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; 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特性如何影响心肌结构和功能，并有助于心血管发病率和死亡率。 1。我们最近在横断面研究中发现，绝经后妇女中的雌激素替代疗法（ERT）降低了血压（BP）和与年龄相关的动脉僵硬度的增加，并且将孕激素添加到ERT中似乎可以减少这些有益作用。 （Aming Clin Exp Res 13：122-130，2001）。在第二项研究中，226名来自巴尔的摩纵向研究的健康，正常的绝经后妇女的平均（ + SD）年龄为64 + 10年，为5.7 + 5.3岁。 77名妇女同时使用雌激素和孕激素（HRT使用者），而149名妇女都没有使用。随着时间的流逝，与非用户相比，HRT使用者的平均收缩压（SBP）少于其他心血管危险因素，体育锻炼和饮酒。因此，与不服用HRT相比，服用HRT的绝经后妇女的SBP随时间增加。这种差异在较老的年龄加剧。 （Ann InternMed。2001; 135：229-238）。 2。为了检查绝经后妇女盐负荷过程中BP变化的作用，我们测量了一种不对称的二甲基精氨酸（ADMA），这是一种有效的内源性内源性抑制剂，这是低 - 盐（70meg/day）或高盐（70meg/day）或高盐（260meg/nota）（260meg/nota）的有效内源性抑制剂（260meg/nota）（70meg/day）。调整年龄调整后，24小时门诊SBP和脉压的敏感性与从低盐的摄入量从低盐摄入到高盐的变化相关。这些发现表明，绝经后妇女的高盐摄入期间的抑制无合成有助于BP的增加。 3。为了确定生长激素或性类固醇补充剂是否可以改善较旧的激素不足的成年人的动脉僵硬特性，我们在65岁以上的男性和女性中测量了激素替代之前和之后的男性和女性的PWV和AGI。 4。在老年人的基于人群的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，即使对超声波读者和读者进行了新训练，平均PWV也可以再现。 （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体育活动。干预前和干预后测量了APWV和冠状动脉危险因素。干预前，年龄较大的年龄与更硬的血管和更高的HDL胆固醇有关。 HDL胆固醇可能是有氧能力或较少动脉粥样硬化的间接指标，这表明了保持血管完整性的机制。 （AM J Cardiol 2001; 87，104-107）。 6。我们正在检验以下假设：1 - 2年的家庭有氧运动训练可以减少810名受试者35 - 75岁的受试者的多中心赞助活动咨询试验中的动脉僵硬。 7。在2488名老年人中评估了血管僵硬与体内脂肪之间的关联（平均年龄74岁，女性为52％，黑色40％），这是对老年人的残疾的前瞻性研究。与年龄和BP无关，PWV与体重，腹膜，腹部皮下脂肪，腹部内脏脂肪，大腿脂肪面积，总脂肪和较高葡萄糖，胰岛素和血红蛋白A1C的水平呈正相关。最强的关联是与腹部内脏脂肪的关联。在多元分析中，与PWV的独立正相关是年龄，SBP，心率，腹部内脏脂肪，吸烟，血红蛋白A1C和高血压史。 PWV和腹部内脏脂肪之间的关联在体重的三分位数之间是一致的。因此，通过前进的年份将体重（特别是内脏脂肪）保持在正常限制中可能会减慢血管衰老的过程，从而降低相关风险。 （Am J高血压，印刷中）。 8。在宾夕法尼亚州匹兹堡的心血管健康研究横截面结果中测量了动脉僵硬，这表明与胰岛素抵抗综合征（高血压，高血糖，高胰岛素血症和体内脂肪的腹部分布）相关的危险因素与老年人的动脉僵硬有关。该队列的长期随访将使我们能够检查老年人群中动脉僵硬的预后意义。 （Am J高血压，印刷中）。 9。通过葡萄糖对蛋白质的非酶糖基化和交联，有助于与年龄相关的血管和心肌刚度增加。一些最近合成的硫唑化合物选择性地分解了这些蛋白质交联，从而降低了胶原蛋白的刚度。我们研究了3-苯基酰基-4,5-二甲基噻嗪氯化物（ALT-711）对动脉和左心室（LV）特性及其在老，健康的，不含糖的MACACA MULATTA PRIRES（年龄21 + 3.6岁）中的动脉（LV）特性的影响。 ALT-711改善了动脉和心室功能以及优化的心室血管耦合，这表明它可能是改善与衰老，糖尿病或高血压相关的心力衰竭，动脉僵硬和心室僵硬相关的心力衰竭的心力衰竭的有效药物。 （PNAS 2001; 98,1171-1175）。 10。我们测试了Alt-711是否是晚期糖基化终产物交联的新型非酶断裂器，有选择地改善动脉依从性并降低血管僵硬的老年人的脉压。 9个美国中心招募并随机分配了静止的动脉脉冲压力> 60 mm Hg，收缩压> 140 mm Hg> 140 mm Hg至一次每日ALT-711（210 mg; n = 62）或安慰剂（n = 31）（n = 31），持续56天。在研究期间，继续存在降压治疗（90％的受试者）。结果表明，ALT-711改善了老年人的总动脉依从性，血管僵硬，它可能会为这种异常提供一种新型的治疗方法，这种异常发生在衰老，糖尿病和分离的收缩压高血压下。 （Circulation。2001; 104：R8-R14）。 11。我们正在尝试确定撒丁岛人口中夸张的动脉僵硬和动脉内膜厚度的遗传因素（“创始人人群”，与“近亲”人群相比相对遗传同质性），并确定这些因素是否会增强对心血管风险的预测性准确性，并添加到标准型cardiavastial Cardiovarpascult cartiovascular Cardipascular Cardipascular Cardipascular Cardipascular Cardipascult。授予研发合同（项目官D. Schlessinger） 12。尽管小动脉和动脉的几何形状会影响它们的扩张性，但在社区人群中尚未表征大动脉不同几何表型的功能相关性。因此，我们表征了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，BP和其他测量的血液动力学变量的关系。总样本中特异性CGP的患病率为：CGP1（正常）为83.4％，CGP2为5.5％（壁厚增加，正常质量增加），CGP3（正常厚度且质量增加）为2.2％，CGP4（质量增加）为8.9％（增加质量增加的壁厚）。与CGP1相比，所有异常CGP都具有颈动脉抗性增加，并且CCA圆周壁应力更高。每个变形的CGP的特征是圆周应力增加的独特组合，以及可变的FS，应变，可扩张性，中央BP和晚压力增加（Hyperension 2001; 38：429-433）。