ESTROGEN RECEPTOR MODULATION--EFFECTS IN POST MENOPAUSAL WOMEN

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已知危险因素的影响。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）中雌激素受体表达的直接影响。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，可能为骨、神经和心血管疾病的治疗提供新的策略。雷洛昔芬是首个获批的SERM，最近发布用于预防骨质疏松症，但数据，包括SCOR（项目3）中提出的新数据支持雷洛昔芬也直接激活雌激素受体，目前已知其在心血管系统中表达。本项目将研究雷洛昔芬对绝经后心肌梗死（MI）妇女心血管结构和功能参数的影响。我们将在四个特定目的中检验雷洛昔芬对心肌梗死后心血管功能直接和有利影响的假设，这些指标包括：(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)室性心律失常的易感性。雷洛昔芬对这四个参数的影响将在一项随机、安慰剂对照的绝经后心肌梗死和左心室功能障碍妇女中进行研究。我们还将通过一系列的血液样本，检查特异性雌激素受体相关的生化和遗传标记物，这些标记物有可能影响这些心血管终点。收集的遗传数据将直接补充SCOR项目1在Framingham人群中提出的研究，并可能为未来患者的药物选择提供起点。本研究在人群中直接和前瞻性地检验了整体SCOR假说，并将进一步了解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。此外，本研究开创了一个临床研究领域，对女性和男性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.