Computational Modeling and Accelerated Aging of the Ascending Aorta

升主动脉的计算模型和加速老化

• 批准号: 8695346
• 负责人: Jay D. Humphrey
• 金额: $ 7.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-08 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695346
• 关键词: Accounting; Aging; Aging-Related Process; Aneurysm; Aorta; Area; Arteries; Biomechanics; Blood Pressure; Blood flow; Cardiac; Cardiovascular system; Cell Lineage; Central Artery; Cessation of life; Child; Code; Collagen; Complement; Complex; Computer Simulation; Coupled; Custom; Data; Development; Disease; Dissection; Elastic Fiber; Elements; Equilibrium; Excision; Extracellular Matrix; FBN1; Feasibility Studies; Fibrillar Collagen; Genes; Genetic; Geometry; Glycosaminoglycans; Goals; Growth Factor Receptors; Health; Heart; Homeostasis; Human; In Vitro; Kidney Diseases; Knockout Mice; Lead; Left Ventricular Function; Length; Measurement; Measures; Mechanics; Modeling; Muscle function; Mutation; Myocardial Infarction; Neural Crest; Normalcy; Operative Surgical Procedures; Physiologic pulse; Pilot Projects; Plant Roots; Production; Property; Proteoglycan; Pulse Pressure; Reporting; Research; Research Methodology; Residual state; Resource Sharing; Risk; Risk Factors; Signal Pathway; Smooth Muscle; Smooth Muscle Myocytes; Stress; Stroke; Structure; Swelling; Syndrome; Technology; Testing; Thick; Thoracic Aortic Aneurysm; Thoracic aorta; Time; Torsion; Transforming Growth Factors; Ultrasonography; Variant; Ventricular Function; age related; alpha Actin; arterial stiffness; ascending aorta; base; beta-Myosin; cerebrovascular; design; disability; experience; fibulin; hemodynamics; heritable connective tissue disorder; improved; insight; kidney vascular structure; next generation; novel; open source; pressure; public health relevance; research and development; validation studies; young adult

DESCRIPTION (provided by applicant): The ascending aorta experiences unique multiaxial loading during each cardiac cycle: finite distension due to changes in blood pressure plus finite extension, torsion, and bending due to the direct action of the beating heart. We hypothesize that this unique, cyclic multiaxial loading coupled with the unique underlying micro- structure and cell lineage of the ascending aorta accelerates a mechano-aging process that manifests as the recently reported earliest reductions in distensibility and wall strain and the earliest and mot dramatic increases in length of any segment of the human aorta. We hypothesize further that heritable connective tissue disorders that commonly lead to aneurysms of, and dissections in, the aortic root or ascending aorta also tend to manifest first in this region of the aorta because they accelerate this mechano-aging process. A singularly important histopathological feature of this aging process is an increased accumulation, and at times pooling, of glycosaminoglycans, the mechanical implications of which have never been studied. The two goals of this R03 application are: (1) Build a next generation computational (finite element) mixture model of the ascending aorta that embodies the unique biomechanics: multiaxial loading, regionally varying residual stresses and nonlinear material properties that off-set regional variations in geometry to give rise to mechanical homeostasis in normalcy, and pre-mature alterations in elastic fibers, smooth muscle, fibrillar collagens, and most importantly glycosaminoglycans (via a Donnan swelling pressure); and (2) Inform and validate the finite element model using data from wild-type and fibulin 5 null mice. Data will include microCT information on the overall geometry, ultrasound information on local blood flow, nonlinear material properties measured using custom in vitro biaxial testing, residual stress related measurements of opening angles, and histo-morphological measures of regional wall thicknesses and composition. This proposal is submitted under the R03 mechanism for it focuses primarily on the "development of research methodology" (i.e., a nonlinear constrained mixture constitutive relation for the ascending aorta that accounts for the first time for progressive losses of elastic fiber integrity, pooling of GAGs PGs, and remodeling of collagen that results in accelerated aging), the "development of new research technology" (i.e., the first open source finite element model capable of modeling the unique evolving histo-mechanics of the ascending aorta), and "pilot or feasibility studies" (i.e., initial validation studies using fibulin 5 null mice, which show accelerated aging). We submit that development of the proposed, next generation computational model of the ascending aorta will enable much more realistic studies by ourselves and (via resource sharing) others to elucidate underlying biomechanical causes of thoracic aortic aneurysms and dissections, diminished left ventricular function due to stiffening of the aorta, and deleterious systemic hemodynamics as well as an improved design of surgical procedures or grafts.

描述（由申请人提供）：升主动脉在每个心动周期经历独特的多轴负荷：由于血压变化而有限的扩张加上由于心脏跳动的直接作用而有限的伸展、扭转和弯曲。我们假设，这种独特的、循环的多轴载荷，加上升主动脉独特的潜在微观结构和细胞谱系，加速了机械老化过程，表现为最近报道的最早的扩张性和壁应变的减少，以及最早的、最不显著的人类主动脉任何部分长度的增加。我们进一步假设，通常导致主动脉根部或升主动脉动脉瘤和夹层的遗传性结缔组织疾病也倾向于首先在主动脉的这一区域表现出来，因为它们加速了这种机械老化过程。这个衰老过程的一个特别重要的组织病理学特征是糖胺聚糖的积累增加，有时是池化，其机械意义从未被研究过。这个R03应用程序的两个目标是：(1)建立一个新一代的升主动脉计算（有限元）混合模型，该模型体现了独特的生物力学：多轴载荷、区域变化的残余应力和非线性材料特性，抵消了几何形状的区域变化