Age Associated Changes In Structural And Functional Vasc

血管结构和功能的年龄相关变化

• 批准号: 7132346
• 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/7132346
• 关键词: age difference; aging; alcoholic beverage consumption; atherosclerosis; biomarker; blood pressure; cardiovascular disorder epidemiology; cardiovascular disorder risk; cardiovascular function; cardiovascular imaging /visualization; cerebrovascular disorders; congestive heart failure; coronary disorder; gene environment interaction; gene expression; genetic susceptibility; human subject; hypertension; longitudinal human study; metabolic syndrome; pulse pressure wave; questionnaires; ultrasonography; 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. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. Aortic PWV was measured at baseline in 2488 older adults. Over an average of 4.6 years of follow-up, 265 deaths occurred with 111 categorized as cardiovascular in cause. Higher aortic aPWV quartile was associated with both total mortality (P = 0.010) and CV mortality (P=.006), independent of age, gender, race, SBP, known CV disease, creatinine, cholesterol and smoking. Thus, among a generally healthy, well-functioning, community dwelling population, aPWV, a marker of arterial stiffness, is associated with higher total and CV mortality (Circulation 2005;111(25):3384-3390). 2. Hypertension (HTN) is generally considered a risk factor for arterial stiffening because chronically increased blood pressure determines structural and functional changes in arterial walls. However, arterial stiffening may also predispose to the development of HTN. We therefore evaluated whether arterial stiffening predicts the development of HTN in normotensive healthy adults. Pulse wave velocity (PWV), a non-invasive index of arterial stiffness, was measured in 364 volunteers from the Baltimore Longitudinal Study of Aging who were normotensive at baseline. After a mean follow-up of 5.1+/-2.9 years, 75 subjects (21%) developed HTN. Variables that were significantly associated with the development of HTN included older age, higher PWV, body mass index, systolic blood pressure, diastolic blood pressurre, and triglycerides, and lower HDL cholesterol. Because of a significant interaction between age and PWV, we examined younger (age<50 years) and older age groups separately. We found that in healthy normotemsive younger, but not older, adults, higher arterial stiffness is an independent predictor of future HTN. Thus, screening for arterial stiffening may identify a subset of normotenisve younger individuals at increased risk for developing HTN, in whom early interventions may be indicated. 3. Intimal medial thickness (IMT) and vascular stiffness have been shown to be independent predictors of adverse cardiovascular events. The metabolic syndrome (MS) is defined as the clustering of 3 or more of the cardiovascular risk factors of dysglycemia, hypertension, dyslipidemia, and obesity. We evaluated whether the clustering of multiple components of the MS has a greater impact on these vascular parameters than individual components of the MS in 471 participants from the Baltimore Longitudinal Study on Aging who were without clinical cardiovascular disease and not on antihypertensive therapy. MS was an independent predictor of increased carotid IMT and stiffness, and conferred a disproportionate increase in carotid IMT (16%) and stiffness (32%,) compared to controls even after taking into account each individual component of the MS. This suggests that the components of the MS interact to synergistically impact vascular thickness and stiffness. Future studies should examine whether the excess cardiovascular risk associated with the MS is, in part, mediated through the amplified alterations in these vascular properties (J Am Coll Cardiol. 