Age Associated Changes In Vascular Stiffness Properties

与年龄相关的血管硬度特性变化

• 批准号: 6535843
• 负责人: Edward G Lakatta
• 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/6535843
• 关键词: aerobic exercise; aging; arteriosclerosis; blood pressure; body composition; cardiovascular disorder; cardiovascular disorder epidemiology; carotid artery; clinical research; heart function; hormone therapy; human subject; myocardium; sex hormones; somatotropin; vascular resistance

SUMMARY OR WORK: The ultimate goals of this project are to determine how arterial stiffness properties influence myocardial structure and function and contribute to cardiovascular morbidity and mortality. 1. We have recently discovered, in cross-sectional studies, that estrogen replacement therapy (ERT) in postmenopausal women reduced blood pressure (BP) and the age-associated increase in arterial stiffness and that the addition of progestins to ERT appeared to reduce these beneficial effects. (Aging Clin Exp Res 13:122-130, 2001). In a second study, 226 healthy, normotensive postmenopausal women from the Baltimore Longitudinal Study of Aging with a mean (+SD) age of 64 + 10 years were followed for 5.7 + 5.3 years. Seventy-seven women used both estrogen and progestin (HRT users), and 149 used neither. Over time, average systolic blood pressure (SBP) increased less in HRT users than nonusers, independent of other cardiovascular risk factors, physical activity and alcohol use. Thus, postmenopausal women taking HRT have a smaller increase in SBP over time than those not taking HRT. This difference is intensified at older ages. (Ann Intern Med. 2001;135:229-238). 2. To examine the role of nitric oxide (NO) synthesis on BP changes during salt loading in postmenopausal women, we measured asymmetric dymethylarginine (ADMA), a potent endogenous inhibitor of NO synthesis before and after 4-7 days of low-salt (70mEg/day) or high-salt (260mEg/day) diet in 12 postmenopausal women. Sodium sensitivity of 24 hour ambulatory SBP and pulse pressure correlated with change in ADMA from low- to high-salt intake, after adjustment for age. These findings suggest that inhibition of NO synthesis contributes to the BP increase during high salt intake in postmenopausal women. 3. To determine whether growth hormone or sex steroid supplementation ameliorates arterial stiffness properties in older hormone-deficient adults, we measured PWV and AGI in men and women aged 65 years and older, before and after hormonal replacement. 4. The reproducibility of aortic pulse wave velocity (APWV) was evaluated in a population-based study of cardiovascular disease in the elderly. The results indicated that the mean PWV is reproducible even when sonographers and readers are newly trained. (Am J Hypertens 2001;14:463-468). 5. The Activity Counseling Trial (ACT) employed various patient education and counseling interventions to increase physical activity in sedentary primary care populations. APWV and coronary risk factors were measured pre- and post-intervention. Pre-intervention, older age was associated with stiffer vessels and a higher HDL cholesterol with more elastic ones. HDL cholesterol may be an indirect indicator of aerobic capacity or of less atherosclerosis, suggesting mechanisms for preserving vascular integrity. (The Am J Cardiol 2001;87, 104-107). 