Towards Personalized Prosthetic Graft Replacement for Genetically Triggered Thoracic Aortic Aneurysms

针对基因触发的胸主动脉瘤的个性化假体移植

基本信息

批准号：
10753115
负责人：
Mario FL Gaudino
金额：
$ 75.02万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753115
关键词：
4D MRI Address Adoption Age Aneurysm Aorta Aortic Diseases Attenuated Biomechanics Blood Blood Vessels Cessation of life Characteristics Clinical Collaborations Compensation Computer Models Computer Simulation Data Data Analyses Development Diffuse Disease Progression Dissection Distal Elasticity Electric Capacitance Event Four-dimensional Frequencies Future Genetic Geometry Goals Image Intervention Length Life Link Liquid substance Marfan Syndrome Mechanical Stress Medical Operative Surgical Procedures Organ failure Patients Persons Phase Physiology Polyethylene Terephthalates Postoperative Period Pre-Clinical Model Productivity Prognosis Property Prospective cohort Prosthesis Registries Reporting Research Resected Residual state Risk Shapes Structure Technology Testing Thinness Thoracic Aortic Aneurysm Tissues United States Vascular remodeling ascending aorta attenuation biomarker identification cardiac magnetic resonance imaging clinical application clinical predictors clinical prognosis dacron design follow-up heart imaging hemodynamics implantation improved outcome insight mechanical load member millimeter personalized medicine prognostic prototype response risk stratification shear stress simulation standard of care stem

项目摘要

PROJECT SUMMARY / ABSTRACT For patients with thoracic aortic aneurysms (TAA), replacement of the ascending aorta with a current standard of care prosthetic graft (polyethylene terephthalate) eliminates risk for dissection in graft-replaced regions and can thus be lifesaving. Nevertheless, accumulating evidence reveals that proximal aortic grafting can increase risk for downstream dissection, which is also life-threatening: Risk is greatest in patients with genetically triggered TAA, who undergo graft replacement at lower thresholds, higher frequency, and younger age - after which risk for dissection in graft-replaced regions is eliminated but possibility of distal complications increases. Up to two thirds of dissections in genetic TAA patients occur in the distal (arch or descending) aorta. We have also shown that over half of distal dissections with genetic TAA occur after graft surgery; proximal grafting has been linked to a >2-fold increase in risk for dissection independent of aortic size. Our clinical observations are consistent with experimental data: In pre-clinical and computational models, the dramatic increase in proximal aortic stiff- ness with grafting induces hemodynamic changes that exacerbate distal stiffening. Aortic stiffness is increased with genetic TAA - it is also known that mechanical loading forces drive adverse aortic remodeling. There is thus a critical need to identify markers of distal aortic disease progression after proximal grafting, with focus on altered hemodynamic loading in relation to graft characteristics (stiffness, length, enclosed volume). Our central hypoth- esis is that loss of proximal aortic compliance due to stiff prosthetic grafts induces adverse distal aortic remod- eling (driven by increased wall and wall shear stress) and predicts adverse prognosis. We also posit that adoption of grafts, for which compliance is tailored to compensate for patient-specific aortic stiffness, will attenuate ad- verse distal aortic remodeling. This will be tested in genetic TAA patients undergoing prosthetic graft replace- ment, via Aims integrated towards the goal of testing if graft implantation produces progressive increments in adverse remodeling (Aim 1A), identifying (native aortic and graft) features most responsible for adverse remod- eling (1B), testing if these features are modifiable via a new class of tailored grafts (Aim 2), and exploring if widely generalizable surrogates of graft-induced remodeling and native aortic stiffness predict clinical events (Aim 3). To do so, cardiac MRI will be integrated with computational modeling of fluid structure interactions and vascular remodeling - informed by material property testing of resected aortic tissue and simulations of tailored grafts for which compliance can be paired to patient-specific aortic features. Our team provides complementary expertise in cardiac imaging, aortic surgery, genetic TAA, computational modeling, and graft design - and a track record of productive collaboration. Results will yield key foundational insights as to mechanisms of adverse remodeling and events after grafting, transform risk stratification for current grafts and inform personalized therapy by guiding design and prototyping of a new class of tailored grafts - towards the goal of improved outcomes for TAA patients who benefit from proximal grafting but remain at risk for serious clinical events in the residual native aorta.

项目概要/摘要对于胸主动脉瘤（TAA）患者，用现行标准更换升主动脉护理假体移植物（聚对苯二甲酸乙二醇酯）消除了移植物替换区域的解剖风险，因此可以挽救生命。然而，越来越多的证据表明，近端主动脉移植可以增加下游解剖的风险，这也危及生命：遗传触发的患者风险最大 TAA，以较低阈值、较高频率和较年轻年龄接受移植物置换 - 此后风险消除了移植物替换区域的解剖，但远端并发症的可能性增加。最多两个遗传性 TAA 患者中三分之一的夹层发生在远端（弓形或降主动脉）。我们还展示了超过一半的遗传性 TAA 远端夹层发生在移植手术后；近端移植已连接无论主动脉大小如何，夹层风险都会增加 2 倍以上。我们的临床观察结果是一致的实验数据：在临床前和计算模型中，近端主动脉僵硬度急剧增加移植引起的血流动力学变化会加剧远端僵硬。主动脉僵硬度增加遗传性TAA——众所周知，机械负荷力会导致不良的主动脉重塑。因此有迫切需要确定近端移植后远端主动脉疾病进展的标志物，重点关注改变的与移植物特性（硬度、长度、封闭体积）相关的血流动力学负荷。我们的中心假设—— esis 是由于僵硬的假体移植物导致近端主动脉顺应性丧失，导致远端主动脉重塑不良。 eling（由壁和壁剪切应力增加驱动）并预测不良预后。我们还假设采用移植物的顺应性是为了补偿患者特定的主动脉僵硬度而定制的，将减弱ad- 相反远端主动脉重塑。这将在接受假体移植置换的基因 TAA 患者中进行测试 ment，通过目标集成到测试移植物植入是否产生渐进增量的目标不良重塑（目标 1A），识别（天然主动脉和移植物）对不良重塑最有影响的特征 eling (1B)，测试这些特征是否可以通过一类新的定制移植物进行修改（目标 2），并探索是否可以广泛使用移植物诱导的重塑和天然主动脉僵硬度的通用替代指标可预测临床事件（目标 3）。为此，心脏 MRI 将与流体结构相互作用和血管的计算模型相结合重塑 - 通过切除主动脉组织的材料特性测试和定制移植物的模拟来提供信息其顺应性可以与患者特定的主动脉特征相匹配。我们的团队提供互补的专业知识在心脏成像、主动脉手术、遗传 TAA、计算建模和移植物设计方面拥有丰富的经验，并拥有良好的业绩记录富有成效的协作。结果将产生关于不良重塑机制的关键基础见解和移植后的事件，改变当前移植物的风险分层，并通过指导为个性化治疗提供信息新型定制移植物的设计和原型制作 - 旨在改善 TAA 患者的治疗效果他们受益于近端移植，但仍然面临残余主动脉发生严重临床事件的风险。