AGE, RACE, VASCULAR STIFFNESS: GENETIC MARKERS

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Aging affects vascular cell function and arterial wall composition/ structure which contributes to vascular stiffness and its underlying role as a risk factor for cardiovascular morbidity and mortality in the elderly. Age-related vascular stiffness is commensurate with a progressive increase in systolic blood pressure, atherosclerosis, matrix remodeling, CAD and evential MI. Impaired blood fibrinolysis will initiate early fibrin deposition, atherogenesis, CAD, CAD-associated vascular stiffness, resulting in atherothrombotic-occlusive events. CAD risk factors (i.e. obesity, diabetes, hypertension, hypertriglyceridemia [HTG], increased Lp(a)/homocysteine/fibrinogen), are associated with impaired blood fibrinolytic activity by altering the expression and/or activity of one or more of the fibrinolytic proteins, PAI-1, t-PA and u-PA. In addition, key multiallelic fibrinolytic proteins (PAI-1, t-PA, u-PA, including '-fibrinogen) play an essential role in CAD-associated arterial matrix remodeling and consequencially also age-related CAD-associated vascular stiffness. The overall goal of this proposed study is to determine whether identification of specific genotypes or genotypic combinations of fibrinolytic proteins (see above), in conjunction with identifiable risk factors or risk factor-associated components (i.e. HTG-VLDL, Lp[a], insulin, homocysteine), may simultaneously identify categories of combined pathogenetic risk for atherosclerosis/CAD and age-related CAD-associated aortic stiffness. This case-control study will be carried out with a racial/gender mix of 1,640 subjects with angiographically identifiable CAD (350% stenosis)(820 cases) and without CAD (normal coronary arteries) or CAD symptoms (820 controls). Specific studies will include: recruitment of cases/controls) (Aim I); identification of the mutation sites in the PAI-1 and u-PA genes to facilitate more cost-effective genotype analysis by PCR (Aim 2); determination of the amount/degree of aortic stiffness in all cases/controls, using Doppler ultrasound (pulse wave velocity) (Aim 3); determination of fibrinolytic protein genotypes (restriction fragment length polymorphisms, RFLPs) (Aim 4) and fibrinolytic protein antigen/activity, including Lp(a) and homocysteine levels in case/control-derived blood samples (Aim 5); and finally, the multifactorial determination and statistical analysis of age-related CAD-associated aortic stiffness (Aim 6).