Age Associated Changes In Vascular Properties

年龄相关的血管特性变化

• 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
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6815450
• 关键词: age difference; aging; angiography; antihypertensive agents; arginine; atherosclerosis; blood glucose; cardiovascular disorder chemotherapy; cardiovascular disorder epidemiology; cardiovascular imaging /visualization; carotid artery; clinical trial phase II; clinical trials; congestive heart failure; human subject; human therapy evaluation; hypertension; leukocytes; longitudinal human study; magnetic resonance imaging; noninvasive diagnosis; patient oriented research; pulse pressure wave; tomography; vascular resistance; vasomotion

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，并评估其对心血管发病率和死亡率的影响1。我们最近研究了脉搏波速度（PWV）的预测作用，脉冲波速度（PWV）是一种无创的血管刚度标志物。 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.但是，当将已知影响心血管发病率和死亡率的其他因素输入到Cox比例危害模型中时，PWV不再是结果的独立预测指标，这表明增加的刚度可能代表了一种重要的变量，通过该机制，重要的变量（当时年龄，禁食性血糖，白血细胞和白血细胞都会对他们的有害效果进行秩序 - 对心脏的疾病效果进行了秩序，并在秩序上占据了秩序2。心血管结构和功能的变化代表了年龄增加对心血管发病率和死亡率的有害影响的机制，并检验了与生理血管特性相关的假设，即生理性血管特性解释了与年龄相关的增加的动脉粥样硬化风险，我们计划评估传统和新的衡量血管属性的测量，以评估他们的血管性质，并与他们的血管性相关性，并与他们相关的是一定的。这将在300名BLSA受试者以及已知缺乏冠状动脉疾病和已知过早冠状动脉疾病的患者的个体中进行。已经授予了一项研究与开发合同，用于购买新颖的非侵入性成像工具，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（Project S. Najjar）。 3。尽管人们认为中央脉冲压力和外围脉压之间的关系随着年龄的增长而变化，但在大型队列中尚未系统地研究。这很重要，因为最近在许多研究中证明了周围脉压是血管刚度的替代度量，是不良结果的独立预测指标。如果外围和中央脉压之间的差异随着年龄的增长而降低，这将表明外周脉冲压力低估了老年人的不良后果风险。因此，我们通过分析具有高忠诚度微米表探针的应用静脉分析技术来确定广泛年龄段的大量BLSA个体中的中央主动脉压力。 4。心血管科学实验室先前的研究先前表明，高级糖基化终产物的新型非酶促断裂器ALT-711，可改善血管僵硬，并降低血管僵硬增加的人类的脉压，并可以改善动脉和心室功能，并改善动脉 - 血管生cOUPLACERAL CACUALCUAL COUPLEYS MONEKERYS ernect in sold Northy Norly Monkeys。我们目前正在参加一项多中心，II期，随机，双盲的，安慰剂对照的研究，该研究在一项正式的剂量调查研究中评估Alt-711在降低孤立的节性高血压受试者血压中的安全性和有效性，这是最常见的高血压形式，这是老年人老年人的高血压。 5。充血性心力衰竭是一种临床综合征，其患病率和发病率正在增加，尤其是在老年人中。我们假设通过加强心室 - 易变不匹配的血管刚度增加，对已经受损的心血管表现不利地影响。 L-精氨酸，但不是其映体D-精氨酸，是一氧化氮合酶的底物，是催化一氧化氮的合成的酶，进而降低血管僵硬，速度迅速降低心室舒张性并增强了心室舒张性并增强了可分解性。因此，在一项随机的双盲跨界研究中，我们正在研究肠胃外L-精氨酸和D-精氨酸给药的急性血管和舒张性心室作用，对心力衰竭和增加血管僵硬的患者，并评估这些影响是否有利地影响心血管表现。