AGE, RACE, VASCULAR STIFFNESS: GENETIC MARKERS

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Aging affects endothelial and smooth muscle cell function and arterial wall composition/structure (matrix remodeling) which contributes to vascular stiffening and its underlying role as a risk factor for cardiovascular morbidity and mortality in the elderly. Age-related vascular stiffness has been closely associated with a progressive increase in systolic blood pressure, atherogenesis, coronary artery disease (CAD) and eventual MI. Impaired blood fibrinolysis plays a major role in the predisposition and increased risk for early fibrin deposition and the initiation of atherogenesis, CAD and presumably vascular stiffening, as well as the later atherothrombotic complications associated with plaque rupture, resulting in cardiovascular morbidity and mortality. Risk factors for CAD including smoking, obesity, diabetes, hypertension, hypertriglyceridemia, increased Lp(a) and increased fibrinogen, are commonly associated with impaired blood fibrinolytic activity altering the expression and/or activity of one or more of the fibrinolytic proteins, PAI-1, t-PA, u-PA and/or fibrinogen. Fibrinolytic activity (plasmin generation) additionally plays a major role in cardiovascular disease-associated arterial matrix remodeling whichmay contribute significantly to age-related vascular stiffening. The overall goal of the proposed cross-sectional clinical studies is to determine the amount of age-related aortic stiffening in ~1,000 varying aged patients (aged 20-90) from different racial/gender groups, with/without angiographically identified CAD and to correlate the amount of aortic stiffening factors. Aortic stiffness with genetic markers for fibrinolytic proteins, PAI-1, t-PA, u-PA and b-fibrinogen and CAD risk factors. Aortic stiffness will be determined by Doppler ultrasound (pulse wave velocity, PWV) (Aim 1), magnetic resonance imaging (Mri) (PWV and distensibility coefficient) (Aim 2) and a new MRI index, vascular impedance (Aim 2), in the same study population. Fibrinolytic protein genotupe analysis (blood samples) will correlate these genetic markers with certain risk factors, age, race/gender and excess aortic stiffening, with/without associated CAD (Aim 3). Results from these studies will indicate whether excess aortic stiffening is correlated with CAD and may be better identifiable by new MRI indices. New formation on vascular stiffness in racial groups will provide insight into the importance of age-related vascular stiffening, with/without CAD, in the differential expression of morbid cardiovascular evens in racial groups. The combination of new MRI indices and fibrinolytic protein genotype profiles may provide powerful new screening tools for identifying those (elder) individuals with the genetic predispositon and hence increased insight to promote more aggressive or earlier secondary preventative measures or primary management of these elderly persons to minimize vascular complications and associated cardiovascular morbidity and mortality.