6. We are testing the hypothesis that 1-2 years of home-based aerobic exercise training can reduce arterial stiffness in the multicenter NIH-sponsored Activities Counseling Trial of 810 subjects 35-75 years old. 7. The association between vascular stiffness and body fat was evaluated in 2488 older adults (mean age 74 years, 52% female, 40% Black) enrolled in Health ABC, a prospective study of disability in the elderly. Independent of age and BP, PWV was positively associated with weight, abdominal circumference, abdominal subcutaneous fat, abdominal visceral fat, thigh fat area, total fat and higher levels of glucose, insulin and hemoglobin A1c (p < .001 for all). The strongest association was with abdominal visceral fat. In multivariate analysis, independent positive associations with PWV were age, SBP, heart rate, abdominal visceral fat, smoking, hemoglobin A1c, and history of hypertension. The association between PWV and abdominal visceral fat was consistent across tertiles of body weight. Thus, keeping weight (specifically visceral fat) within normal limits through the advancing years may slow the process of vascular aging, possibly reducing the associated risks. (Am J Hypertension, in press). 8. Arterial stiffness was measured in the Pittsburgh, PA site for the Cardiovascular Health Study Cross-sectional results indicate that risk factors associated with the insulin resistance syndrome (hypertension, hyperglycemia, hyperinsulinemia, and abdominal distribution of body fat) are associated with arterial stiffening in older adults. Long-term follow-up of this cohort will allow us to examine the prognostic significance of arterial stiffness in an older population. (Am J Hypertension, in press). 9. Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently synthesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 + 3.6 years). ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling, suggesting that it may be an effective agent to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased. (PNAS 2001;98,1171-1175). 10. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening. Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures > 60 mm Hg and systolic pressures > 140 mm Hg to once-daily ALT-711 (210 mg; n= 62) or placebo (n = 31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. The results show that ALT-711 improved total arterial compliance in aged human with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension. (Circulation. 2001;104:r8-r14). 11. We are attempting to identify genetic factors contributing to exaggerated arterial stiffness and arterial intima-medial thickness in a Sardinian population (a "founder population", relatively genetically homogenous compared to "outbred" populations) and to determine whether these factors enhance the predictive accuracy for overall cardiovascular risk, when added to a standard cardiovascular risk profile. R&D contract awarded (D. Schlessinger, Project Officer) 12. Although the geometry of small arteries and arterioles affects their distensibility, the functional correlates of different geometric phenotypes of large arteries have not been characterized in a community based population. We therefore characterized the distribution of carotid arterial geometric phenotypes, their functional correlates, and relationships to gender, age, body size, BP and other measured