Role of Animal Models in Transcatheter Valve Intervention: A Mechanistic, Age-dep

描述（由申请人提供）：微创经导管主动脉瓣（TAV）介入治疗有望用于大量高风险患者（高龄和/或合并症），否则这些患者的治疗选择可能有限或没有治疗选择。虽然通过动物和人体临床试验获得了重要的经验，但动物试验和人体试验的结果之间往往存在差异。在本提案中，我们假设：1）动物和人体瓣膜组织之间的机械性能和解剖结构存在显著差异，2）TAV植入物和宿主主动脉组织之间的生物力学相互作用在动物中与人体中显著不同。如果上述假设被验证为真，将对经导管瓣膜介入动物试验的有效性提出质疑。 如果其中任何一个假设被证明是错误的，该研究可以提供关于解释动物和人体试验结果之间差异的见解，以促进器械开发和临床试验。在初步研究中，我们发现6-9月龄猪和~90岁人主动脉组织之间存在显著的机械性能差异。为了进一步检验假设1是否适用于猪、羊和人的其他年龄组，在本研究中，将研究1岁和2岁猪、6-9个月、1岁和2岁羊以及60岁和75岁人的主动脉组织。 为了验证这两个假设，我们提出了以下具体目标：1）研究不同年龄组动物和老年人主动脉根部之间的力学性能差异; 2）研究动物和老年人主动脉根部之间的解剖结构差异; 3）研究TAV在动物和老年人主动脉根部中展开的反应。 项目里程碑是：1）建立不同年龄组的猪、绵羊和人主动脉根部的机械性能和解剖结构数据库（知识库），2）阐明动物试验在TAV介入中的作用，3）最后，有足够的数据证明TAV-主动脉根部相互作用与血栓栓塞和血流动力学效应的R 01研究。 公共卫生相关性：主动脉瓣狭窄影响许多老年人，其患病率随着人口老龄化而增加。 目前正在研究经导管主动脉瓣（TAV）置换术作为一种替代血管内微创治疗选择。本研究涉及动物（猪和羊）模型在经导管主动脉瓣临床试验中的适用性研究。将量化动物主动脉组织特性的血管依赖性。将利用计算建模来阐明TAV器械在不同年龄组的动物和人体主动脉根部展开时的不同交互反应。

DESCRIPTION (provided by applicant): Minimally invasive transcatheter aortic valve (TAV) intervention holds promise for a large number of high- risk patients (advanced age and/or with co-morbidities) who might otherwise have limited or no treatment options. Although significant experience has been gained through animal and human clinical trials, disparity between the results of animal trials and those of human trials often exists. In this proposal, we hypothesize that 1) significant differences in the mechanical properties and the anatomic structure exist between animal and human valve tissues, and 2) the biomechanical interaction between a TAV implant and the hosting aortic tissue is significantly different in an animal than in a human. If the above hypotheses are tested to be true, it will raise questions on the validity of animal trials in transcatheter valve intervention. If either of the hypotheses is tested to be false, the study can provide insight on interpreting differences between animal and human trial results to facilitate device development and clinical trials. In a preliminary study, we have found that significant differences in mechanical properties exist between 6-9 months porcine and ~90 year old human aortic tissues. To further test if the hypothesis 1 is valid for other age groups of pig, sheep and human, in this study, aortic tissues of 1- and 2-year old pigs, 6-9 months, 1- and 2-year old sheep, and 60- and 75-year old humans will be studied. To test both of hypotheses, specifically, we propose the following specific aims: 1) Investigation of mechanical property difference between animal and aged human aortic roots at different age groups; 2) Investigation of anatomic structural difference between animal and aged human aortic roots; 3) Investigation of responses of TAV deployment into animal and aged human aortic roots. Project milestones are to: 1) establish databases (knowledge-bases) of mechanical properties and anatomic structures of porcine, ovine and human aortic roots from different age groups, 2) clarify the role of animal trials in TAV intervention and 3) at the conclusion, have sufficient data to warrant a R01 study of TAV-aortic root interaction with thromboembolic and flow dynamic effects. PUBLIC HEALTH RELEVANC: Aortic stenosis affects many individuals of the elderly population, and its prevalence is increasing with an aging population. Transcatheter aortic valve (TAV) replacement is now being investigated as an alternative endovascular, minimally invasive treatment option. This study is related to the investigation of applicability of animal (porcine and ovine) models in transcatheter aortic valve clinical trials. Age-dependency of animal aortic tissue properties will be quantified. Computational modeling will be utilized to elucidate different interactive responses when a TAV device is deployed into animal and human aortic roots of various age groups.