Emerging factors in the pathophysiology of endothelial dysfunction in HIV+ women

人类免疫缺陷病毒阳性（HIV+）患者使用抗逆转录病毒药物后的寿命更长 治疗（ART），但现在正经历冠状动脉疾病（CAD）作为一个重要的死因， 尤其是随着年龄的增长。由于这种CAD不能很好地解释传统的CAD风险因素，我们 假设HIV体内组成发生变化导致代谢活性增加 腹部和冠状动脉周围的内脏脂肪组织（VAT）（心外膜脂肪 组织：EAT），其释放炎性细胞因子，全身性和局部性地促进基本的 加速HIV+个体CAD的过程。EAT引起的局部炎症增加 可能导致冠状动脉内皮功能障碍的过程， CAD的进展和临床表现，是亚临床疾病的标志物，是一种独立的 不良心脏事件的预测因子，以及医疗干预的潜在目标。在HIV+ 女性其他因素可能是重要的内皮功能障碍，如卵巢储备减少， 其他激素异常通常影响艾滋病毒感染妇女。我们最近开发 无创、可重复的基于MRI的方法来测量冠状动脉内皮功能（CEF）。这个新 非侵入性评估CEF的能力提供了一种探测CAD机制的方法 艾滋病毒阳性妇女和男子。在本申请中，我们建议确定1）持续进修基金是否 炎症和EAT的标志物在HIV +人群中呈负相关，2）这种关系是否 女性与男性艾滋病毒感染者之间的差异，以及3）卵巢储备减少是否是 与HIV阳性女性的内皮异常相关。我们将在HIV+人群中确定 减少的CEF可以至少部分地通过增加的炎症来解释。这些研究将 为HIV相关血管疾病提供了新的病理生理学见解， 艾滋病毒感染者男女之间可能存在差异。这些研究是关键的第一步， 了解艾滋病毒中常见的血管疾病的性别差异。拟定研究 在拟定时间段内具有临床可行性，可用于设计未来的治疗干预 研究，并可能提供一个从根本上新的理解的最重要的影响因素， 内皮功能障碍

Human immunodeficiency virus positive (HIV+) individuals are living longer with antiretroviral therapy (ART) but are now experiencing coronary artery disease (CAD) as an important cause of death, especially as they age. Because this CAD is not well explained by conventional CAD risk factors, we hypothesize that changes that occur in body composition in HIV result in increased metabolically-active visceral adipose tissue (VAT) in the abdomen and around the coronary arteries (epicardial adipose tissue: EAT) that releases inflammatory cytokines contributing systemically and locally to the fundamental processes accelerating CAD in HIV+ individuals. The increased local inflammation resulting from EAT may contribute to the process of coronary endothelial dysfunction which plays a critical role in the progression and clinical manifestations of CAD, and is a marker for sub-clinical disease, an independent predictor of adverse cardiac events, and a potential target for medical interventions. Moreover in HIV+ women other factors may be important in endothelial dysfunction such as a reduced ovarian reserve and other hormonal abnormalities that commonly affect women with HIV. We recently developed noninvasive, reproducible MRI-based methods to measure coronary endothelial function (CEF). This new ability to noninvasively evaluate CEF offers a means to probe mechanisms contributing to CAD pathophysiology HIV+ women and men. We propose in this application to determine 1) whether CEF and markers of inflammation and EAT are inversely related in HIV + people, 2) whether this relationship differs in women compared with men living with HIV and 3) whether reduced ovarian reserve is associated with endothelial abnormalities in HIV+ women. We will determine in HIV+ people whether reduced CEF can be explained, at least in part, by increased inflammation. Together these studies will offer new pathophysiologic insights into HIV-associated vascular disease, and how the pathophysiology may differ between women and men living with HIV. These studies are critical first steps to better understanding sex-differences in vascular disease that develops commonly in HIV. The proposed study is clinically feasible in the proposed time period, and could be used to design future therapeutic intervention studies, and may offer a fundamentally new understanding of the most important contributing factors of endothelial dysfunction in HIV.