Oxidation-mediated structural degeneration of bioprosthetic heart valves

生物假体心脏瓣膜氧化介导的结构退化

• 批准号: 10202704
• 负责人: Giovanni Ferrari
• 金额: $ 76.58万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202704
• 关键词: Address; Advanced Glycosylation End Products; Affect; Amino Acids; Biological Models; Biomechanics; Bioprosthesis device; Cardiac Surgery procedures; Cattle; Cells; Chemistry; Clinical; Coronary Arteriosclerosis; Data; Devices; Diabetes Mellitus; Epitopes; Failure; Family suidae; Feasibility Studies; Functional disorder; Glutaral; Glyoxal; Goals; Heart Valve Diseases; Heart Valves; Immunohistochemistry; Implant; In Vitro; Incubated; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Laboratories; Ligands; Mass Spectrum Analysis; Mediating; Methodology; Microscopic; Modeling; Modification; N(6)-carboxymethyllysine; Operative Surgical Procedures; Outcome; Oxides; Paraffin; Production; Proteins; Rattus; Research; Rest; Role; Sampling; Sampling Studies; Signal Transduction; Stains; Structural Protein; Structure; Study models; Testing; Time; Tyrosine; Work; Xenograft procedure; aortic valve; bone; calcification; clinically relevant; comorbidity; crosslink; experimental study; glycation; heart valve replacement; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; insight; macrophage; mechanical properties; monocyte; novel; oxidation; pericardial sac; programs; receptor for advanced glycation endproducts; repaired; response; subcutaneous; valve replacement

Summary/Abstract Heart valve disease at this time can only be treated surgically, with either valve replacement or repair. Bioprosthetic heart valves (BHV), fabricated from glutaraldehyde fixed heterografts, such as bovine pericardium (BP) or porcine aortic valves (PAV), are widely used in both cardiac surgery and in transcatheter valve replacements. Despite outstanding short term outcomes, BHV dysfunction due to structural valve leaflet degeneration (SVD) develops over time, frequently necessitating device replacement. Calcification is observed in the majority of SVD cases; however, 25% or more SVD cases are not associated with calcification. Recent work from the applicants’ laboratories utilizing the Penn Cardiac Valve Bioregistry demonstrated that BHV are susceptible to non-calcification induced failure mechanisms, involving the formation of unique oxidized amino acids (OxAA) in BHV, such as the crosslink, di-tyrosine (di-Tyr). Feasibility studies also recently documented in BHV explant samples the presence of advanced glycation end products (AGE). The contributions of both AGE and OxAA to SVD pathophysiology has not been previously investigated by our group or others. Hypotheses: The accumulation of AGE in BHV leaflets together with the receptor for AGE (RAGE) mediated inflammatory response, and OxAA modification of structural proteins contribute to BHV SVD. These mechanisms also are hypothesized to interact with BHV calcification and co-morbidities, such as diabetes and coronary artery disease to enhance SVD. To test these hypotheses, we will pursue the following specific aims: Aim 1: To investigate the primary role of AGE in BHV dysfunction. Working hypothesis—AGE/RAGE signaling, related inflammation and AGE-induced crosslinking contribute to SVD pathophysiology Subaim 1a: These investigations will utilize the Columbia-U.Penn-U.Ottawa Bioregistry to completely characterize the impact of AGE/RAGE mechanisms on the clinical pathophysiology of SVD. Subaim 1b: To study RAGE/AGE formation and material-biomechanical effects using in vitro model systems Aim 2: Investigate AGE/RAGE mechanisms and the monocyte derived macrophage (MDM) response to BHV, calcification and OxAA. Working hypothesis—AGE/RAGE mediated mechanisms affect both OxAA and calcification in SVD. Subaim 2a: In vitro MDM studies of AGE modified BHV leaflets. These studies will also investigate the effects on MDM of: 1) an inhibitor of AGE formation, 2) a RAGE antagonist, and 3) an AGE breaker. Subaim 2b: In vivo model studies of calcification, OxAA and AGE. Rat subdermal BHV implants will also investigate the compounds used in Subaim2a for their effects in vivo on AGE, OxAA and calcification. The long term objective of these studies is to provide novel insights about the role of AGE and OxAA formation in SVD of BHV. The mechanistic advances from our program will provide critical directions for research to improve BHV durability and outcomes in surgical and transcatheter heart valve replacement.

