ESTROGEN RECEPTOR MODULATION--EFFECTS IN POST MENOPAUSAL WOMEN

雌激素受体调节——对绝经后女性的影响

• 批准号: 6858698
• 负责人: JAMES E UDELSON
• 金额: $ 23.1万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858698
• 关键词: arrhythmia; autonomic reflex; baroreceptors; cardiovascular disorder chemotherapy; cardiovascular function; chemoprevention; clinical research; clinical trials; estrogen inhibitor; estrogen receptors; estrogens; female; genetic markers; genetic polymorphism; genotype; heart contraction; heart ventricle; hormone regulation /control mechanism; human subject; human therapy evaluation; myocardial infarction; myocardial ischemia /hypoxia; osteoporosis; postmenopause; raloxifene; receptor sensitivity

Substantial evidence exists regarding the favorable influence of estrogen on cardiovascular outcomes in women. These favorable effects extend beyond those explained by estrogen effects on lipid profile and other recognized risk factors. Accumulating evidence strongly supports these favorable outcome are in part due to direct effects of estrogen on estrogen receptors expressed in cardiovascular tissues, including both the vascular and myocardium. Attenuating the untoward effects of current hormone replacement strategies on non-cardiovascular tissues such as uterus and breast by development of tissue selective estrogen modulators (SERMS) will likely provide novel strategies for the treatment of bone, neurologic, and cardiovascular diseases. Raloxifene, the first SERM approved, was released recently for prevention of osteoporosis, but data, including new data presented in the SCOR (Project 3) support that raloxifene also directly activates the estrogen receptors now know to be expressed in the cardiovascular system. This project will examine the effects of raloxifene on parameters of cardiovascular structure and function in a population of post-menopausal women who have had a myocardial infarction (MI). We will test the hypothesis that raloxifene directly and favorable influences cardiovascular function following MI, in four Specific Aims that examine indices of: (1) left ventricular remodeling, (2) endothelial function, (3) autonomic tone and neurohormonal activation and (4) vulnerability to ventricular arrhythmias. The influence of raloxifene on these four parameters will be studied in a randomized, placebo-controlled, among post-menopausal women with MI and left ventricular dysfunction. We will also examine, through serial blood samples, specific estrogen receptor-related biochemical and genetic markers with the potential to influence these cardiovascular endpoints. Genetic data collected will directly complement the studies proposed in the Framingham population in SCOR Project 1 and may provide a starting point for pharmacogenic selection of therapies in future patients. This study directly and prospectively tests the overall SCOR hypothesis in a human population and will further our understanding of the underlying mechanisms by which estrogen receptor modulation may diminish the burden of cardiovascular diseases and their sequelae in women. Moreover, this study initiates an area of clinical investigation with potential implications for the therapy of ischemic cardiovascular disease sin both women and men.

有大量证据表明雌激素对女性心血管结局有有利影响。这些有利的影响超出了雌激素对血脂和其他公认危险因素的影响所解释的范围。 越来越多的证据有力地支持这些有利的结果，部分原因是雌激素对心血管组织（包括血管和心肌）表达的雌激素受体的直接影响。通过开发组织选择性雌激素调节剂（SERMS）来减轻当前激素替代策略对子宫和乳房等非心血管组织的不良影响，可能会为治疗骨骼、神经系统和心血管疾病提供新策略。雷洛昔芬是第一个获得批准的 SERM，最近发布用于预防骨质疏松症，但数据，包括 SCOR（项目 3）中提供的新数据，支持雷洛昔芬还直接激活目前已知在心血管系统中表达的雌激素受体。该项目将研究雷洛昔芬对患有心肌梗塞 (MI) 的绝经后妇女群体心血管结构和功能参数的影响。我们将在四个具体目标中检验雷洛昔芬直接且有利地影响 MI 后心血管功能的假设，这些目标检查以下指标：(1) 左心室重塑，(2) 内皮功能，(3) 自主神经张力和神经激素激活，以及 (4)容易发生室性心律失常。雷洛昔芬对这四个参数的影响将在患有心肌梗死和左心室功能障碍的绝经后女性中进行随机、安慰剂对照研究。我们还将通过连续血液样本检查可能影响这些心血管终点的特定雌激素受体相关生化和遗传标记。收集的遗传数据将直接补充 SCOR 项目 1 中 Framingham 人群提出的研究，并可能为未来患者治疗的药理学选择提供起点。这项研究直接、前瞻性地测试了人群中的整体 SCOR 假设，并将进一步加深我们对雌激素受体调节可能减轻女性心血管疾病及其后遗症负担的潜在机制的理解。此外，这项研究启动了一个临床研究领域，对女性和男性的缺血性心血管疾病的治疗具有潜在影响。