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

人类免疫缺陷病毒阳性(HIV+)患者服用抗逆转录病毒药物后寿命延长 治疗(ART)，但现在正在经历冠状动脉疾病(CAD)作为重要的死亡原因， 尤其是随着年龄的增长。由于传统的冠心病风险因素不能很好地解释这种冠心病，我们 假设HIV的身体成分发生变化会导致代谢活性增加 腹部和冠状动脉周围的内脏脂肪组织(心外膜脂肪) 组织：EAT)释放炎症细胞因子，对全身和局部基础 加速HIV+患者的CAD过程。由EAT引起的局部炎症增加 可能在冠状动脉内皮功能障碍的过程中起着关键作用。 冠心病的进展和临床表现，是亚临床疾病的标志，是一种独立的 不良心脏事件的预测指标，以及医疗干预的潜在目标。此外，在HIV+ 女性内皮功能障碍的其他因素可能很重要，如卵巢储备减少和 其他通常影响艾滋病毒携带者女性的荷尔蒙异常。我们最近开发了 基于MRI的非侵入性、可重复性的方法测量冠状动脉内皮功能(CEF)。这是一项新的 非侵入性评估CEF的能力提供了一种探索导致CAD的机制的手段 病理生理学艾滋病毒阳性的女性和男性。我们在本申请中建议确定1)CEF是否 在HIV携带者中，炎症和进食的标记物呈负相关，2)这种关系 与艾滋病毒携带者相比，女性与男性不同；3)卵巢储备减少是否 与HIV+女性血管内皮细胞异常有关。我们将在HIV+人群中确定 CEF的减少至少部分可以由炎症增加来解释。这些研究将结合在一起 为HIV相关血管疾病提供新的病理生理学见解，以及 艾滋病毒携带者的女性和男性之间可能存在差异。这些研究是更好地 了解艾滋病毒中常见的血管疾病的性别差异。建议的研究是 在建议的时间段内在临床上可行，并可用于设计未来的治疗干预 研究，并可能从根本上提供一个新的理解最重要的促成因素 HIV中的内皮功能障碍。

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.