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

主动脉顺应性和 Windkessel 减少对心脏和主动脉病理生理学的影响

• 批准号: 10477378
• 负责人: Anastasia S Desyatova
• 金额: $ 58.92万
• 依托单位: UNIVERSITY OF NEBRASKA OMAHA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477378
• 关键词: Abdomen; Age; Aging; Animals; Aorta; Beds; Biopsy; Blood; Blood Pressure; Blood flow; Caliber; Cardiac; Cardiomegaly; Catheters; Cell Survival; Characteristics; Chest; Clinical; Collagen; Coronary; Coronary artery; Coupling; Data; Descending aorta; Devices; Disease; Distal; Elasticity; Electrocardiogram; Endothelium; Evaluation; Family suidae; Fibrosis; Functional disorder; Gelatinase A; Gelatinase B; Generations; Heart; Human; Hypertrophy; Implant; In Vitro; Intervention; Lead; Left ventricular structure; Literature; Long-Term Effects; Measurement; Measures; Mechanics; Microscopic; Modeling; Organ; Outcome; Pathologic; Pathology; Patients; Performance; Permeability; Polyethylene Terephthalates; Polymers; Polytetrafluoroethylene; Pulsatile Flow; Relaxation; Reporting; Risk Factors; Stents; Stress; System; Systole; Testing; Thick; Thoracic aorta; Trauma patient; Ventricular; Work; age group; aortic valve; ascending aorta; base; coronary fibrosis; decubitus ulcer; elastomeric; experience; hemodynamics; implantation; in vivo; injured; mechanical properties; minimally invasive; mortality; nanofiber; nanofibrillar; older patient; porcine model; preservation; pressure; prevent; repaired

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.

项目概要 主动脉弹性产生 Windkessel 效应。也就是说，血液从左侧喷出后主动脉扩张 心脏收缩期间，心室 (LV) 收缩，主动脉瓣关闭后反冲。心室动脉的这一特点 耦合可以减弱峰值血压和血流波，提供缓冲作用，保护心脏免受 压力损伤。此外，Windkessel 效应有助于血液通过冠状动脉向远端移动， 心脏舒张时的外周。主动脉覆膜支架由硬质材料制成，可以人为地使主动脉变硬 并减弱 Windkessel 效应。这可能会使心脏过度劳累，最终导致病理变化。 虽然人们普遍认为坚硬的覆膜支架在主动脉中效果良好，但与之相关的微妙的长期影响 主要关注死亡率和局部情况的支架移植文献中可能没有报道支架移植的情况。 需要重新干预的并发症。我们团队的最新证据表明，植入僵硬的 年轻创伤患者的胸主动脉覆膜支架与左室质量和室壁显着增加相关 厚度，在猪中会导致主动脉硬化和早期左心室纤维化。最近报道了类似的结果 适用于接受胸主动脉和腹主动脉覆膜支架的老年患者。为了减轻这些影响并 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 具有类似主动脉的机械性能和微观结构，能够保持主动脉的弹性和 Windkessel 效应，并保持正常的压力波形，与刚性的传统覆膜支架不同 体外。此外，我们的纳米纤丝材料在体内保持其顺应性，经历快速 内皮化，并迅速融入动脉壁。我们建议检验以下假设： 使用新一代顺应性覆膜支架保持主动脉顺应性结果正常 血流动力学并预防心脏和主动脉病变。该假设将通过 3 步进行检验 具体目标。在目标 1 中，我们将制造具有可调节顺应性的纳米纤维弹性覆膜支架。在 目标 2 我们将量化覆膜支架顺应性对人类和猪主动脉 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体内的影响 猪模型中的血流动力学以及心脏和主动脉病理学。这将通过比较来完成 使用商业产品时主动脉顺应性和 Windkessel 减少对心脏和主动脉的影响 支架移植物与使用刚性且柔顺的纳米纤丝材料制成的装置的比较。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- 新一代覆膜支架，保护主动脉和心脏免受病理性重塑。虽然合规性是 在年轻的主动脉中最高，心脏较弱的老年患者可能对其改变最敏感。考虑到 硬性覆膜支架在所有年龄段的患者中普遍使用，更好的微创技术的临床重要性 主动脉装置的作用很难被高估。