Age Associated Changes In Vascular Properties

年龄相关的血管特性变化

基本信息

批准号：
6815450
负责人：
Samer Najjar
金额：
--
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

The overall goals of this project are to characterize the determinants of vascular structure and function, and evaluate their effects on cardiovascular morbidity and mortality 1. We recently examined the predictive role of pulse wave velocity (PWV), a non-invasive marker of vascular stiffness. In a cross-sectional study involving 504 Baltimore Longitudinal Study of Aging (BLSA) participants who were free of cardiovascular disease at baseline, and with an average follow-up of 6.2 years, we found that PWV was a predictor of cardiovascular events (defined as cardiovascular death, myocardial infarction, revascularization, or stroke) and of total mortality. However, when other factors known to influence cardiovascular morbidity and mortality were entered into the Cox proportional hazards model, PWV was no longer an independent predictor of outcomes, suggesting that increased stiffness may represent a mechanism through which the significant variables (namely age, fasting blood sugar, and white blood cells) exert their deleterious effects on cardiovascular morbidity and mortality 2. In order to investigate the hypothesis that the age-associated changes in cardiovascular structure and function represent the mechanism through which increased age exerts its deleterious effects on cardiovascular morbidity and mortality, and to test the related hypothesis that physiologic vascular properties explain the chronologic age-associated increased risk of atherosclerosis, we plan to evaluate traditional as well as novel measures of vascular properties, and examine how they relate to non-invasive assessments of atherosclerosis. This will be performed in 300 BLSA subjects as well as individuals with known absence of coronary artery disease and patients with known premature coronary artery disease. A research and development contract has been awarded to procure novel non-invasive imaging tools such as electron beam computed tomography, vascular magnetic resonance imaging, and vascular magnetic resonance angiography (Project Officer, S. Najjar). 3. Although it is thought that the relationship between central and peripheral pulse pressure changes with advancing age, this has not been systematically investigated in a large cohort. This is important because peripheral pulse pressure, a surrogate measure of vascular stiffness, has recently been shown in numerous studies to be an independent predictor of adverse outcomes. If the difference between peripheral and central pulse pressure decreases with age, this would suggest that peripheral pulse pressure underestimates the risk of adverse outcomes in older individuals. We are therefore determining the central aortic pressures in a large cohort of BLSA individuals across a broad age-range, by analyzing carotid arterial pulse wave contours obtained non-invasively by the technique of applanation tonometry with high fidelity micromanometer probes. 4. Previous studies from the Laboratory of Cardiovascular Science had previously shown that a novel nonenzymatic breaker of advanced glycation end-products, ALT-711, improves vascular stiffness and lowers pulse pressure in humans with increased vascular stiffness, and that it improves both arterial and ventricular function and optimizes ventriculo-vascular coupling in old healthy monkeys. We are presently participating in a multi-center, phase II, randomized, double-blinded, placebo-controlled study that evaluates, in a formal dose-finding study, the safety and efficacy of ALT-711 in reducing blood pressure in subjects with isolated systolic hypertension, which is the most common form of hypertension that afflicts older individuals. 5. Congestive heart failure is a clinical syndrome whose prevalence and incidence are increasing, especially in older individuals. We hypothesize that increased vascular stiffness, by accentuating the ventriculo-vacular mismatch, adversely affects the already compromised cardiovascular performance. L-arginine, but not its enantiomer D-arginine, is the substrate for nitric oxide synthase, the enzyme that catalyzes the synthesis of nitric oxide, which, in turn, decreases vascular stiffness, hastens ventricular diastolic relaxation and enhances diastolic distensibility. We are therefore investigating, in a randomized double-blinded cross-over study, the acute vascular and diastolic ventricular effects of parenteral L-arginine and D-arginine administration in patients with heart failure and increased vascular stiffness, and evaluating whether these effects favorably impact cardiovascular performance.

该项目的总体目标是表征血管结构和功能的决定因素，并评估它们对心血管发病率和死亡率的影响1。我们最近检查了脉搏波速度（PWV）的预测作用，脉搏波速度是血管僵硬度的非侵入性标志物。在一项涉及 504 名巴尔的摩纵向衰老研究 (BLSA) 参与者的横断面研究中，他们在基线时没有心血管疾病，平均随访时间为 6.2 年，我们发现 PWV 是心血管事件的预测因子（定义为心血管死亡、心肌梗死、血运重建或中风）和总死亡率。然而，当其他已知影响心血管发病率和死亡率的因素被输入 Cox 比例风险模型时，PWV 不再是结果的独立预测因子，这表明硬度增加可能代表了一种机制，通过该机制，显着变量（即年龄、空腹血糖和白细胞）对心血管发病率和死亡率产生有害影响 2. 为了研究以下假设：心血管结构和功能与年龄相关的变化代表了年龄增长对心血管产生有害影响的机制发病率和死亡率，并检验生理血管特性解释与年龄相关的动脉粥样硬化风险增加的相关假设，我们计划评估传统和新颖的血管特性测量方法，并研究它们与非侵入性评估的关系动脉粥样硬化。这项研究将在 300 名 BLSA 受试者以及已知没有冠状动脉疾病的个体和已知患有早发冠状动脉疾病的患者中进行。已授予采购新型非侵入性成像工具的研发合同，例如电子束计算机断层扫描、血管磁共振成像和血管磁共振血管造影（项目官员，S. Najjar）。 3. 尽管人们认为中枢脉压和外周脉压之间的关系随着年龄的增长而变化，但这还没有在大型队列中进行系统研究。这一点很重要，因为外周脉压（血管僵硬度的替代指标）最近在许多研究中被证明是不良后果的独立预测因子。如果外周脉压和中心脉压之间的差异随着年龄的增长而减小，则表明外周脉压低估了老年人不良后果的风险。因此，我们通过分析采用高保真微压计探头的压平眼压测量技术非侵入性获得的颈动脉脉搏波轮廓，确定了一大群不同年龄范围的 BLSA 个体的中心主动脉压。 4. 心血管科学实验室之前的研究表明，一种新型的高级糖基化终产物非酶破坏剂 ALT-711 可以改善血管僵硬度并降低血管僵硬度增加的人体脉压，并且它可以改善动脉和心室功能并优化老年健康猴子的心室-血管耦合。我们目前正在参与一项多中心、II 期、随机、双盲、安慰剂对照研究，该研究在正式的剂量探索研究中评估 ALT-711 在降低孤立性高血压受试者血压方面的安全性和有效性。收缩期高血压，这是困扰老年人的最常见的高血压形式。 5. 充血性心力衰竭是一种临床综合征，其患病率和发病率不断增加，特别是在老年人中。我们假设，血管硬度的增加会加剧心室-血管的不匹配，从而对已经受损的心血管功能产生不利影响。 L-精氨酸（而非其对映体 D-精氨酸）是一氧化氮合酶的底物，一氧化氮合酶催化一氧化氮的合成，从而降低血管僵硬度，加速心室舒张期舒张并增强舒张期扩张性。因此，我们正在一项随机双盲交叉研究中，研究肠外给予 L-精氨酸和 D-精氨酸对心力衰竭和血管僵硬度增加的患者的急性血管和舒张心室影响，并评估这些影响是否有利地影响心血管功能。