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

摘要 心血管疾病（CVD）仍然是接受抗逆转录病毒治疗的成人艾滋病毒感染者（AHIV）的一个重大问题 治疗（ART）。关于青年人亚临床或早期上游CVD发病机制知之甚少， 围产期获得性HIV（YPHIV）患者从亚临床CVD的早期识别中获益最多。 抗逆转录病毒疗法的推广降低了儿童艾滋病毒死亡率，使YPHIV能够进入成年期，但并非没有 终身暴露于免疫激活、炎症和ART，所有这些都会增强CVD。几项研究 包括我们的研究显示，YPHIV患者存在亚临床心肌功能障碍，但很少有人评估潜在的心肌功能障碍。 代谢途径或与非代谢途径的年轻人进行了良好匹配的对照组， 撒哈拉以南非洲的围产期获得性艾滋病毒（YNPHIV）和艾滋病毒未暴露未感染（HUU）青年， 目前，世界上90%的艾滋病毒感染儿童居住在我们已经证明了高比率（25%）的权利 心室收缩功能障碍和胰岛素抵抗（21%）在我们的队列南非YPHIV。此外，本发明还提供了一种方法， 与未感染的年轻人相比，我们的YPHIV具有增加的内皮功能障碍和血脂异常的风险。 然而，详细敏感的成像数据可以全面测量心肌和血管功能障碍 在YPHIV中迫切需要了解这些前体在终末期疾病中的作用， 失败和心血管疾病，我们已经证明这在AHIV中更普遍。此外，对YPHIV的研究表明， 参与心肌/血管级联反应中早期/原始因子的潜在代谢途径 功能障碍导致心血管疾病是缺乏和关键提供洞察早期预测和潜在的 缓解YPHIV患者成年后心脏代谢并发症的发展。对这一建议 我们将利用开普敦青少年和抗逆转录病毒队列（CTAAC）来评估ART治疗的 围产期获得性HIV与随着时间推移亚临床心肌或血管功能障碍恶化有关 使用年龄、性别和体表面积（BSA）相似的YNPHIV和HUU青年对照组， 采用心血管磁共振成像（CMR），一种灵敏的多参数方法， 研究多个心血管领域。接下来，我们将使用新的代谢组学技术来探索 是否是代表类花生酸的中间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移位不同 与YPHIV的亚临床心肌或血管功能障碍有关。最后，我们将探索 炎症如何与这些类花生酸失衡和线粒体脂肪酸氧化的变化相关， YPHIV。这些结果将扩大我们对代谢性疾病的发病机制和相互作用的理解。 失调和亚临床心肌功能障碍，并阐明心功能障碍的关键途径 这可能会识别出那些处于心血管疾病最高风险的YPHIV，为未来潜在的有针对性的干预提供信息。 例如改变代谢燃料利用的饮食措施或可能的免疫调节疗法。

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.