ESTROGEN RECEPTOR MODULATION--EFFECTS IN POST MENOPAUSAL WOMEN

有大量证据表明雌激素对女性心血管结局具有有利影响。这些有利的影响超出了雌激素对血脂的影响和其他公认的风险因素。 越来越多的证据强烈支持这些有利的结果，部分是由于雌激素对心血管组织（包括血管和心肌）中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）来减轻目前激素替代策略对非心血管组织（如子宫和乳腺）的不良影响，可能会为骨、神经和心血管疾病的治疗提供新的策略。雷洛昔芬是第一个被批准的SERM，最近被发布用于预防骨质疏松症，但数据，包括SCOR（项目3）中提出的新数据支持雷洛昔芬也直接激活雌激素受体，现在已知在心血管系统中表达。本项目将研究雷洛昔芬对患有心肌梗死（MI）的绝经后妇女人群心血管结构和功能参数的影响。我们将检验雷洛昔芬直接和有利地影响MI后心血管功能的假设，在四个特定目的中检查指标：（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，（4）室性心律失常的脆弱性。将在患有MI和左心室功能不全的绝经后女性中进行随机化、安慰剂对照研究，研究雷洛昔芬对这四个参数的影响。我们还将通过系列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物。收集的遗传数据将直接补充SCOR项目1中在Frachial人群中拟定的研究，并可能为未来患者的药物治疗选择提供起点。这项研究直接和前瞻性地测试了总体SCOR假设在人群中，并将进一步了解雌激素受体调节可能减少女性心血管疾病及其后遗症的负担的潜在机制。此外，这项研究还开创了一个临床研究领域，对男女缺血性心血管疾病的治疗具有潜在的意义。

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.