Research Project
8296586
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.
