Immunologic, Inflammatory, and Clinical contributors to HIV-Related Heart Failure with Preserved Ejection Fraction (HFpEF)

摘要 此应用程序的目的是确定导致以下疾病的临床、免疫学和炎症因素 人类免疫缺陷病毒(HIV)感染者的心力衰竭保留射血分数(HFpEF)， 与临床相关的目标是改进对HIV感染者的HFpEF筛查、预防和治疗 (威尔斯亲王医院)。HFpEF是一种高死亡率的复杂综合征：50%的HFpEF患者在5年内死亡 诊断。HFpEF和舒张期功能不全的比率--HFpEF背后的关键结构异常--是 PWH的患病率明显高于未感染艾滋病毒的人，最近的研究发现， PWH患者的舒张期功能障碍明显高于未感染HIV患者。总体而言，炎症和免疫功能障碍 HFpEF的重要沉淀物，可能对艾滋病毒相关的HFpEF特别重要。然而，数据 关于PWH中HFpEF的临床危险因素和病理生理方面的研究有限。造成这种情况的一个关键原因 持续的科学差距是，没有一个大型、多样化、多中心的PWH队列可以判定心力衰竭。 事件或将这些事件与生物标本联系起来--这是准确描述和研究特定 心力衰竭的亚型。我们建议在临床护理的35,000名现代大型队列中进行这项工作 在整个美国；这个队列有广泛的独立连接的生物样本，患者- 报告的结果，以及对临床成像数据的访问，这些数据在大型艾滋病毒队列和 有必要对HIV中的HFpEF进行全面表征。我们的中心假设是不完全的PWH 免疫恢复，如较低的CD4计数和CD4/CD8比率，特别容易受到HFpEF的影响 在存在从高血压到与脱靶相关的特定艺术课程的“二次打击”的情况下 合并症(如体重增加)。在第一个目标中，我们将调查临床风险因素及其相互作用。 其中与PWH的入射HFpEF关联最强的是。在第二个目标中，我们寻求更多 深入了解HIV相关HFpEF的生物学，因此将利用多标记蛋白质组学 Panel-我们在非HIV HFpEF患者中有广泛的试点数据-以定义免疫学和 炎症性因素在PWH的HFpEF中的作用。在目标3中，我们将使用一种新的方法来确定一个单一的- 细胞水平，免疫细胞基因表达的有意义的差异可能导致系统性生物标记物 PWH的异常和HFpEF；我们将在AIM 4的心脏组织中验证这些发现。我们有数据 支持每个目标的前提和可行性，我们的PI非常适合领导拟议的分析；作为 心脏病专家，他最近担任美国心脏协会关于艾滋病毒的科学声明的撰写主席 和《气候变化公约》，这是一份里程碑式的文件，需要广泛的多学科协调。在PI的带领下，我们的团队 具备成功执行分析所需的方法和内容专业知识。通过完成 这些目标，我们打算产生关键的临床和病理生理学知识与艾滋病毒相关的心衰 这将为改进PWH中HFpEF的预防、诊断和最终治疗提供信息。

SUMMARY The purpose of this application is to determine clinical, immunologic, and inflammatory factors that lead to heart failure with preserved ejection fraction (HFpEF) for people with human immunodeficiency virus (HIV), with the clinically relevant goal of improving HFpEF screening, prevention, and therapy for people with HIV (PWH). HFpEF is a complex syndrome with high mortality: 50% of persons with HFpEF die within 5 years of diagnosis. Rates of HFpEF and diastolic dysfunction – the key structural abnormality underlying HFpEF – are significantly higher for PWH than people without HIV, with recent studies finding a 4-8-fold higher prevalence of diastolic dysfunction for PWH than people without HIV. In general, inflammation and immune dysfunction are important precipitants of HFpEF, and may be particularly important for HIV-associated HFpEF. However, data are limited regarding HFpEF clinical risk factors and pathophysiology in PWH. One key reason for this continued scientific gap is that no large, diverse, multi-center cohorts of PWH have adjudicated heart failure events or linked these to biospecimens – a necessary step to accurately characterize and investigate specific subtypes of heart failure. We propose to do this in a large, modern cohort of >35,000 PWH in clinical care throughout the United States; this cohort has an extensive array of individually-linked bio-specimens, patient- reported outcomes, and access to clinical imaging data that are unique among large HIV cohorts and necessary to comprehensively characterize HFpEF in HIV. Our central hypothesis is that PWH with incomplete immune recovery, as indicated by lower CD4 counts and CD4/CD8 ratios, are especially susceptible to HFpEF in the presence of “second hits” ranging from hypertension to specific ART classes associated with off-target comorbidities (such as weight gain). In the first aim, we will investigate clinical risk factors and interactions thereof which are most strongly associated with incident HFpEF for PWH. In the second aim, we seek to more deeply understand the biology of HIV-associated HFpEF and will therefore leverage a multi-marker proteomics panel – for which we have extensive pilot data in non-HIV HFpEF patients – to define immunologic and inflammatory contributors to HFpEF for PWH. In Aim 3, we will use a novel method to determine, at a single- cell level, meaningful differences in immune cell gene expression that may lead to systemic biomarker abnormalities and HFpEF for PWH; we will validate these findings in cardiac tissue in Aim 4. We have data to support the premise and feasibility of each aim, and our PI is ideally suited to lead the proposed analyses; as a cardiologist, he recently served as writing chair of the American Heart Association's scientific statement on HIV and CVD, a landmark document that required extensive multidisciplinary coordination. Led by the PI, our team has the requisite methods and content expertise to successfully perform the analyses. Through completion of the aims, we intend to generate key clinical and pathophysiological knowledge regarding HIV-associated HF which will inform improved prevention, diagnosis, and ultimately treatment of HFpEF among PWH.