AORTA, BRAIN AND KIDNEY STRUCTURE AND FUNCTION IN THE AGES-REYKJAVIK STUDY

主动脉、大脑和肾脏的各个时代的结构和功能-雷克雅未克研究

• 批准号: 7736223
• 负责人: Gary Frank Mitchell
• 金额: $ 63.61万
• 依托单位: CARDIOVASCULAR ENGINEERING, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736223
• 关键词: 7 year old; Abdomen; Accounting; Adverse effects; Age; Age-Years; Aging; Albuminuria; Anatomy; Aorta; Arteries; Award; Biological; Blood Pressure; Blood Vessels; Blood flow; Brain; Caliber; Cardiovascular system; Chest; Clinical Trials; Cognitive; Collaborations; Communities; Contracts; Coronary; Data; Dementia; Elderly; Encephalitis; Environment; Epidemiology; Evaluation; Framingham Heart Study; Functional disorder; Funding; Genetic; Glomerular Filtration Rate; Health; High Prevalence; Homeostasis; Hypertrophy; Iceland; Image Analysis; Imaging Techniques; Impaired cognition; Incidence; Indium; Individual; Institution; Investigation; Kidney; Kidney Diseases; Length; Lesion; Longitudinal Studies; Macular degeneration; Magnetic Resonance Imaging; Measures; Medical; Microcirculation; North America; Observational Study; Organ; Outcome; Participant; Pathogenesis; Pathway interactions; Peripheral; Phase; Phenotype; Photography; Physiological; Physiology; Population; Population Study; Predisposition; Prevalence; Protocols documentation; Public Health; Pulse Pressure; Renal function; Research; Research Personnel; Resistance; Retinal; Risk Factors; Sampling; Societies; Source; Stroke; Structure; Surrogate Markers; Technology; Testing; Thick; Time; Tissues; Ventricular; Woman; age related; aging gene; aortic arch; arterial stiffness; arterial tonometry; base; burden of illness; calcification; cardiovascular disorder risk; cerebrovascular; cognitive function; cohort; electric impedance; epidemiology study; experience; follow-up; genetic epidemiology; genome wide association study; heart disease risk; hemodynamics; high risk; insight; kidney vascular structure; men; middle age; novel; older women; pressure; prevent; public health relevance; research clinical testing; vascular bed; white matter

DESCRIPTION (provided by applicant): Aortic stiffness increases dramatically after 60 years of age and is associated with increased risk for heart disease, stroke, cognitive impairment and kidney disease. Although several risk factors for abnormal aortic stiffness have been identified, basic mechanisms in the causal pathway from risk factor to aortic dysfunction to excessive pressure pulsatility and downstream damage in the brain and kidney remain incompletely understood. Aortic stiffening and excessive blood pressure pulsatility are associated with microvascular remodeling, hypertrophy and impaired reactivity, which may contribute to end-organ damage. We propose to perform arterial tonometry and detailed magnetic resonance imaging (MRI) of the brain in 4000 participants and MRI of the aorta and kidneys in 600 participants in the Age, Gene/Environment Susceptibility- Reykjavik study (AGES-Reykjavik). Our hypotheses for this proposal are 3 fold: 1) that wall stiffening in the proximal aortic arch and mismatch between aortic diameter and flow are major sources of excessive pressure pulsatility in older people, 2) that the consequent increase in pulse pressure has detrimental effects on small vessel structure and function that manifest as abnormal pressure-flow relations in the brain (cerebrovascular input impedance) and kidneys (renovascular input impedance) because these high-flow organs are highly susceptible to pulsatile damage and 3) that the resulting abnormalities in cerebrovascular and renovascular function are associated with abnormal brain and kidney structure (MRI) and function (cognitive testing, glomerular filtration rate, albuminuria). Our specific aims are: 1) To relate central and peripheral pulse pressure to detailed measures of aortic structure and function. Using MRI, we will examine aortic diameter, wall thickness, stiffness and flow at key levels along the full length of the aorta in order to evaluate comprehensively the spatially heterogeneous contribution of each component of aortic function to the pathogenesis of increased pulse pressure. 2) To examine relations between aortic function (arterial tonometry), cerebrovascular input impedance and brain structure (quantitative MRI) and function (standardized cognitive testing). Using arterial tonometry and total brain blood flow, we will perform a comprehensive noninvasive assessment of cerebrovascular input impedance and will relate cerebrovascular abnormalities to brain structure and cognitive function in 4000 participants in the community-based AGES-Reykjavik study. 3) To relate measures of aortic and renovascular function to kidney structure and function. This study will provide critical mechanistic insights into the relations between cardiovascular disease risk factors, increased pulse pressure and declining brain and kidney function with advancing age. PUBLIC HEALTH RELEVANCE: Project Narrative Abnormal aortic stiffness and increased blood pressure pulsatility are highly prevalent after 60 years of age and convey increased risk of heart disease, stroke, dementia and kidney disease. The combination of high prevalence of aortic stiffness, high risk for an adverse outcome and aging of the population portends a dramatic increase in the burden of disease attributable to abnormal aortic function unless steps are taken to prevent or reverse aortic stiffening in older people. This study will identify factors that contribute to aortic stiffening and will define the adverse effects of abnormal stiffness on structure and function of brain and kidneys.

