Multiscale, Multiphysics Model of Thrombus Biomechanics in Aortic Dissection

描述（由申请人提供）：主动脉夹层是一种危及生命的事件;它是导致从儿童到年轻人和老年人的显著发病率和死亡率的原因。当夹层与真腔相通并在主动脉壁内形成所谓的假腔时，该假腔可能保持通畅或部分或完全形成血栓。越来越多的临床证据表明，完全血栓形成的假腔导致预后改善，而部分血栓形成的假腔可能使壁更容易进一步夹层或破裂。然而，迫切需要更好地理解假腔预期发展部分或完全血栓的机制和条件，以及为什么后者是有益的。我们假设血栓形成的程度主要取决于假腔内的血流动力学，部分血栓形成的夹层是危险的，因为与流动血液接触的壁内血栓持续释放纤溶酶可激活残余主动脉壁内组成性产生的潜伏性基质金属蛋白酶，从而削弱壁。我们将开发第一个数据驱动的、多尺度的、多物理场的主动脉夹层壁内血栓生物力学模型。具体而言，我们将扩展并耦合血流、血小板动力学、纤维蛋白组织和纤溶酶转运的多尺度模型（Karniadakis组）与主动脉壁力学和纤维蛋白/胶原重塑的多尺度模型（Humphrey组），该模型将通过最广泛接受的夹层主动脉瘤小鼠模型（即，在载脂蛋白缺失小鼠中输注血管紧张素II 28天）。此外，我们的模型将被设计为模拟两种抗凝剂在递送时间方面的潜在益处。我们三个具体目标的实现将显著增加我们对血栓在主动脉夹层中作用的理解，并有望最终改善预后能力和介入计划。此外，本研究中获得的见解将具有重要意义 用于许多其他血管疾病，包括其他动脉夹层、导管插入术后用凝血酶治疗假性动脉瘤以及腔内血栓在腹主动脉瘤和颅内动脉瘤中的不同作用。因此，我们认为，该项目具有重要的承诺，以增加我们的血管生物学的一个关键问题的基本理解，以及有助于更好地治疗广泛的一类临床问题。1

DESCRIPTION (provided by applicant): Aortic dissection is a life threatening event; it is responsible for significant morbidity and mortality in individuals ranging in age from children to young and older adults. When a dissection communicates with the true lumen and forms a so-called false lumen within the aortic wall, this false lumen may remain patent or become either partially or completely thrombosed. Increasing clinical evidence suggests that a completely thrombosed false lumen results in an improved prognosis whereas a partially thrombosed false lumen may render the wall more vulnerable to further dissection or rupture. Yet, there is a pressing need to understand better the mechanisms by which, and conditions under which, a false lumen is expected to develop either a partial or a full thrombus and why the latter is beneficial. We hypothesize that the extent of thrombus formation depends primarily on the hemodynamics within the false lumen and that partially thrombosed dissections are dangerous because the continued release of plasmin by an intramural thrombus in contact with flowing blood can activate constitutively produced, latent matrix metalloproteinases within the remnant aortic wall, which in turn weaken the wall. We will develop the first data-driven, multiscale, multiphysics model of the biomechanics of intramural throm- bus in aortic dissection. Specifically, we will extend and then couple a multiscale model of blood flow, platelet kinetics, fibrin organization, and plasmin transport (Karniadakis group) with a multiscale model of aortic wall mechanics and fibrin/collagen remodeling (Humphrey group) that will be informed and validated with extensive new imaging and immuno-histological data from the most widely accepted mouse model of dissecting aortic aneurysms (i.e., 28 day infusion of angiotensin II in the apolipoprotein null mouse). In addition, our model will be designed to simulate the potential benefits of two anti-coagulants in terms of the time(s) of delivery. Realization of our three Specific Aims will significantly increase our understanding of roles of thrombus in aortic dissection, with the promise of eventually leading to an improved prognostic capability and interventional planning. In addition, insight gained in this study will have important implications for a host of other vascular conditions, including dissections of other arteries, treatment of pseudo-aneurysms with thrombin following catheterization, and the different roles of intraluminal thrombus in abdominal aortic aneurysms and intracranial aneurysms. We submit, therefore, that this project has significant promise to increase our basic understanding of a key issue in vascular biology as well as to contribute to treating better a broad class of clinical problems. 1