AGE, RACE, VASCULAR STIFFNESS: GENETIC MARKERS

年龄、种族、血管僵硬：遗传标记

• 批准号: 6302990
• 负责人: FRANCOIS M BOOYSE
• 金额: $ 2.95万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302990
• 关键词: aging; atherosclerosis; clinical research; coronary disorder; disease /disorder proneness /risk; ethnic group; fibrinolysis; gene mutation; genetic mapping; genetic markers; genotype; human subject; polymerase chain reaction; racial /ethnic difference; restriction fragment length polymorphism; ultrasound blood flow measurement; vascular resistance

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.

衰老影响内皮和平滑肌细胞功能以及动脉壁组成/结构（基质重塑），这有助于血管硬化及其作为老年人心血管发病率和死亡率风险因素的潜在作用。 心血管相关的血管僵硬度与收缩压、动脉粥样硬化形成、冠状动脉疾病（CAD）和最终MI的进行性升高密切相关。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形成、CAD和可能的血管硬化以及与斑块破裂相关的晚期动脉粥样硬化血栓并发症的易感性和风险增加中起主要作用，导致心血管发病率和死亡率。 CAD的风险因素，包括吸烟、肥胖、糖尿病、高血压、高脂血症、增加的Lp（a）和增加的纤维蛋白原，通常与改变一种或多种纤维蛋白溶解蛋白派-1、t-PA、u-PA和/或纤维蛋白原的表达和/或活性的受损的血液纤维蛋白溶解活性相关。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作用. 拟定的横断面临床研究的总体目标是确定来自不同种族/性别组的约1，000例不同年龄（20-90岁）患者（有/无血管造影确定的CAD）的年龄相关主动脉硬化量，并将主动脉硬化因子的量关联起来。主动脉僵硬与纤溶蛋白、派-1、t-PA、u-PA和b-纤维蛋白原的遗传标记物和CAD风险因素。 在同一研究人群中，将通过多普勒超声（脉搏波速度，PWV）（目标1）、磁共振成像（Mri）（PWV和扩张系数）（目标2）和新的MRI指标血管阻抗（目标2）确定主动脉僵硬度。 纤溶蛋白基因组分析（血液样本）将这些遗传标记与某些风险因素、年龄、种族/性别和过度主动脉硬化、伴/不伴相关CAD相关（目标3）。 这些研究的结果将表明是否过度主动脉硬化与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形成将提供对年龄相关的血管硬化（伴/不伴CAD）在种族群体中病态心血管事件差异表达中的重要性的深入了解。 新的MRI指标和纤溶蛋白基因型谱的组合可能提供强大的新的筛选工具，用于识别具有遗传易感性的（老年）个体，从而增加对这些老年人的洞察力，以促进更积极或更早的二级预防措施或初级管理，以最大限度地减少血管并发症和相关的心血管发病率和死亡率。