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.

摘要/摘要 目前，心脏瓣膜疾病只能通过瓣膜置换或修复进行手术治疗。 生物假发瓣膜（BHV），由戊二醛固定异孕作用，例如牛心包 （BP）或猪主动脉瓣（PAV）广泛用于心脏手术和经导管瓣 替换。尽管出现了出色的短期结果，但由于结构瓣膜传单引起的BHV功能障碍 随着时间的推移，变性（SVD）开发，通常需要更换设备。观察到钙化 在大多数SVD案件中；但是，25％或更多的SVD病例与钙化无关。最近的 使用Penn Cardiac Valve BioreGertistry的申请人实验室的工作证明了BHV是 容易受到非估计诱导失败机制的影响，涉及形成独特的氧化氨基 BHV中的酸（OxaA），例如交叉链接，二苯胺（di-tyr）。可行性研究最近还记录了 BHV外植体样品存在晚期糖基化终产物（年龄）的存在。两个年龄的贡献 我们的小组或其他人以前尚未研究OXAA至SVD病理生理学。 假设：BHV传单中年龄的积累以及年龄（愤怒）介导的接收者 结构蛋白的炎症反应和OXAA修饰有助于BHV SVD。这些机制 还假设与BHV计算和合并症相互作用，例如糖尿病和冠状动脉 疾病以增强SVD。为了检验这些假设，我们将追求以下具体目标： 目标1：研究年龄在BHV功能障碍中的主要作用。工作假设 - 年龄/愤怒信号， 相关的炎症和年龄引起的交联有助于SVD病理生理学 Subaim 1A：这些调查将利用哥伦比亚 - u.penn-u.ottawa生物学家 表征年龄/愤怒机制对SVD临床病理生理学的影响。 Subaim 1b：使用体外模型系统研究愤怒/年龄形成和材料生物力学效应 AIM 2：研究年龄/愤怒机制和对BHV的单核细胞衍生巨噬细胞（MDM）的反应， 钙化和OXAA。工作假设 - 年龄/愤怒介导的机制都会影响OXAA和 SVD钙化。 Subaim 2A：年龄修饰的BHV小叶的体外MDM研究。这些研究还将调查影响 在MDM上：1）年龄形成的抑制剂，2）愤怒的拮抗剂和3）年龄段。 Subaim 2b：钙化，OXAA和年龄的体内模型研究。大鼠次级bhv也将 研究Subaim2a中使用的化合物，以了解其体内对年龄，OxaA和钙化的影响。 这些研究的长期目标是提供有关年龄和OXA形成作用的新颖见解 在BHV的SVD中。我们计划的机理进步将为研究提供关键方向 提高手术和经导管心脏瓣膜的BHV耐用性和结果。

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

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

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