Gender Specific Evolution of Abdominal Aortic Aneurysm Composition and Properties

腹主动脉瘤成分和性质的性别特异性演变

• 批准号: 8244123
• 负责人: Jay D. Humphrey
• 金额: $ 19.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244123
• 关键词: 3-Dimensional; Abdomen; Abdominal Aortic Aneurysm; Address; Aneurysm; Angiotensin II; Animal Model; Animals; Aorta; Aortic Aneurysm; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Award; Biomechanics; Blood Vessels; Caliber; Cell Proliferation; Cessation of life; Clinical; Code; Complex; Computer Simulation; Computing Methodologies; Custom; Data; Development; Dilatation - action; Elements; Evolution; Excision; Exploratory/Developmental Grant; Extracellular Matrix; Female; Future; Gender; Goals; Growth; Human; Image; Infusion procedures; Intervention; Lesion; Liquid substance; Literature; Location; Longitudinal Studies; Matrix Metalloproteinases; Measures; Mechanics; Medical Imaging; Methods; Metric; Modeling; Morbidity - disease rate; Mus; Optics; Patients; Phenotype; Production; Property; Relative (related person); Research; Rupture; Ruptured Abdominal Aortic Aneurysm; Ruptured Aneurysm; Shapes; Solid; Stress; Structure; System; Time; Variant; Work; aging population; base; digital imaging; experience; hemodynamics; male; mathematical model; men; mortality; mouse model; novel; novel strategies; regional difference; simulation

DESCRIPTION (provided by applicant): Aortic aneurysms are focal dilatations of the arterial wall that are increasingly responsible for significant mortality and morbidity. Although maximum diameter has long been the primary clinical metric for assessing rupture-potential, recent studies demonstrate that wall stress is a far better predictor. This finding is intuitive because aneurysms rupture when wall stress exceeds wall strength. Fortunately, advances in medical imaging and computational biomechanics provide a special opportunity to estimate, on a patient-specific basis, both the hemodynamic loads experienced by an aneurysm and the associated wall stresses that exist within the lesion. Nevertheless, all prior calculations of wall stresses in aortic aneurysms are limited by the assumption of material homogeneity, that is, the assumption that material properties are the same throughout a lesion. It is known, however, that the underlying wall structure is not homogeneous and that the scant data available show regional variations in properties. Indeed, our recent computational simulations of aneurysmal enlargement suggest that composition / properties must vary regionally to enable mechanobiologically driven remodeling. Our recent advances in developing a novel theoretical framework for modeling evolving human aneurysms have revealed two important gaps in the literature that can only be filled using animal models. First, there is a pressing need to measure directly the changing regional mechanical properties of aneurysms as they evolve. Second, there is a need to infer directly from longitudinal data appropriate functional forms for the mass production (e.g., extracellular matrix synthesis and cellular proliferation) and removal (e.g., MMP degradation of matrix and apoptosis), two of the three fundamental classes of constitutive relations needed in models of lesion enlargement and rupture-potential. In this work, we will quantify, for the first time, evolving regional differences in wall composition and cellular phenotype in both dilating (ascending) and dissecting (abdominal) aneurysms from a well accepted angiotensin-II infusion model in ApoE-/- mice over 4 weeks of lesion development; we will also combine in a novel way a 3-D digital image correlation based method and a custom nonlinear sub-domain inverse finite element method to quantify regionally the associated evolving mechanical properties. Finally, we recently showed for the first time that atherosclerotic lesions from ApoE-/- mice differ in stiffness between males and females. Thus, we will delineate, for the first time, potential differences in aortic and aneurysmal wall properties in males and females as well as possible gender-related differences in rates of lesion evolution. This proposal is submitted under the R21 mechanism because we propose to develop a truly novel method for characterizing multiaxial material properties regionally in complex shaped aneurysms, a method that could revolutionize the way vascular experimentation will be done in the future. PUBLIC HEALTH RELEVANCE: Aortic aneurysms are localized dilatations of the aortic wall that are increasingly responsible for death in our aging population. Advances in medical imaging and computer modeling now allow patient-specific calculations that promise to better predict rupture-potential and thereby to better guide clinical intervention. Yet, two main gaps remain in our understanding: how the strength of these aneurysms varies from one region to another and how this strength changes as the aneurysm enlarges. We will develop a new combined optical - computational method that will allow the evolution of these regional differences in strength to be quantified for the very first time. Toward that end, we will use a well accepted mouse model of evolving aneurysms.

描述（由申请人提供）：主动脉瘤是动脉壁的局灶性扩张，日益导致显着的死亡率和发病率。尽管最大直径长期以来一直是评估破裂可能性的主要临床指标，但最近的研究表明，壁应力是一个更好的预测指标。这一发现很直观，因为当壁应力超过壁强度时，动脉瘤就会破裂。幸运的是，医学成像和计算生物力学的进步提供了一个特殊的机会，可以根据患者具体情况估计动脉瘤所经历的血流动力学负荷以及病变内存在的相关壁应力。然而，所有先前对主动脉瘤壁应力的计算都受到材料同质性假设的限制，即材料特性在整个病变中相同的假设。然而，众所周知，下面的墙体结构并不均匀，并且可用的数据很少显示属性的区域差异。事实上，我们最近对动脉瘤扩大的计算模拟表明，成分/特性必须因区域而异，以实现机械生物学驱动的重塑。我们最近在开发一种新的理论框架来模拟不断演变的人类动脉瘤方面取得了进展，揭示了文献中的两个重要空白，而这些空白只能使用动物模型来填补。首先，迫切需要直接测量动脉瘤演变过程中区域力学特性的变化。其次，需要直接从纵向数据推断出用于大规模生产（例如，细胞外基质合成和细胞增殖）和去除（例如，MMP 基质降解和细胞凋亡）的适当功能形式，这是组成性的三个基本类别中的两个。病变扩大和破裂潜力模型中所需的关系。在这项工作中，我们将首次量化 ApoE-/- 小鼠中广泛接受的血管紧张素-II 输注模型中扩张（升行）和解剖（腹部）动脉瘤的壁成分和细胞表型的区域差异。病变发展4周；我们还将以一种新颖的方式结合基于 3D 数字图像相关的方法和定制的非线性子域逆有限元方法来量化区域相关的不断变化的机械性能。最后，我们最近首次表明 ApoE-/- 小鼠的动脉粥样硬化病变在雄性和雌性之间的硬度不同。因此，我们将首次描述男性和女性主动脉和动脉瘤壁特性的潜在差异，以及病变演变速率中可能存在的性别相关差异。该提案是在 R21 机制下提交的，因为我们建议开发一种真正新颖的方法来表征复杂形状动脉瘤的局部多轴材料特性，这种方法可能会彻底改变未来血管实验的方式。 公共健康相关性：主动脉瘤是主动脉壁的局部扩张，在老龄化人口中日益成为死亡的原因。医学成像和计算机建模的进步现在允许针对患者进行特定计算，从而有望更好地预测破裂可能性，从而更好地指导临床干预。然而，我们的理解仍然存在两个主要差距：这些动脉瘤的强度如何从一个区域到另一个区域变化，以及随着动脉瘤的扩大，这种强度如何变化。我们将开发一种新的组合光学计算方法，该方法将首次量化这些区域强度差异的演变。为此，我们将使用一种广为接受的进化动脉瘤小鼠模型。