2004;43(8):1388-95). 4. The prevalence of the metabolic syndrome, a potent risk factor for cardiovascular diseases, has not been adequately explored in older individuals. Moreover, 2 sets of criteria have been proposed for the definition of the metabolic syndrome, one by the World Health Organization (WHO) and one by the National Cholesterol Education Program (ATPIII). We found that the prevalence of this syndrome in a subgroup of 2175 older participants from the Cardiovascular Health Study (CHS) free of cardiovascular disease at baseline to be 28.1% by ATPIII criteria, and 21.0%, by WHO criteria. The two sets of criteria provided concordant classification for 80.6% of participants. Multivariate Cox propotional hazard models showed that the metabolic syndrome defined with the ATPIII criteria, but not with the WHO criteria, was an independent predictor of coronary or cerebrovascular events, and was associated with a 38% increased risk (HR 1.38, 95%CI 1.06-1.79, p< 0.01). Thus, as defined by the ATPIII criteria, the metabolic syndrome yields independent prognostic information, even after adjusting for traditional cardiovascular risk factors and the individual domains of the metabolic syndrome (Diabetes Care 2005;28(4):882-887). 5. Increased thickness and stiffness of large arteries may contribute to why aging is the most important risk for cardiovascular diseases. Several large studies have shown that moderate alcohol consumption reduces the risk for heart disease and stroke. We examined whether alcohol consumption alters age-associated increases in arterial stiffness and intimal medial thickness (IMT). A total of 563 volunteers from the Baltimore Longitudinal Study of Aging had carotid duplex ultrasonography with measurements of IMT and an arterial stiffness index. Alcohol intake was assessed by a standard questionnaire. A U-shaped relationship was found between alcohol intake and stiffness index, with the lowest index in moderate drinkers (1 ? 9.9 drinks per week); this relationship persisted after adjustment for cardiovascular risk parameters. Moderate drinkers showed ~ 50% less age-associated increase in arterial stiffness than heavy drinkers and nondrinkers, both before and after adjusting for other cardiovascular risk factors. A significant positive u-shaped relationship was found between alcohol intake and IMT, which did not persist after adjustment for risk factors. Thus, light to moderate alcohol intake favorably modulates aging of the arterial tree. This effect may explain in part the J- or U-shaped relationship between alcohol intake and cardiovascular disease (Am J Cardiol. 2005;95(8):1006-10). 6. Arterial thickness and stiffness increase with advancing age, and are increasingly recognized as risk factors for cardiovascular morbidity and mortality. Because these complex traits are likely to be affected by a multiplicity of genetic and environmental factors, the search for novel genes that may underlie these phenotypes will require genome wide linkage and association studies. As a first step, we evaluated the heritability of blood pressure and central arterial structure and function in a founder population, i.e. one with high degrees of interrelatedness among its individuals due to limited external