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)仍然是成人艾滋病毒携带者(AHIV)抗逆转录病毒治疗的一个重要问题 治疗(ART)。对青少年心脑血管疾病的亚临床或早期上游发病机制知之甚少 围产期获得性艾滋病毒(YPHIV)，他们将从亚临床心血管疾病的早期识别中受益最大。 ART的扩大降低了儿童艾滋病毒的死亡率，使YPHIV得以成年，但并非没有 终生暴露于免疫激活、炎症和抗逆转录病毒治疗，所有这些都会加剧心血管疾病。几项研究 包括我们在内的研究人员已经显示出YPHIV的亚临床心肌功能障碍，但很少有人对潜在的 代谢途径或在匹配良好的对照组中进行，这些青年生活在 撒哈拉以南非洲的围产期获得性艾滋病毒(YNPHIV)和未暴露于艾滋病毒的未感染(HUU)青年 目前，世界上90%的艾滋病毒携带者儿童居住在这里。我们已经证明了很高的正确率(25%) 在我们的南非YPHIV队列中，心脏收缩功能障碍和胰岛素抵抗(21%)。此外, 我们的YPHIV与未感染的年轻人相比，内皮功能障碍和血脂异常的风险增加。 然而，详细的敏感成像数据全面衡量心肌和血管功能障碍 在YPHIV中迫切需要了解这些前体在心脏等终末期疾病中的作用 失败和心血管疾病，我们已经证明在AHIV中更普遍。此外，对YPHIV的研究还包括 跨心肌/血管级联的早期/原始因子涉及的潜在代谢途径 导致心血管疾病的功能障碍是缺乏的，对于洞察早期预测和潜力至关重要 YPHIV患者成年后心脏代谢并发症的缓解。对于这项建议 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治疗是否 围产期获得性艾滋病毒与随着时间推移而恶化的亚临床心肌或血管功能障碍有关 使用YNPHIV和HUU年龄、性别和身体表面积(BSA)相似的青年对照组和 利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，我们将利用新陈代谢组学技术来探索 无论是代表二十烷类化合物的标志性中间代谢物或促炎代谢物簇 与YNPHIV或HUU相比，YPHIV患者脂肪酸氧化的失衡和线粒体移位不同 并与YPHIV的亚临床心肌或血管功能障碍有关。最后，我们将探索 炎症如何与这些二十烷类化合物失衡和脂肪酸氧化中线粒体的变化相关 YPHIV。这些结果将扩大我们对发病机制和代谢之间相互作用的理解。 调节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 它可以识别那些心血管疾病风险最高的YPHIV，为未来可能的有针对性的干预提供信息 例如改变新陈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.