Effects of Hormone Therapy on Heart fat and Atherosclerosis Progression in Early Postmenopausal Women from the KEEPS Trial

项目摘要/摘要 越来越多的证据支持心脏脂肪在冠心病(CHD)发病机制中的作用。相对于 心包，两个不同的心脏脂肪储存库可以被定义；心外膜脂肪组织(EAT)，心脏内的脂肪 心包和心包旁脂肪组织(PAT)，即心包外的脂肪。我们最近在 绝经后妇女的全国妇女健康研究(SWAN)队列研究 与绝经前的女性相比，心脏脂肪的体积明显更大， 尤其是PAT，与较低的水平和围绝经期胰岛素水平的急剧下降显著相关 内源性雌二醇(E2)。这些发现表明，心脏脂肪可能是一种容易检测的、无创的 绝经后妇女新的冠心病危险标志及雌激素在心脏脂肪堆积中的作用 这可能仅限于PAT Depot。类似于内源性雌激素，外源性雌激素，也称为 更年期激素治疗(HT)，可能会对心脏脂肪堆积和 女性心脏脂肪含量与动脉粥样硬化风险之间的联系。此外，HT方案的类型 (例如，口服和透皮)对绝经后妇女心脏脂肪堆积的影响可能不同。 有关心脏脂肪、更年期和冠心病风险的横断面数据有限。克罗诺斯人很早 雌激素预防研究(Keep)为研究羟色胺的不同影响提供了一个独特的机会 心脏脂肪堆积的养生法及其与动脉粥样硬化发展的关系。保持 是一项多中心、随机、安慰剂对照的两种HT方案(口服和对照)的临床试验 与安慰剂相比，在727名早期患者中，研究了亚临床动脉粥样硬化的4年进展 绝经后的女性。心脏脂肪体积和亚临床动脉粥样硬化的基线和随访数据 测量冠状动脉钙化(CAC)，以及羟色胺使用、病史、心脏代谢、 炎症和脂肪细胞因子标记物被收集为Keep的一部分，并完成了一项辅助研究 留着。这些现有数据将用于进行二次分析，以评估以下具体情况 目的：目的1：评价口服和透皮给药与安慰剂对心脏脂肪累积的影响； 目的2a：研究心脏脂肪储备基础容量的纵向关系及其变化 与亚临床动脉粥样硬化的变化；以及目标2b：探讨HT方案改变 心脏脂肪堆积与亚临床动脉粥样硬化的纵向关联。计划中的研究需要 探讨衰老和绝经导致女性心血管疾病风险增加的新机制。 这项提案将为正在进行的关于高血压对心血管影响的辩论提供关键信息。 在选择绝经后妇女时，可以用来为临床决策提供信息。 在绝经后早期妇女中选择合适的高血压治疗方案并平衡其风险和益处。

PROJECT SUMMARY/ABSTRACT Mounting evidence support a role of heart fat in the pathogenesis of coronary heart disease (CHD). Relative to the pericardium, two distinct heart fat depots can be defined; epicardial adipose tissue (EAT), the fat within the pericardium, and paracardial adipose tissue (PAT), the fat outside the pericardium. We have recently shown in the Study of Women’s Health Across the Nation (SWAN) cohort study that postmenopausal women have significantly greater volumes of heart fat than premenopausal women, and that higher volumes of heart fat, particularly PAT, are significantly associated with lower levels and a steeper perimenopausal decline of endogenous estradiol (E2). These findings indicate that heart fat could be a readily-detectable, noninvasive novel CHD risk marker for postmenopausal women and suggest a role of estrogens in heart fat accumulation that could be limited to PAT depot. Similar to endogenous estrogen, exogenous estrogens, also known as menopause hormone therapy (HT), could have a significant impact on heart fat accumulation and on associations linking heart fat volumes with risk of atherosclerosis in women. Additionally, type of HT regimens (e.g. oral vs. transdermal) could have differential effects on heart fat accumulation in postmenopausal women. Limited cross-sectional data are available linking heart fat, menopause, and CHD risk. The Kronos Early Estrogen Prevention Study (KEEPS) provides a unique opportunity to examine the differential effects of HT regimens on heart fat accumulation and their associations with atherosclerosis development overtime. KEEPS was a multi-center, randomized, placebo-controlled clinical trial of the effects of two HT regimens (oral and transdermal), compared to placebo, on 4-year progression of subclinical atherosclerosis among 727 early postmenopausal women. Baseline and follow-up data on heart fat volumes and subclinical atherosclerotic measure coronary artery calcification (CAC), in addition to data on HT use, medical history, cardiometabolic, inflammatory and adipocytokine markers were collected as part of KEEPS and a completed ancillary study to KEEPS. These existing data will be used to conduct a secondary analysis to assess the following specific aims: Aim 1: to assess the effect of oral and transdermal HT vs. placebo on heart fat accumulations over time; Aim 2a: to examine the longitudinal relationships of baseline volumes of heart fat depots and their changes with changes in subclinical atherosclerosis; and Aim 2b: to explore the extent to which HT regimens modify the longitudinal associations of heart fat depots with subclinical atherosclerosis. The planned study entails investigation of novel mechanisms by which aging and menopause contribute to raise in CVD risk in women. This proposal will provide key information on the ongoing debate on the cardiovascular impact of HT in postmenopausal women, and could be used to inform clinical decision-making in selecting women who are appropriate candidates for HT and balancing its risks and benefits in early postmenopausal women.