉伸弯曲疲劳和体内植入后的变性。我们的新型以新霉素为基础的交联方法将与临床使用的乙醇抗钙化预处理相结合。a)在体外储存和循环疲劳期间（超过25年的功能寿命）测试GAG的稳定性，b)在大鼠皮下植入模型中进行体内测试。2)增强细胞外基质稳定性和乙醇预处理以防止钙化的bhv将改善生物力学功能并增强长期耐久性。天然GAGs在维持glut交联猪主动脉瓣尖生物力学性能中的作用将在两种与瓣膜功能相关的主要变形模式下进行研究：存在或不存在GAGs时的平面双轴张力和弯曲。b)将研究8亿次（25年的功能寿命）体外循环疲劳过程中的尖端生物力学功能。3)增强细胞外基质稳定性和乙醇预处理以防止钙化的BHVs将被赋予更高的生物耐久性。在羊二尖瓣置换术模型中，将gag靶向化学/GLUT/乙醇与临床使用的乙醇预处理GLUT固定bhv进行比较。公共卫生相关性：约17.5万名患者因瓣膜受损或功能失调需要心脏瓣膜置换术。生物人工心脏瓣膜来源于化学固定的猪心脏瓣膜，经常用于此目的。大多数瓣膜在5-15年后因退变和钙化而失效，需要再次更换。这项拨款提案是研究新的化学固定剂，以提高这些瓣膜的功能寿命，使瓣膜比病人寿命更长。