Towards Personalized Prosthetic Graft Replacement for Genetically Triggered Thoracic Aortic Aneurysms

项目摘要/摘要 对于胸主动脉瘤(TAA)患者，用现有标准替换升主动脉 护理假体移植物(聚对苯二甲酸乙二醇酯)可消除移植物替换区域和 可以因此拯救生命。然而，越来越多的证据表明，近端的主动脉移植可以增加 下游解剖的风险，这也是危及生命的：风险最大的是遗传触发的患者 TAA，以较低的门槛、较高的频率和较年轻的年龄接受移植物替换-之后有风险 移植物置换区的夹层被排除，但远端并发症的可能性增加。最多两个 在遗传性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 超过一半的患有遗传性TAA的远端夹层是在移植物手术后发生的；近端的移植物与 与主动脉大小无关，夹层风险增加2倍。我们的临床观察是一致的 实验数据：在临床前和计算模型中，近端主动脉僵硬的急剧增加- 移植后的Ness会引起血流动力学改变，从而加剧远端僵硬。主动脉僵硬增加 对于遗传性TAA-也已知机械负荷力驱动不利的主动脉重构。这样就有了 迫切需要确定近端移植后主动脉疾病进展的标记物，重点是改变 血流动力学负荷与移植物特性(硬度、长度、封闭体积)的关系。我们的中心假设是- Esis是由于僵硬的假体移植物导致的近端主动脉顺应性的丧失导致不利的远端主动脉重建。 Eling(由增加的壁面和壁面切应力驱动)，并预测不良预后。我们还假设领养 移植物的顺应性是为补偿患者特定的主动脉僵硬而量身定做的，它将减弱- 反向主动脉远端重塑。这将在接受假体移植置换的遗传性TAA患者身上进行测试。 VIA的目标是测试移植物植入是否会产生渐进性增量 不良重塑(目标1A)，识别(固有的主动脉和移植物)特征，对不良重塑最负责- Eling(1B)，测试这些特征是否可以通过一种新的定制移植物类别进行修改(目标2)，并探索是否可以广泛使用 移植物诱导的重塑和固有的主动脉僵硬可预测临床事件(目标3)。 要做到这一点，心脏MRI将与流体结构相互作用和血管的计算模型相结合 重建-由切除的主动脉组织的材料特性测试和定制移植物的模拟提供信息 这种顺应性可以与患者特定的主动脉特征配对。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--以及往绩 卓有成效的协作。结果将对不良重塑的机制产生关键的基础性见解 和移植后的事件，改变当前移植的风险分层，并通过指导告知个性化治疗 一种新型定制移植物的设计和原型--旨在改善TAA患者的预后 他们从近端移植中受益，但仍有可能在残留的天然主动脉中发生严重的临床事件。

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.