AGE ASSOCIATED CHANGES IN VASCULAR STIFFNESS PROPERTIES

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。答：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）可降低血压和与年龄相关的动脉硬化增加，而在ERT中添加黄体酮似乎会降低这些有益效果。ERT也被发现可以减少收缩压的纵向变化。在年龄较大的绝经后妇女和BMI较低的妇女中，ERT引起的收缩压纵向增加的减少更为明显。B.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名不敏感的绝经后妇女在低盐（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AD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。C.为了确定补充生长激素或性类固醇是否能改善这些物质缺乏的老年人的动脉僵硬特性，我们测量了65岁及以上的男性和女性在激素替代前后的脉搏波速度和AGI。D.我们正在测试一个假设，即1-2年的家庭有氧运动训练可以减少动脉僵硬，这是在美国国立卫生研究院赞助的多中心活动咨询试验中进行的，共有810名35-75岁的受试者。E.为了确定有氧运动训练是否可以降低老年心力衰竭患者升高的动脉僵硬度，我们将在3个月有氧训练计划前后测量动脉僵硬度和峰值VO2。一项多中心研究确定动脉僵硬是否是自由生活老年人心血管事件的独立危险因素。动脉僵硬度将在宾夕法尼亚州匹兹堡市进行心血管健康研究。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。H.一项多中心研究已经启动，该研究将胶原交联破坏化合物ALT-711给予轻度高血压受试者8周，以确定其对动脉僵硬和心室结构和功能的影响。1 .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。

SUMMARY OF 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. A. We have recently discovered, in cross-sectional studies, that estrogen replacement therapy (ERT) in postmenopausal women reduced BP and the age-associated increase in arterial stiffness and that the addition of progestins to ERT appeared to reduce these beneficial effects. ERT has also been found to reduce longitudinal changes in SBP. This reduction of the longitudinal increase in SBP exerted by ERT was more pronounced in older postmenopausal women, and in those with lower BMI. B. To examine the role of nitric oxide (NO) synthesis on blood pressure 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 nonsensitive postmenopausal women. Sodium sensitivity of 24 hour ambulatory SBP and pulse pressure correlated with change in AD as A 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. C. To determine whether growth hormone or sex steroid supplementation ameliorates arterial stiffness properties in older adults with deficiencies of these substances, we measured pulse wave velocity and AGI in men and women aged 65 years and older, before and after hormonal replacement. D. 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. E. To determine whether aerobic exercise training can reduce the elevated arterial stiffness of older heart failure patients, we will measure arterial stiffness and peak VO2 before and after a 3 month program of aerobic training. F. A multicenter study to determine whether arterial stiffness is an independent risk factor for cardiovascular events in elderly free-living persons has been initiated. G. Arterial stiffness will be measured in the Pittsburgh, PA site for the Cardiovascular Health Study. Long-term follow-up of this cohort will allow us to examine the prognostic significance of arterial stiffness in an older population. H. A multicenter study has been initiated in which The collagen crosslink-breaking compound ALT-711 previously shown to reduce arterial stiffness in monkeys, is being given to mildly hypertensive human subjects for eight (8) weeks to determine its effects on arterial stiffness and ventricular structure and function. I. 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.