Aortic Wall Distensibility in the Growth and Rupture of Abdominal Aortic Aneurysm

描述(由申请人提供)：腹主动脉瘤(AAA)破裂是美国第13大主要死亡原因。虽然预防性手术修复是一种有效的治疗方法，但与该过程相关的死亡风险也很大。由于大多数动脉瘤不会破裂，在许多情况下，这些手术风险可能会超过修复的好处。然而，目前还没有方法准确地识别将破裂的动脉瘤，以有效地评估破裂与修复的相对风险。这项研究计划的总体目标是通过建立敏感的、非侵入性的动脉瘤破裂标志物来改善对AAA患者的临床护理，这些标志物可以用来更好地识别哪些患者应该接受手术修复。由医学成像确定的动脉瘤大小是目前最常用的评估AAA破裂风险的方法。然而，磁共振成像(MRI)的最新进展允许对主动脉力学进行更复杂、更高分辨率的评估，这是众所周知的更敏感的评估。例如，用收缩压脉冲来量化主动脉大小和形状的动态变化可以用来评估主动脉壁的扩张性。这些图像还可以用来创建动脉瘤的计算机模型，以计算壁应力较高的区域。由于AAA破裂发生在动脉瘤应力超过机械强度时，我们假设对这些机械和结构特性的非侵入性量化将导致更好的破裂预测。评估我们假设的第一步是在动物疾病模型中证明这一基于成像的范例的概念证据。AAA应用最广泛的模型是ApoE-/-/Angitensin-II小鼠模型，该模型是我所在过去15年中开发和广泛研究的。这种专业知识，再加上我们在小鼠和人类身上的心血管成像能力，使我们有资格成功开展这项研究。为了开发机械破裂标记，我们提出了一种双管齐下的方法。我们首先试图将MRI测量的宏观力学与细胞和酶的微观功能联系起来，例如基质金属蛋白酶(MMPs)，这是动脉瘤生长和重塑的重要决定性因素。在小鼠AAA中对这些机械测量的系列评估将与破裂结果相关，以评估它们的预测价值。这项建议的长期目标是将这些敏感的成像标记物转化为人体研究，以改善临床决策。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) rupture is the 13th leading cause of death in the US. While prophylactic surgical repair is an effective treatment, there is significant mortality risks associated with the procedure. Since most aneurysms do not rupture, these surgical risks may outweigh the benefits of repair in many cases. However, there are currently no means to accurately identify an aneurysm that will rupture to effectively evaluate the relative risk of rupture versus repair. The big-picture goal of this research program is to improve clinical care for patients with AAA by establishing sensitive, non-invasive markers for aneurysm rupture that can be used to better identify patients who should undergo surgical repair. Aneurysm size, as determined by medical imaging, is currently the most common method used to evaluate AAA rupture risk. However, recent advances in magnetic resonance imaging (MRI) allow for more sophisticated, high resolution assessments of aortic mechanics, which are known to be more sensitive. For example, quantifying the dynamic changes in aortic size and shape with systolic pressure pulses can be used to assess the distensibility of the aortic wall. These images can also be used to create computer models of the aneurysm to calculate areas of high wall stress. Since AAA rupture occurs when aneurysm stress exceeds mechanical strength, we hypothesize that non-invasive quantification of these mechanical and structural properties will lead to better rupture predictions. The first step in evaluating our hypothesis is to demonstrate proof of concept for this imaging-based paradigm in an animal disease model. The most widely used model of AAA is the ApoE-/-/angiotensin-II mouse model, which was developed and has been extensively studied our institution over the past 15 years. This expertise, coupled with our cardiovascular imaging abilities in both mice and humans, uniquely qualifies us to successfully carry out this research. To develop mechanical rupture markers, we propose a two-pronged approach. We first seek to relate the macroscopic mechanics measured via MRI to the microscopic function of cells and enzymes, such a matrix metalloproteinases (MMPs), which are important deterministic factors in aneurysm grown and remodeling. Serial assessment of these mechanical measures in mouse AAA will then be related to rupture outcomes to evaluate their predictive value. The long-term objective of this proposal is to take these sensitive imaging markers and translate them to human studies to improve clinical decision-making.