Age Associated Changes In Vascular Stiffness Properties

摘要或工作：该项目的最终目标是确定动脉硬度特性如何影响心肌结构和功能，并促进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，而在ERT中添加黄体酮似乎会降低这些有益效果。[中国老年医学杂志]，2001。在第二项研究中，226名来自巴尔的摩老龄化纵向研究的健康、血压正常的绝经后妇女，平均（+SD）年龄为64 + 10岁，随访5.7 + 5.3年。77名妇女同时使用雌激素和黄体酮（HRT使用者），149名不使用。随着时间的推移，HRT使用者的平均收缩压（SBP）比不使用者的增加更少，独立于其他心血管危险因素，身体活动和酒精使用。因此，绝经后接受激素替代疗法的妇女随着时间的推移，收缩压的增加比未接受激素替代疗法的妇女要小。这种差异随着年龄的增长而加剧。（实习医学，2001;135:229-238）。2. 为了研究一氧化氮（NO）合成在绝经后妇女盐负荷期间血压变化中的作用，我们测量了12名绝经后妇女在低盐（70mEg/天）或高盐（260mEg/天）饮食前后4-7天的不对称二甲基精氨酸（ADMA），一种有效的内源性NO合成抑制剂。经年龄调整后，24小时动态收缩压和脉压的钠敏感性与ADMA从低盐摄入到高盐摄入的变化相关。这些发现表明，抑制NO合成有助于绝经后妇女高盐摄入时血压升高。3. 为了确定补充生长激素或性类固醇是否能改善老年激素缺乏成年人的动脉僵硬特性，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，评估了主动脉脉冲波速度（APWV）的可重复性。结果表明，即使超声师和读取器是新培训的，平均PWV也是可重复的。[J] .中华医学杂志2001；14:463-468。5. 活动咨询试验（ACT）采用各种患者教育和咨询干预措施来增加久坐的初级保健人群的身体活动。干预前后分别测量APWV和冠状动脉危险因素。干预前，年龄越大，血管越硬，高密度脂蛋白胆固醇越高，血管越有弹性。高密度脂蛋白胆固醇可能是有氧能力或动脉粥样硬化程度较低的间接指标，提示维持血管完整性的机制。（美国医学杂志2001；87,104-107）。6. 在美国国立卫生研究院赞助的多中心活动咨询试验中，我们对810名35-75岁的受试者进行了1-2年的家庭有氧运动训练可以降低动脉僵硬的假设进行了验证。7. 研究人员对2488名老年人（平均年龄74岁，52%为女性，40%为黑人）进行了血管僵硬和体脂之间的关联评估，这些老年人参加了一项关于老年人残疾的前瞻性研究Health ABC。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、总脂肪和较高的葡萄糖、胰岛素和血红蛋白A1c水平呈正相关（均p < 0.001）。相关性最强的是腹部内脏脂肪。在多变量分析中，与PWV有独立正相关的是年龄、收缩压、心率、腹部内脏脂肪、吸烟、血红蛋白A1c和高血压史。PWV与腹部内脏脂肪之间的关系在体重的每五分之一中都是一致的。因此，将体重（特别是内脏脂肪）保持在正常范围内，可以减缓血管老化的过程，可能降低相关风险。（Am J Hypertension，出版）。8. 动脉硬化是在宾夕法尼亚州匹兹堡市的心血管健康研究中心进行的。横断面研究结果表明，与胰岛素抵抗综合征（高血压、高血糖、高胰岛素血症和腹部体脂分布）相关的危险因素与老年人动脉硬化有关。该队列的长期随访将使我们能够检查动脉僵硬在老年人群中的预后意义。（Am J Hypertension，出版）。9. 非酶糖基化和葡萄糖交联蛋白质有助于血管和心肌僵硬的年龄相关的增加。最近合成的一些噻唑类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-dimethylthiazolium chloride （ALT-711）对老龄、健康、非糖尿病猕猴灵长类动物（21 + 3.6岁）动脉和左心室（LV）特性及其耦合的影响。ALT-711改善了动脉和心室功能，优化了心室-血管耦合，这表明它可能是一种有效的药物，可以改善心血管功能受损，这些心血管功能受损发生在与衰老、糖尿病或高血压相关的心力衰竭中，这些情况下动脉和心室僵硬度增加。(PNAS 2001; 98年,1171 - 1175)。10. 我们测试了ALT-711，一种新型的晚期糖基化终产物交联的非酶破断剂，是否选择性地改善血管硬化老年人的动脉顺应性和降低脉压。9个美国中心招募并随机分配静息动脉脉压bbb60 mm Hg和收缩压>40 mm Hg的受试者，每天一次ALT-711 （210 mg, n= 62）或安慰剂（n = 31），持续56天。已有的抗高血压治疗（90%的受试者）在研究期间继续进行。结果表明，ALT-711可改善老年血管硬化患者的总动脉顺应性，可能为老年、糖尿病和孤立性收缩期高血压患者的血管硬化异常提供一种新的治疗方法。(循环。2001;104:r8-r14)。11. 我们试图在撒丁岛人群（“创始人群”，与“近亲繁殖”人群相比，基因相对同质）中确定导致动脉僵硬和动脉内膜-内侧厚度夸大的遗传因素，并确定这些因素在加入标准心血管风险概况时是否提高了对整体心血管风险的预测准确性。研发合同授予（D. Schlessinger，项目官员）尽管小动脉和小动脉的几何形状会影响它们的扩张性，但在以社区为基础的人群中，大动脉不同几何表型的功能相关性尚未得到表征。因此，我们对老年人群中颈动脉几何表型的分布、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进行了表征。特异性cgp在总样本中的患病率为：CGP1（正常）为83.4%,CGP2（正常质量增加壁厚）为5.5%,CGP3（正常厚度增加质量）为2.2%,CGP4（壁厚增加质量）为8.9%。与cgp相比，所有异常的cgp均有颈动脉阻力增加，CCA周壁应力增加。每一个异常的CGP都有一个独特的特点：环壁应力增加，伴有可变的FSS、应变、膨胀性、中央血压和晚期血压升高（Hypertension 2001;38:429-433）。

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).