The Pediatric Heart Valve Center, Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Biomaterials. 2022 Oct;289:121782. doi: 10.1016/j.biomaterials.2022.121782. Epub 2022 Sep 6.
Bioprosthetic heart valves (BHV) fabricated from heterograft tissue, such as glutaraldehyde pretreated bovine pericardium (BP), are the most frequently used heart valve replacements. BHV durability is limited by structural valve degeneration (SVD), mechanistically associated with calcification, advanced glycation end products (AGE), and serum protein infiltration. We investigated the hypothesis that anti-AGE agents, Aminoguanidine, Pyridoxamine [PYR], and N-Acetylcysteine could mitigate AGE-serum protein SVD mechanisms in vitro and in vivo, and that these agents could mitigate calcification or demonstrate anti-calcification interactions with BP pretreatment with ethanol. In vitro, each of these agents significantly inhibited AGE-serum protein infiltration in BP. However, in 28-day rat subdermal BP implants only orally administered PYR demonstrated significant inhibition of AGE and serum protein uptake. Furthermore, BP PYR preincubation of BP mitigated AGE-serum protein SVD mechanisms in vitro, and demonstrated mitigation of both AGE-serum protein uptake and reduced calcification in vivo in 28-day rat subdermal BP explants. Inhibition of BP calcification as well as inhibition of AGE-serum protein infiltration was observed in 28-day rat subdermal BP explants pretreated with ethanol followed by PYR preincubation. In conclusion, AGE-serum protein and calcification SVD pathophysiology are significantly mitigated by both PYR oral therapy and PYR and ethanol pretreatment of BP.
生物瓣（BHV）由异种移植物组织制成，例如戊二醛预处理的牛心包（BP），是最常使用的心脏瓣膜置换物。BHV 的耐久性受到结构瓣膜退化（SVD）的限制，其与钙化、晚期糖基化终产物（AGE）和血清蛋白渗透有关。我们假设抗 AGE 剂氨基胍、吡哆胺[PYR]和 N-乙酰半胱氨酸可以减轻体外和体内 AGE-血清蛋白 SVD 机制，并且这些试剂可以减轻钙化或与乙醇预处理 BP 表现出抗钙化相互作用。在体外，这些试剂中的每一种都显著抑制了 BP 中的 AGE-血清蛋白渗透。然而，在 28 天大鼠皮下 BP 植入物中，只有口服 PYR 显示出对 AGE 和血清蛋白摄取的显著抑制作用。此外，BP-PYR 预孵育可减轻 BP 中的 AGE-血清蛋白 SVD 机制，并在 28 天大鼠皮下 BP 外植体中减轻 AGE-血清蛋白摄取和减少钙化。在经乙醇预处理后再用 PYR 预孵育的 28 天大鼠皮下 BP 外植体中，观察到 BP 钙化的抑制以及 AGE-血清蛋白渗透的抑制。结论是，PYR 口服治疗和 PYR 及乙醇预处理 BP 均可显著减轻 AGE-血清蛋白和钙化 SVD 的病理生理学。