描述（由申请人提供）：主动脉僵硬度在 60 岁后急剧增加，并且与心脏病、中风、认知障碍和肾脏疾病的风险增加相关。尽管已经确定了主动脉僵硬度异常的几个危险因素，但从危险因素到主动脉功能障碍、过度压力脉动以及大脑和肾脏下游损伤的因果途径的基本机制仍不完全清楚。主动脉僵硬和过度的血压搏动与微血管重塑、肥大和反应性受损有关，这可能导致终末器官损伤。我们建议在年龄、基因/环境易感性-雷克雅未克研究 (AGES-Reykjavik) 中对 4000 名参与者进行动脉张力测量和详细的大脑磁共振成像 (MRI)，并对 600 名参与者进行主动脉和肾脏 MRI。我们对此提议的假设有 3 个方面：1) 近端主动脉弓壁硬化以及主动脉直径和流量之间的不匹配是老年人压力脉动过度的主要原因，2) 随之而来的脉压增加对老年人产生不利影响。小血管结构和功能，表现为大脑（脑血管输入阻抗）和肾脏（肾血管输入阻抗）中异常的压力-流量关系，因为这些高流量器官非常容易受到搏动性损伤；3) 由此产生的脑血管和肾血管功能异常与大脑和肾脏结构 (MRI) 和功能异常（认知测试、肾小球滤过率、蛋白尿）有关。我们的具体目标是： 1) 将中心和外周脉压与主动脉结构和功能的详细测量联系起来。使用 MRI，我们将检查主动脉全长关键水平的主动脉直径、壁厚度、硬度和血流，以便全面评估主动脉功能各组成部分对脉压增高发病机制的空间异质性贡献。 2) 检查主动脉功能（动脉张力测定）、脑血管输入阻抗与脑结构（定量 MRI）和功能（标准化认知测试）之间的关系。我们将利用动脉张力测定法和脑总血流量，对脑血管输入阻抗进行全面的无创评估，并将脑血管异常与 4000 名参加基于社区的 AGES-Reykjavik 研究的参与者的大脑结构和认知功能联系起来。 3) 将主动脉和肾血管功能的测量与肾脏结构和功能联系起来。这项研究将为心血管疾病危险因素、脉压增加以及随年龄增长而下降的大脑和肾功能之间的关系提供重要的机制见解。公共健康相关性：项目叙述 主动脉僵硬度异常和血压搏动增加在 60 岁以后非常普遍，并且会增加患心脏病、中风、痴呆和肾病的风险。主动脉僵硬的高患病率、不良后果的高风险以及人口老龄化，预示着主动脉功能异常导致的疾病负担将急剧增加，除非采取措施预防或逆转老年人的主动脉僵硬。这项研究将确定导致主动脉硬化的因素，并确定异常僵硬对大脑和肾脏结构和功能的不利影响。