Effects of aortic compliance and Windkessel reduction on cardiac and aortic pathophysiology

项目摘要 主动脉弹性产生了Windkessel效应。也就是说，左心房在血液从左心房排出后扩张 心室（LV）在收缩期，然后回缩后主动脉瓣关闭。心室动脉的这一特征 耦合减弱峰值血压和流量波，提供缓冲效果， 压力伤。此外，Windkessel效应有助于血液通过冠状动脉向远端移动， 在心脏舒张期间的外周。主动脉支架移植物是由人工包裹主动脉的坚硬材料制成的 减弱温凯塞尔效应这可能会使心脏过度工作，最终导致病理变化。 虽然刚性支架移植物通常被认为在主动脉中工作良好，但与之相关的微妙的长期影响 在主要关注死亡率和局部出血的覆膜支架文献中， 需要再次干预的并发症。我们团队最近的证据表明， 年轻创伤患者的胸主动脉覆膜支架与左室质量和室壁厚度显著增加相关 在猪中导致主动脉硬化和早期LV纤维化。最近报告了类似的结果 胸主动脉和腹主动脉覆膜支架老年患者。为了减轻这些影响， 为了保持主动脉顺应性，我们的团队开发了一种新的弹性纳米纤维主动脉覆膜支架， 具有类主动脉的机械性能和微观结构，能够保持主动脉弹性， Windkessel效应，并保持正常的压力波形，而不是僵硬的传统覆膜支架， 体外此外，在体内，我们的纳米原纤材料保持其顺应性，经历快速降解。 内皮化，并迅速融入动脉壁。我们建议检验这个假设， 使用新一代顺应性覆膜支架保持主动脉顺应性， 血液动力学和预防心脏和主动脉病变。这一假设将通过3 具体目标。在目标1中，我们将制造具有可调顺应性的纳米纤维弹性覆膜支架。在 目的2：我们将量化覆膜支架顺应性对人类和猪动脉粥样硬化Windkessel功能的影响 使用离体流动模型。最后，在目标3中，我们将评估覆膜支架顺应性对 血液动力学和心脏和主动脉病理学。这将通过比较 当使用商用时，主动脉顺应性和Windkessel减少对心脏和主动脉的影响 支架移植物与使用刚性和顺应性纳米纤维材料制成的装置。该项目将量化 刚性覆膜支架对主动脉顺应性和心脏病理生理学的影响，并将提出一种新的- 新一代支架移植物，保护主动脉和心脏免受病理性重塑。虽然合规是 最高的在年轻的心脏病患者中，心脏较弱的老年患者可能对它的改变最敏感。考虑 刚性覆膜支架在所有年龄段患者中的普遍使用，更好的微创治疗的临床重要性， 主动脉器械的价值难以高估。

PROJECT SUMMARY Aortic elasticity creates a Windkessel effect. That is, aortas distend following ejection of blood from the left ventricle (LV) during systole, and then recoil after aortic valve closure. This feature of ventricular-arterial coupling blunts peak blood pressure and flow waves providing a cushioning effect that protects the heart from pressure injury. In addition, the Windkessel effect helps move blood distally through the coronary arteries and periphery during cardiac relaxation. Aortic stent-grafts are made of stiff materials that artificially stiffen the aorta and diminish the Windkessel effect. This may overwork the heart, eventually leading to pathological changes. While stiff stent-grafts are generally thought to work well in the aorta, the subtle long-term effects associated with stent-grafting may not be reported in the stent-graft literature that focuses primarily on mortality and local complications requiring re-intervention. Recent evidence from our team demonstrates that implantation of stiff thoracic aortic stent-grafts in young trauma patients is associated with significantly increased LV mass and wall thickness, and in pigs results in aortic stiffening and early LV fibrosis. Similar outcomes were recently reported in elderly patients with thoracic and abdominal aortic stent-grafts. In order to mitigate these effects and preserve aortic compliance, our team has developed a new elastomeric nanofibrillar aortic stent-graft that possesses aorta-like mechanical properties and microstructure, and is able to preserve aortic elasticity and the Windkessel effect, and maintain normal pressure waveforms as opposed to stiff conventional stent-grafts in vitro. Furthermore, in vivo our nanofibrillar material maintains its compliance, undergoes rapid endothelialization, and gets quickly incorporated into the arterial wall. We propose to test the hypothesis that preservation of aortic compliance with a new-generation compliant stent-graft results in normal hemodynamics and prevents cardiac and aortic pathologies. This hypothesis will be tested through 3 Specific Aims. In Aim 1 we will manufacture nanofibrillar elastomeric stent-grafts with tunable compliance. In Aim 2 we will quantify the effect of stent-graft compliance on Windkessel function in human and porcine aortas using an ex vivo flow model. Finally, in Aim 3 we will assess the in vivo effects of stent-graft compliance on hemodynamics and cardiac and aortic pathologies in a swine model. This will be done by comparing the effects of aortic compliance and Windkessel reduction on the heart and the aorta when using commercial stent-grafts versus devices made using stiff and compliant nanofibrillar materials. This project will quantify the effects of stiff stent-grafts on aortic compliance and cardiac pathophysiology, and will propose a new- generation stent-graft that protects the aorta and the heart from pathologic remodeling. While compliance is highest in young aortas, older patients with weaker hearts may be most sensitive to its alteration. Considering the ubiquitous use of stiff stent-grafts in patients of all ages, the clinical importance of better minimally-invasive aortic devices is difficult to overestimate.