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）：主动脉僵硬在60岁后大幅增加，并与心脏病，中风，认知障碍和肾脏疾病的风险增加有关。尽管已经确定了多种异常主动脉僵硬度的危险因素，但因果途径的基本机制从危险因素到主动脉功能障碍再到过度压力搏动性和脑和肾脏下游损害的过度危害。主动脉僵硬和过度血压搏动性与微血管重塑，肥大和反应性受损有关，这可能导致最终器官损伤。我们建议在4000名参与者的大脑和详细的磁共振成像（MRI）以及该年龄的600名参与者的主动脉和肾脏的MRI中进行动脉渗透学和详细的磁共振成像（MRI）。我们对该提议的假设是3倍：1）壁在主动脉弓近端的壁僵硬以及主动脉直径和流动之间的不匹配是老年人过度压力脉动性过高的主要来源，2）随之而来的脉搏压力增加，对脉动的增加对脑部的小血管结构和功能有害，这表现为脑部压力型（塞氏症）（塞氏症）（塞氏症）（cerse）（塞氏症）（cerse）（塞氏症）输入阻抗）因为这些高流量器官非常容易受到脉动损害的影响，而3）脑血管和肾血管功能的异常与脑和肾脏结构（MRI）和功能（认知测试，肾小球过滤率，蛋白尿）有关。我们的具体目的是：1）将中央和周围脉压压力与主动脉结构和功能的详细度量相关联。使用MRI，我们将沿主动脉的全长进行主动脉直径，壁厚，刚度和钥匙水平的流动，以全面评估主动脉函数每个成分对增加脉搏压力的发病机理的空间异质贡献。 2）检查主动脉功能（动脉渗透学），脑血管输入阻抗和大脑结构（定量MRI）与功能（标准化认知测试）之间的关系。我们将使用动脉神经术和总脑血流，对脑血管输入障碍进行全面的无创评估，并将在基于社区的年龄雷伊卡维克研究的社区中的4000名参与者中，将脑血管异常与脑结构和认知功能联系起来。 3）将主动脉和肾血管功能的度量与肾脏结构和功能联系起来。这项研究将提供有关心血管疾病风险因素，脉搏压力增加以及随着年龄增长的大脑和肾功能下降的关键机理见解。公共卫生相关性：项目叙事异常主动脉僵硬和血压搏动性的增加在60岁之后非常普遍，并传达了心脏病，中风，痴呆和肾脏疾病的风险增加。主动脉僵硬，高风险的高风险和人口衰老的高风险的结合预示着归因于异常主动脉功​​能的疾病负担的急剧增加，除非采取措施预防或反向老年人主动脉僵硬。这项研究将确定导致主动脉僵硬的因素，并定义异常刚度对脑和肾脏的结构和功能的不利影响。