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

艾滋病毒女性内皮功能障碍病理生理学的新因素

• 批准号: 10115108
• 负责人: Allison G Hays
• 金额: $ 28.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115108
• 关键词: Abdomen; Address; Adipose tissue; Affect; Age; Age Factors; Atherosclerosis; Biological Markers; Blood Vessels; Body Composition; Cardiac; Cardiovascular Diseases; Cardiovascular system; Catheterization; Cause of Death; Cessation of life; Cholesterol Homeostasis; Chronic; Clinical; Clinical Research; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Depressed mood; Development; Disease; Endothelium; Estrogens; Event; Experimental Models; Functional disorder; Funding; Future; General Population; Gonadal Steroid Hormones; HIV; HIV Infections; Heart Diseases; Hematological Disease; Hormonal; Imaging Techniques; Impairment; Individual; Inflammation; Inflammatory; Intervention; Intervention Studies; Knowledge; Link; Liver; Longevity; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Medical; Menopause; Metabolic; Methods; Myocardial Infarction; Obesity; Observational Study; Pathway interactions; Peptide Hydrolases; Play; Population; Premenopause; Prevalence; Process; Prognostic Marker; Proprotein Convertases; Reporting; Reproducibility; Risk; Risk Factors; Role; Sex Differences; Source; Subtilisins; Testing; Testosterone; Therapeutic Intervention; Time; Vascular Diseases; Visceral; Woman; Work; antiretroviral therapy; base; cardiovascular disorder risk; cardiovascular risk factor; cytokine; design; endothelial dysfunction; experience; heart disease risk; high risk population; immune activation; inflammatory marker; insight; lipid metabolism; men; mullerian-inhibiting hormone; non-invasive imaging; novel; ovarian reserve; paracrine; prevent; sex; systemic inflammatory response

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.

人类免疫缺陷病毒阳性（HIV+）个体服用抗逆转录病毒药物后寿命更长 治疗（ART），但现在冠状动脉疾病（CAD）已成为重要的死亡原因， 尤其是随着年龄的增长。由于这种 CAD 无法用传统的 CAD 风险因素很好地解释，我们 假设 HIV 体内发生的身体成分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）释放炎症细胞因子，对全身和局部的基本功能有贡献 过程加速 HIV+ 个体的 CAD。 EAT 引起的局部炎症增加 可能有助于冠状动脉内皮功能障碍的过程，在冠状动脉内皮功能障碍中起关键作用 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。此外，在艾滋病毒+ 女性其他因素可能对内皮功能障碍也很重要，例如卵巢储备减少和 其他通常影响女性艾滋病毒感染者的荷尔蒙异常。我们最近开发了 基于 MRI 的无创、可重复的测量冠状动脉内皮功能 (CEF) 的方法。这个新的 非侵入性评估 CEF 的能力提供了一种探索 CAD 机制的方法 病理生理学 HIV+ 女性和男性。我们建议在此申请中确定 1) 是否 CEF HIV + 人群中炎症标志物和 EAT 呈负相关，2) 这种关系是否存在 与感染艾滋病毒的男性相比，女性的情况有所不同，3) 卵巢储备功能下降是否会导致 与 HIV+ 女性的内皮异常有关。我们将确定艾滋病病毒感染者是否 CEF 降低至少部分可以通过炎症增加来解释。这些研究将共同 为 HIV 相关血管疾病提供新的病理生理学见解，以及病理生理学如何 感染艾滋病毒的女性和男性之间可能有所不同。这些研究是迈向更好的关键的第一步 了解艾滋病毒中常见的血管疾病的性别差异。拟议的研究是 在建议的时间段内临床可行，并可用于设计未来的治疗干预措施 研究，并可能对最重要的影响因素提供全新的理解 HIV 中的内皮功能障碍。