ELASTIN CAMAGE: MECHANISM OF BIOPROSTHETIC VALUE FAILURE

描述（改编自申请人摘要）：每年有70，000名患者， 美国要求心脏直视手术来修复或替换病变的心脏， 心脏瓣膜许多外科医生考虑组织型人工心脏瓣膜，或 生物瓣膜，是理想的人工瓣膜，因为它们在 短期和OD不需要长期抗凝。可惜这些 阀门磨损后约10-12年，使他们不适合那些 年龄小于65岁。许多研究小组的目标是了解 生物瓣膜退化，提高瓣膜耐久性。阀 人工瓣膜尖端的钙化和破裂导致失效。 这些失效模式现在被认为是两种不同形式的退化， 每个都有不同的机制。我们的研究已经解决了机械 退化，并专注于了解结构/功能 主动脉瓣尖组织的关系。通过这项研究，我们 确定弹性蛋白，而组成只有百分之十的尖端由干 重量在瓣尖力学中是关键的。我们已经通过实验证明， 弹性蛋白的损伤导致胶原纤维波纹的损失， 瓣尖和弹性降低。这些特点是典型的 在植入的生物瓣膜中观察到的形态和机械变化。 我们认为，弹性蛋白的损伤引起这些变化，并最终导致 瓣尖疲劳失效。为此事提供确凿证据 阀门失效的机制，我们建议进行以下研究： 假设：观察到的机械和形态学变化， 可以通过破坏猪主动脉瓣的弹性蛋白来模拟异种移植物 通过在弹性蛋白酶中的受控孵育。 具体目的：我们将证明（i）弹性蛋白的渐进性损伤 导致海绵体塌陷、纤维组织伸长和减少 在瓣膜尖端的径向可伸展性方面，（ii）移植的异种移植瓣膜 具有降低的延展性，类似于具有实验性的瓣膜 受损的弹性蛋白，（iii）破裂的异种移植瓣膜有弹性蛋白的证据 损伤，和（iv）弹性蛋白变性的外植体增加与 植入时间。通过这些拟议的研究，我们的目标是将 弹性蛋白变性导致外植体机械失效，并证实 这是生物瓣膜退化的关键机制。一旦这个 机制被证明，化学稳定弹性蛋白的适当步骤 可以探索。

DESCRIPTION (Adapted from Applicant's Abstract): Each year 70,000 patients in the United States require open heart surgery to repair or replace a diseased cardiac valve. Many surgeons consider tissue-based artificial heart valves, or bioprostheses, to be the ideal prosthetic valve since they perform well in the short term and od not require chronic anticoagulation. Unfortunately, these valves wear out after about 10-12 years, making them inappropriate for those younger than 65. Many groups have aimed to understand the mechanism of bioprosthetic valve degeneration and improve the valves durability. Valve failure results from calcification and rupture of the prosthetic valve cusps. These modes of failure are now considered two separate forms of degeneration, each with a different mechanism. Our studies have addressed mechanical degeneration, and have focused on understanding the structure/function relationship of aortic valve cusp tissues. Through this research, we have determined that elastin, while composing only 10 percent of the cusp by dry weight, is critical in valve cusp mechanics. We have shown experimentally that damage to elastin leads to a loss of collagen fiber waviness, extension of the valve cusps and reduction in elasticity. These features are typical of the morphologic and mechanical changes observed in explanted bioprosthetic valves. We propose that damage to elastin induces these changes and ultimately leads to fatigue failure of the valve cusps. To provide confirming evidence for this mechanism of valve failure, we propose to carry out the following studies: Hypothesis: The mechanical and morphologic changes observed in explanted xenografts can be simulated by damaging the elastin of porcine aortic valves through controlled incubation in elastase. Specific Aims: We will demonstrate that (i) progressive damage to elastin results in collapse of the spongiosa, elongation of the fibrosa and reduction in the radial extensibility of the valve cusps, (ii) explanted xenograft valves have a reduced extensibility, similar to that of valves with experimentally damaged elastin, (iii) explanted xenograft valves have evidence of elastin damage, and (iv) elastin degeneration in the explants increased with the duration of implantation. Through these proposed studies, we aim to link the degeneration of elastin to the mechanical failure of the explants and confirm this as a key mechanism of bioprosthetic valve degeneration. Once this mechanism is demonstrated, appropriate steps for chemically stabilizing elastin can be explored.