Vascular Stiffness as a Precursor of Hypertension in a Middle-aged Cohort

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 DESCRIPTION (provided by applicant): The prevalence of abnormal aortic stiffness increases dramatically and nonlinearly with age, from <1% prior to 50 years of age to over 60% after 70 years. We have previously demonstrated markedly nonlinear cross-sectional relations between age and key hemodynamic measures such as pulse pressure (PP). We demonstrated that aortic wall stiffening and mismatch between aortic flow and diameter contribute to the late increase in PP. Whether longitudinal changes in hemodynamics will mirror these cross-sectional relations is unknown. Our hypotheses for this application are 3 fold: 1) early aortic adaptations to environmental stressors (such as obesity) reduce PP despite aortic wall stiffening, but contribute to later life deterioration in aortic structure and function; 2) the consequent increasein pulsatile hemodynamic stress contributes to the development of wide PP, systolic hypertension, left ventricular remodeling with systolic and diastolic dysfunction and abnormal small vessel structure and function, resulting in microvascular damage in the brain and kidneys; and 3) changes in arterial properties are associated with increased risk for incident subclinical and clinical events. We will test these hypotheses with the following specific aims: Aim 1. To examine prospectively hemodynamic mechanisms of and risk factors for nonlinear transition in forward pressure wave amplitude from falling with age in young adults to increasing with age after midlife. We will perform arterial tonometry and echocardiography in ~3800 Framingham third generation and minority Omni-II cohort participants at their next exam cycle to characterize longitudinal changes in arterial stiffness during the falling phase (2001-2005), nadir (2007-2011) and rising phase (2015-2018) of pressure pulsatility; Aim 2. To examine relations between change in key central hemodynamic measures and measures of left ventricular diastolic function over a 12-year interval. Aim 3. To relate baseline values and nonlinear change in measures of aortic function to baseline and change in measures of target organ damage and clinical events involving the heart, brain, and kidneys. Our application will evaluate individual nonlinear longitudinal (three time points) changes in arterial stiffness in the community during a critical age range, providing novel insights into the pathogenesis of hypertension and target organ damage in the heart, brain and kidneys.