AGE, RACE, VASCULAR STIFFNESS: GENETIC MARKERS

衰老影响内皮和平滑肌细胞功能和动脉壁组成/结构（基质重塑），这有助于血管硬化，并作为老年人心血管发病率和死亡率的潜在危险因素。与年龄相关的血管僵硬与收缩压的逐渐增加、动脉粥样硬化、冠状动脉疾病（CAD）和最终的心肌梗死密切相关。受损的血液纤维蛋白溶解在早期纤维蛋白沉积和动脉粥样硬化、CAD和可能的血管硬化以及后来与斑块破裂相关的动脉粥样硬化血栓并发症的易感和风险增加中起主要作用。导致心血管疾病的发病率和死亡率。CAD的危险因素包括吸烟、肥胖、糖尿病、高血压、高甘油三酯血症、Lp(a)升高和纤维蛋白原升高，这些因素通常与血液纤维蛋白溶解活性受损有关，改变一种或多种纤维蛋白溶解蛋白（PAI-1、t-PA、u-PA和/或纤维蛋白原）的表达和/或活性。纤溶活性（纤溶酶生成）在心血管疾病相关的动脉基质重塑中也起着重要作用，这可能对年龄相关的血管硬化有重要影响。所提出的横断面临床研究的总体目标是确定来自不同种族/性别群体的约1000名不同年龄患者（20-90岁）与年龄相关的主动脉硬化数量，这些患者有/没有血管造影识别的CAD，并将主动脉硬化因素的数量联系起来。主动脉硬度与纤维蛋白溶解蛋白、PAI-1、t-PA、u-PA和b-纤维蛋白原和CAD危险因素的遗传标记。在同一研究人群中，主动脉硬度将通过多普勒超声（脉冲波速度，PWV） （Aim 1）、磁共振成像（Mri） （PWV和扩张性系数）（Aim 2）和新的Mri指标血管阻抗（Aim 2）来确定。纤溶蛋白基因型分析（血液样本）将这些遗传标记与某些危险因素，年龄，种族/性别和主动脉过度硬化，伴有/不伴有CAD（目的3）相关联。这些研究的结果将表明主动脉过度硬化是否与CAD相关，并可能通过新的MRI指标更好地识别。种族群体中血管硬化的新发现将有助于深入了解年龄相关血管硬化在有/没有冠心病的情况下在种族群体中病态心血管疾病差异表达中的重要性。新的MRI指标和纤溶蛋白基因型谱的结合可能为识别具有遗传易感性的老年人提供强大的新筛查工具，从而增加对这些老年人更积极或更早的二级预防措施或初级管理的见解，以尽量减少血管并发症和相关的心血管发病率和死亡率。

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.