admixture. We recruited 6,148 subjects (57% women, 711 families), representing over 60% of the total population aged 14-102, from a cluster of 4 towns on the island of Sardinia. Heritabilities were assessed with simple variance components models, which assume that all similarities between genetic factors are due to additive genetic effects. The narrow heritability estimates for systolic BP, diastolic BP, DiamD, IMT and PWV, adjusted for sex, age and age2, are 0.258, 0.187, 0.443, 0.185 and 0.226 respectively, and indicate that 18% to 44% of the variance can be attributed to genetic factors. A significant difference in heritability between young (age<42 years) and older persons was only observed for systolic BP (0.09 vs 0.30, p<0.05), suggesting an interaction between age and the contribution of genes to variations in this trait. Thus, in this study of a large founder population, indexes of arterial structure and function show robust heritability estimates, indicating that genome wide linkage and association studies will likely succeed in identifying genes that contribute to the variance in these traits.

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。增加的主动脉脉冲波速度（APWV）与临床但一般人群中的死亡率有关。在2488名老年人的基线时测量主动脉PWV。在平均4。6年的随访中，有265例死亡发生，有111例被归类为心血管。较高的主动脉APWV四分位数与总死亡率（P = 0.010）和CV死亡率（P = .006）有关，独立于年龄，性别，种族，SBP，已知CV疾病，肌酐，胆固醇和吸烟。因此，在通常健康，功能良好的，社区住宅人群中，APWV是动脉僵硬的标志，与较高的总和CV死亡率有关（Circulation 2005; 111（25）：3384-3390）。 2。高血压（HTN）通常被认为是动脉僵硬的危险因素，因为慢性血压决定了动脉壁的结构和功能变化。但是，动脉僵硬也可能易于HTN的发展。因此，我们评估了动脉僵硬是否预测了正常健康的成年人中HTN的发展。脉冲波速度（PWV）是一种无创的动脉刚度指数，在巴尔的摩纵向研究的364名志愿者中测量了基线时正常衰老的衰老纵向研究。在平均随访为5.1 +/- 2。9年后，有75名受试者（21％）发展了HTN。与HTN的发展显着相关的变量包括年龄较大，PWV，体重指数，收缩压，舒张血压，舒张血压和甘油三酸酯以及较低的HDL胆固醇。由于年龄与PWV之间存在显着的相互作用，我们分别检查了年轻人（<50岁）和年龄段。我们发现，在健康的正常人较年轻而不是年龄较大的成年人中，较高的动脉僵硬是未来HTN的独立预测指标。因此，对动脉僵硬的筛查可能会鉴定出一个正常分离的年轻个体的子集，患有HTN的风险增加，其中可能会表明早期干预措施。 3。内侧厚度（IMT）和血管刚度已显示为不良心血管事件的独立预测指标。代谢综合征（MS）定义为3个或更多的患者性血糖，高血压，血脂异常和肥胖的心血管危险因素的聚类。我们评估了在巴尔的摩纵向研究的471名参与者中，MS的多个组成部分的聚类对这些血管参数的影响是否比没有临床性心血管疾病而不是对抗高血管治疗的471名参与者更大。 MS是颈动脉IMT和刚度增加的独立预测指标，即使考虑到MS的每个单独成分，也相比，颈动脉IMT（16％）和刚度（32％）的较差不成比例。这表明MS的成分相互作用，以协同影响血管厚度和刚度。未来的研究应检查与MS相关的过量心血管风险是否部分通过这些血管特性的扩增变化介导（J Am CollCardiol。2004; 43（8）：1388-95）。 4。代谢综合征的患病率是心血管疾病的有效危险因素，在老年人中尚未得到充分探索。此外，已经提出了两套标准，以定义代谢综合症，一个由世界卫生组织（WHO）和国家胆固醇教育计划（ATPIII）提出。我们发现，通过ATPIII标准，该综合征在2175名来自心血管健康研究（CHS）的2175名年长参与者的亚组中的患病率为28.1％，而21.0％的人则通过WHO标准为21.0％。这两套标准为80.6％的参与者提供了一致的分类。多元COX促二危险危害模型表明，与ATPIII标准定义的代谢综合征，但与WHO标准不定义，是冠状动脉或脑血管事件的独立预测指标，与风险增加38％（HR 1.38，95％CI 1.06-1.79，P <0.01）。因此，如ATPIII标准所定义的那样，即使在调整了传统的心血管危险因素和代谢综合征的各个领域后，代谢综合征也会产生独立的预后信息（Diabetes Care 2005; 28（4）：882-887）。 5。大动脉的厚度和刚度增加可能导致为什么衰老是心血管疾病最重要的风险。几项大型研究表明，适度的饮酒降低了心脏病和中风的风险。我们检查了饮酒是否会改变与年龄相关的动脉刚度和内膜内侧厚度（IMT）的增加。巴尔的摩纵向研究的总共563名志愿者具有颈动脉双工超声检查，具有IMT和动脉僵硬指数的测量。酒精摄入量由标准问卷进行评估。在酒精摄入量和僵硬指数之间发现了U形的关系，中等饮酒者的指数最低（每周1？9.9饮料）；调整心血管风险参数后，这种关系持续存在。在调整其他心血管危险因素之前和之后，中度饮酒者的动脉僵硬相比，与重饮酒者和非饮酒者相比，年龄相关的动脉僵硬量降低了约50％。发现酒精摄入量与IMT之间存在明显的阳性U形关系，在调整危险因素后，这并没有持续。因此，光到中度的酒精摄入良好地调节了动脉树的衰老。这种效果可以解释酒精摄入与心血管疾病之间的J或U形关系（Am JCardiol。2005; 95（8）：1006-10）。 6。随着年龄的增长，动脉厚度和僵硬增加，并且被越来越被认为是心血管发病率和死亡率的危险因素。由于这些复杂的特征可能会受到多种遗传和环境因素的影响，因此寻找可能是这些表型的新基因的搜索将需要广泛的基因组链接和关联研究。作为第一步，我们评估了创始人人群中血压和中央动脉结构和功能的遗传力，即由于外部混合物有限，其个体之间相互关联的程度很高。我们从撒丁岛岛上的4个城镇招募了6,148名受试者（57％的女性，711个家庭），占14-102岁总人口的60％以上。通过简单的方差成分模型评估遗产，该模型假设遗传因素之间的所有相似性都是由于加性遗传效应引起的。针对性别，年龄和年龄2的收缩压，舒张压，DIAMD，IMT和PWV的狭窄遗传力估计分别为0.258、0.187、0.443、0.185、0.185和0.226，并指出，差异的18％至44％可以归因于遗传因素。仅观察到年轻人（年龄<42岁）和老年人之间的遗传力差异显着差异（0.09 vs 0.30，p <0.05），这表明年龄与基因对该性状变化的贡献之间存在相互作用。因此，在这项对大型创始人人群的研究中，动脉结构和功能的索引表现出强大的遗传力估计，表明广泛的基因组联系和关联研究可能会成功识别有助于这些性状方差的基因。