总结/摘要 心脏瓣膜疾病在这个时候只能通过手术治疗，无论是瓣膜置换或修复。 生物人工心脏瓣膜（BHV），由戊二醛固定的异种移植物制成，如牛心包 (BP)或猪主动脉瓣（PAV），广泛用于心脏手术和经导管瓣膜 替代品尽管短期结局突出，但由于结构性瓣叶导致的BHV功能障碍 退行性变（SVD）随着时间的推移而发展，经常需要更换设备。观察到钙化 在大多数SVD病例中;然而，25%或更多的SVD病例与钙化无关。最近 申请人实验室利用Penn心脏瓣膜生物注册中心的工作证明，BHV 易受非钙化诱导的失效机制影响，包括形成独特的氧化氨基 BHV中的酸（OxAA），如交联、二酪氨酸（di-Tyr）。可行性研究最近也记录在 BHV外植体样本存在晚期糖基化终产物（AGE）。两个年龄段的贡献 OxAA与SVD的病理生理学关系尚未被我们的小组或其他人研究过。 假设：AGE在BHV小叶中的积累与AGE受体（AGE）介导的 炎症反应和结构蛋白的OxAA修饰有助于BHV SVD。这些机制 也被假设与BHV钙化和合并症（如糖尿病和冠状动脉）相互作用 疾病，以提高SVD。为了检验这些假设，我们将追求以下具体目标： 目的1：探讨晚期糖基化终产物（AGE）在BHV功能障碍中的作用。工作假设-AGE/AGEs信号， 相关炎症和AGE诱导的交联有助于SVD的病理生理学 Subaim 1a：这些研究将利用哥伦比亚-U.Penn-U.渥太华生物登记处， 描述AGE/VEGF机制对SVD临床病理生理学的影响。 Subaim 1b：使用体外模型系统研究骨/AGE形成和材料生物力学效应 目的2：探讨AGE/BHV的作用机制及BHV诱导的单核细胞源性巨噬细胞（MDM）反应， 钙化和OxAA。工作假设-AGE/AGEs介导的机制影响OxAA和 SVD钙化。 Subaim 2a：AGE修饰的BHV瓣叶的体外MDM研究。这些研究还将调查 1）AGE形成抑制剂，2）AGE拮抗剂，和3）AGE破坏剂。 Subaim 2b：钙化、OxAA和AGE的体内模型研究。大鼠皮下BHV植入物也将 研究Subaim 2a中使用的化合物在体内对AGE、OxAA和钙化的影响。 这些研究的长期目标是提供关于AGE和OxAA形成的作用的新见解 BHV的SVD。从我们的计划的机械进步将提供关键的研究方向， 改善外科和经导管心脏瓣膜置换术中BHV耐久性和结局。

项目成果

A novel in vivo assessment of fluid dynamics on aortic valve leaflet using epi-aortic echocardiogram.

• DOI: 10.1111/echo.14596
• 发表时间: 2020-02
• 期刊: Echocardiography (Mount Kisco, N.Y.)
• 作者: Hayashi H;Akiyama K;Itatani K;DeRoo S;Sanchez J;Ferrari G;Colombo PC;Takeda K;Wu IY;Kainuma A;Takayama H
• 通讯作者: Takayama H

Model studies of advanced glycation end product modification of heterograft biomaterials: The effects of in vitro glucose, glyoxal, and serum albumin on collagen structure and mechanical properties.

• DOI: 10.1016/j.actbio.2020.12.053
• 发表时间: 2021-03-15
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Rock CA;Keeney S;Zakharchenko A;Takano H;Spiegel DA;Krieger AM;Ferrari G;Levy RJ
• 通讯作者: Levy RJ

Poly-2-methyl-2-oxazoline-modified bioprosthetic heart valve leaflets have enhanced biocompatibility and resist structural degeneration.

• DOI: 10.1073/pnas.2120694119
• 发表时间: 2022-02-08
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Zakharchenko A;Xue Y;Keeney S;Rock CA;Alferiev IS;Stachelek SJ;Takano H;Thomas T;Nagaswami C;Krieger AM;Chorny M;Ferrari G;Levy RJ
• 通讯作者: Levy RJ

Inhibition of advanced glycation end product formation and serum protein infiltration in bioprosthetic heart valve leaflets: Investigations of anti-glycation agents and anticalcification interactions with ethanol pretreatment.

• DOI: 10.1016/j.biomaterials.2022.121782
• 发表时间: 2022-10
• 期刊: Biomaterials
• 影响因子: 14