hemodynamic variables in an older adult populations . The prevalence of specific CGPs in the total sample was: 83.4% for CGP1 (normal), 5.5% for CGP2 (increased wall thickness with normal mass), 2.2% for CGP3 (normal thickness with increased mass), and 8.9% for CGP4 (increased wall thickness with increased mass). Compared to CGP1, all deviant CGPs had increased carotid resistance and had higher CCA circumferential wall stress. Each deviant CGP is characterized by a unique combination of increased circumferential wall stress, with variable FSS, strain, distensibility, central BP, and late pressure augmentation (Hypertension 2001;38:429-433).

摘要或工作：该项目的最终目标是确定动脉僵硬度特性如何影响心肌结构和功能以及如何导致心血管发病率和死亡率。 1. 我们最近在横断面研究中发现，绝经后妇女的雌激素替代疗法 (ERT) 可以降低血压 (BP) 和与年龄相关的动脉僵硬度增加，并且在 ERT 中添加孕激素似乎可以减少这些症状有益的影响。 (老化临床实验研究 13:122-130, 2001)。在第二项研究中，来自巴尔的摩老龄化纵向研究的 226 名健康、血压正常的绝经后女性，平均 (+SD) 年龄为 64 + 10 岁，随访时间为 5.7 + 5.3 年。 77 名女性同时使用雌激素和孕激素（HRT 用户），149 名女性则两者均未使用。随着时间的推移，HRT 使用者的平均收缩压 (SBP) 上升幅度低于非使用者，与其他心血管危险因素、体力活动和饮酒无关。因此，与不服用 HRT 的绝经后女性相比，接受 HRT 的绝经后女性收缩压随时间的增加幅度较小。这种差异随着年龄的增长而加剧。 （安实习医生。2001；135：229-238）。 2. 为了研究绝经后妇女盐负荷期间一氧化氮 (NO) 合成对血压变化的作用，我们在低盐 4-7 天之前和之后测量了不对称二甲基精氨酸 (ADMA)，它是一种有效的内源性 NO 合成抑制剂。 12 名绝经后女性的饮食习惯（70mEg/天）或高盐（260mEg/天）。在调整年龄后，24 小时动态 SBP 和脉压的钠敏感性与 ADMA 从低盐摄入量到高盐摄入量的变化相关。这些发现表明，NO 合成的抑制导致绝经后妇女高盐摄入期间血压升高。 3. 为了确定补充生长激素或性类固醇是否可以改善激素缺乏的老年患者的动脉僵硬度，我们测量了 65 岁及以上男性和女性在激素替代前后的 PWV 和 AGI。 4. 在一项基于人群的老年人心血管疾病研究中评估了主动脉脉搏波速度 (APWV) 的再现性。结果表明，即使超声检查人员和读数员刚刚接受培训，平均 PWV 也是可重复的。 （Am J Hypertens 2001；14：463-468）。 5. 活动咨询试验（ACT）采用了各种患者教育和咨询干预措施，以增加久坐的初级保健人群的身体活动。在干预前后测量 APWV 和冠状动脉危险因素。干预前，年龄越大，血管越僵硬，高密度脂蛋白胆固醇越高，血管弹性越大。高密度脂蛋白胆固醇可能是有氧能力或动脉粥样硬化减少的间接指标，提示了保持血管完整性的机制。 （美国心脏杂志 2001；87, 104-107）。 6. 我们正在 NIH 资助的多中心活动咨询试验中测试这样的假设：1-2 年的家庭有氧运动训练可以减少动脉僵硬度，该试验对 810 名 35-75 岁的受试者进行。 7. Health ABC 是一项针对老年人残疾的前瞻性研究，对 2488 名老年人（平均年龄 74 岁，52% 女性，40% 黑人）进行了评估，评估了血管硬度与身体脂肪之间的关联。与年龄和血压无关，PWV 与体重、腹围、腹部皮下脂肪、腹部内脏脂肪、大腿脂肪面积、总脂肪以及较高水平的葡萄糖、胰岛素和血红蛋白 A1c 呈正相关（全部 p < 0.001）。最强的关联是与腹部内脏脂肪。在多变量分析中，与 PWV 呈独立正相关的是年龄、SBP、心率、腹部内脏脂肪、吸烟、血红蛋白 A1c 和高血压病史。 PWV 与腹部内脏脂肪之间的关联在体重的三分位数中是一致的。因此，在未来的岁月里，将体重（特别是内脏脂肪）保持在正常范围内可能会减缓血管老化的过程，从而可能降低相关风险。 （Am J Hypertension，待出版）。 8. 在宾夕法尼亚州匹兹堡心血管健康研究中心测量了动脉僵硬度。横断面结果表明，与胰岛素抵抗综合征相关的危险因素（高血压、高血糖、高胰岛素血症和腹部脂肪分布）与动脉僵硬有关在老年人中。对这一队列的长期随访将使我们能够检查老年人群中动脉僵硬度的预后意义。 （《Am J Hypertension》，待出版）。 9. 葡萄糖的非酶糖基化和蛋白质交联导致与年龄相关的血管和心肌硬度增加。一些最近合成的噻唑化合物选择性地破坏这些蛋白质交联，降低胶原蛋白的硬度。我们研究了 3-phenacyl-4,5-二甲基噻唑氯化物 (ALT-711) 对老年、健康、非糖尿病猕猴灵长类动物（年龄 21 + 3.6 岁）的动脉和左心室 (LV) 特性的影响及其耦合。 ALT-711 改善了动脉和心室功能，并优化了心室-血管耦合，这表明它可能是改善心血管功能受损的有效药物，这种功能受损是在与衰老、糖尿病或高血压相关的心力衰竭的情况下发生的。和心室僵硬度增加。 (PNAS 2001;98,1171-1175)。 10. 我们测试了 ALT-711（一种高级糖基化终产物交联的新型非酶破坏剂）是否选择性地改善血管硬化老年人的动脉顺应性并降低脉压。美国 9 个中心招募了静息动脉脉压 > 60 mm Hg 和收缩压 > 140 mm Hg 的受试者，并将其随机分配至每日一次 ALT-711（210 mg；n = 62）或安慰剂（n = 31），为期 56 天。研究期间继续进行先前的抗高血压治疗（90% 的受试者）。结果表明，ALT-711改善了患有血管硬化的老年人的总动脉顺应性，并且它可能为这种因衰老、糖尿病和单纯性收缩期高血压而发生的异常提供一种新的治疗方法。 （流通。2001 年；104：r8-r14）。 11. 我们正在尝试确定撒丁岛人群（“创始人群”，与“远交”人群相比在遗传上相对同质）中导致动脉僵硬度和动脉内膜中层厚度过大的遗传因素，并确定这些因素是否增强了预测性。当添加到标准心血管风险概况中时，总体心血管风险的准确性。授予研发合同（D. Schlessinger，项目官员） 12. 虽然小动脉和小动脉的几何形状影响其扩张性，但大动脉不同几何表型的功能相关性尚未在社区人群中得到表征。因此，我们描述了老年人群中颈动脉几何表型的分布、其功能相关性以及与性别、年龄、体型、血压和其他测量的血流动力学变量的关系。总样本中特定 CGP 的患病率是：CGP1（正常）为 83.4%，CGP2（壁厚增加，质量正常）为 5.5%，CGP3（壁厚正常，质量增加）为 2.2%，CGP4 为 8.9%（壁厚随着质量的增加而增加）。与 CGP1 相比，所有异常 CGP 的颈动脉阻力均增加，且 CCA 周壁应力较高。每个异常 CGP 的特点是周壁应力增加、FSS、应变、扩张性、中心血压和晚期压力增加的独特组合（Hypertension 2001；38：429-433）。