Understanding Inflammatory and Metabolic Pathways of Myocardial and Vascular Dysfunction in South African Youth Living with Perinatal HIV

了解南非围产期艾滋病毒感染者心肌和血管功能障碍的炎症和代谢途径

• 批准号: 10391500
• 负责人: Jennifer Jao
• 金额: $ 55.08万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391500
• 关键词: Acids; Address; Adolescent; Adult; Africa South of the Sahara; Age; Anti-Retroviral Agents; Biological; Blood Vessels; Body Surface Area; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Child; Data; Development; Dyslipidemias; Early identification; Eicosanoid Production; Eicosanoids; Exposure to; Functional disorder; Funding; Future; HIV; Heart failure; Hydroxyeicosatetraenoic Acids; Image; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Intervention; Life; Magnetic Resonance Imaging; Measures; Metabolic; Metabolic Pathway; Methods; Mitochondria; Muscle Cells; Myocardial; Myocardial dysfunction; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Perinatal; Permeability; Prevention strategy; Process; Public Health; Research Infrastructure; Risk; Role; South African; Techniques; Time; United States National Institutes of Health; Vascular Diseases; Ventricular; Youth; acylcarnitine; antiretroviral therapy; cardiac magnetic resonance imaging; cardiometabolism; cardiovascular disorder risk; cardiovascular health; cohort; comparison group; dietary; endothelial dysfunction; experience; fatty acid oxidation; high risk; immune activation; immunomodulatory therapies; insight; interest; metabolomics; mitochondrial dysfunction; mortality; novel; pediatric human immunodeficiency virus; perinatal HIV; sex; systemic inflammatory response; time use

ABSTRACT Cardiovascular disease (CVD) remains a significant concern in adults living with HIV (AHIV) on antiretroviral therapy (ART). Little is known about subclinical or early upstream CVD pathogenesis in youth living with perinatally acquired HIV (YPHIV) who stand to benefit the most from early identification of subclinical CVD. ART expansion has reduced pediatric HIV mortality, allowing YPHIV to reach adulthood, but not without lifelong exposure to immune activation, inflammation, and ART, all of which potentiate CVD. Several studies including ours have shown subclinical myocardial dysfunction in YPHIV, but few have evaluated underlying metabolic pathways or been conducted with well-matched comparison groups of youth living with non- perinatally acquired HIV (YNPHIV) and HIV-unexposed uninfected (HUU) youth in sub-Saharan Africa, where currently 90% of the world’s children with HIV reside. We have demonstrated high rates (25%) of right ventricular systolic dysfunction and insulin resistance (21%) in our cohort of South African YPHIV. In addition, our YPHIV have an increased risk for endothelial dysfunction and dyslipidemia compared to uninfected youth. However, detailed sensitive imaging data to comprehensively measure myocardial and vascular dysfunction are urgently needed in YPHIV to understand the role of these precursors in end conditions such as heart failure and CVD which we have shown to be more prevalent in AHIV. In addition, studies in YPHIV of underlying metabolic pathways involved in early/primordial factors across the cascade of myocardial/vascular dysfunction resulting in CVD are lacking and critical to providing insight into early prediction and potential mitigation of the development of cardiometabolic complications among YPHIV into adulthood. For this proposal we will leverage the Cape Town Adolescent and Antiretroviral Cohort (CTAAC) to assess whether ART-treated perinatally acquired HIV is associated with worsened subclinical myocardial or vascular dysfunction over time using YNPHIV and HUU youth comparison groups of similar age, sex, and body surface area (BSA) and employing cardiovascular magnetic resonance imaging (CMR), a sensitive multiparametric method of investigating multiple cardiovascular domains. Next, we will use novel metabolomics techniques to explore whether a signature cluster of intermediary or proinflammatory metabolites representing eicosanoid imbalances and mitochondrial shifts in fatty acid oxidation are different in YPHIV compared to YNPHIV or HUU youth and are associated with subclinical myocardial or vascular dysfunction in YPHIV. Lastly, we will explore how inflammation correlates with these eicosanoid imbalances and mitochondrial shifts in fatty acid oxidation in YPHIV. These results will expand our understanding of the pathogenesis and interplay between metabolic dysregulation and subclinical myocardial dysfunction as well as elucidate key pathways of cardiac dysfunction which may identify those YPHIV at highest risk for CVD, informing future potentially targetable interventions such as dietary measures to alter metabolic fuel utilization or possible immune-modulating therapy.

抽象的 心血管疾病 (CVD) 仍然是接受抗逆转录病毒治疗的艾滋病毒 (AHIV) 成人感染者的一个重大问题 对于青年人的亚临床或早期上游 CVD 发病机制知之甚少。 围产期感染艾滋病毒 (YPHIV) 的人将从亚临床 CVD 的早期识别中受益最多。 ART 的推广降低了儿科 HIV 死亡率，使 YPHIV 能够进入成年期，但并非没有 多项研究表明，终生接触免疫激活、炎症和抗逆转录病毒疗法，所有这些都会加剧心血管疾病。 包括我们在内的 YPHIV 患者已表现出亚临床心肌功能障碍，但很少有人评估潜在的 代谢途径或与生活在非代谢途径中的青年的匹配良好的比较组进行 撒哈拉以南非洲地区围产期感染艾滋病毒 (YNPHIV) 和未接触艾滋病毒的未感染者 (HUU) 青少年，其中 目前，世界上 90% 的艾滋病毒儿童都居住在我们身边，我们已证明其感染率很高（25%）。 此外，我们的南非 YPHIV 人群中还存在心室收缩功能障碍和胰岛素抵抗（21%）。 与未感染的青少年相比，我们的 YPHIV 患者出现内皮功能障碍和血脂异常的风险更高。 然而，详细的敏感成像数据可以全面测量心肌和血管功能障碍 YPHIV 中迫切需要了解这些前体在心脏病等最终疾病中的作用 此外，我们还发现，YPHIV 中的失败和 CVD 更为常见。 涉及心肌/血管级联的早期/原始因素的潜在代谢途径 缺乏导致 CVD 的功能障碍，这对于提供早期预测和潜力至关重要 缓解 YPHIV 成年后心脏代谢并发症的发展。 我们将利用开普敦青少年和抗逆转录病毒队列 (CTAAC) 来评估是否接受了 ART 治疗 随着时间的推移，围产期感染艾滋病毒与亚临床心肌或血管功能障碍加剧有关 使用具有相似年龄、性别和体表面积 (BSA) 的 YNPHIV 和 HUU 青少年比较组，以及 采用心血管磁共振成像 (CMR)，这是一种敏感的多参数方法 接下来，我们将使用新颖的代谢组学技术来探索多个心血管领域。 是否是代表类二十烷酸的中间代谢物或促炎代谢物的特征簇 与 YNPHIV 或 HUU 相比，YPHIV 中脂肪酸氧化的不平衡和线粒体变化是不同的 青年人并与 YPHIV 亚临床心肌或血管功能障碍相关。 炎症如何与这些类二十烷酸不平衡和脂肪酸氧化中的线粒体变化相关 这些结果将扩大我们对 YPHIV 发病机制和代谢之间相互作用的理解。 失调和亚临床心肌功能障碍以及阐明心功能障碍的关键途径 这可能会识别那些罹患 CVD 风险最高的 YPHIV，从而为未来潜在的针对性干预措施提供信息 例如改变代谢燃料利用率的饮食措施或可能的免疫调节疗法。