Administrative Supplement to Immunologic, Inflammatory, and Clinical contributors to HIV-Related Heart Failure with Preserved Ejection Fraction

对 HIV 相关心力衰竭的免疫学、炎症和临床因素的行政补充，保留射血分数

• 批准号: 10822723
• 负责人: Matthew Joel Feinstein
• 金额: $ 4.99万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-25 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10822723
• 关键词: Address; Administrative Supplement; American Heart Association; Anti-Retroviral Agents; Autopsy; Biological Markers; Biological Specimen Banks; Biology; CD4 Lymphocyte Count; CD8B1 gene; Cardiac; Cardiovascular Diseases; Cells; Clinical; Clinical Data; Complex; Data; Diabetes Mellitus; Diagnosis; EFRAC; Endothelium; Epidemiology; Event; Female; Fibroblasts; Freezing; Functional disorder; Funding; Gene Expression; General Population; Genes; Goals; HIV; Heart Rate; Heart failure; High Prevalence; Hispanic; Hypertension; Immune; Immune System Diseases; Immune response; Immunologics; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Knowledge; Link; Longevity; Maps; Methods; Modernization; Multicenter Studies; Myocardial; Myocardial tissue; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Obesity; Pathogenesis; Patient Outcomes Assessments; Patients; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Predisposition; Prevention; Proteins; Proteomics; Protocols documentation; RNA; Recovery; Regulation; Regulatory T-Lymphocyte; Request for Proposals; Research; Research Priority; Resolution; Risk; Risk Factors; Role; Sampling; Specimen; Structural defect; Syndrome; T-Cell Activation; T-Lymphocyte; Therapeutic Intervention; Time; Tissues; United States; Update; Validation; Weight Gain; Writing; abacavir; adjudication; aged; antiretroviral therapy; candidate marker; cardiometabolism; cardiovascular disorder risk; case control; clinical care; clinical imaging; clinical risk; clinically relevant; cohort; comorbidity; design; hemodynamics; high risk; immunoregulation; improved; inflammatory marker; insight; kidney dysfunction; male; middle age; migration; monocyte; mortality; multidisciplinary; novel; overexpression; peripheral blood; power analysis; preservation; protein biomarkers; response; screening; senescence; targeted treatment; trafficking; transgender

SUMMARY The purpose of this application is to determine clinical, immunologic, and inflammatory factors that may 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.

概括 本应用的目的是确定可能导致的临床、免疫和炎症因素 人类免疫缺陷病毒（HIV）感染者的射血分数保留的心力衰竭（HFpEF）， 临床相关目标是改善 HIV 感染者的 HFpEF 筛查、预防和治疗 （艾滋病毒）。 HFpEF 是一种死亡率很高的复杂综合征：50% 的 HFpEF 患者在 5 年内死亡 诊断。 HFpEF 和舒张功能障碍（HFpEF 的关键结构异常）的发生率是 艾滋病毒感染者的患病率明显高于未感染艾滋病毒的人，最近的研究发现，艾滋病毒感染者的患病率高出 4-8 倍。 与未感染 HIV 的人相比，PWH 的舒张功能障碍更严重。一般来说，炎症和免疫功能障碍是 HFpEF 的重要诱因，并且对于 HIV 相关的 HFpEF 可能尤其重要。然而，数据 关于 HFpEF 临床危险因素和 PWH 病理生理学的研究有限。造成这一现象的一个关键原因是 持续的科学差距是，没有大规模、多样化、多中心的 PWH 队列能够判定心力衰竭 事件或将其与生物样本联系起来——这是准确表征和研究特定事件的必要步骤 心力衰竭的亚型。我们建议在超过 35,000 名 PWH 临床护理的大型现代化队列中开展这项工作 美国各地；该队列拥有大量单独关联的生物样本、患者- 报告的结果，以及获得在大型艾滋病毒队列中独一无二的临床影像数据， 全面描述 HIV 中 HFpEF 的特征是必要的。我们的中心假设是 PWH 不完全 CD4 计数和 CD4/CD8 比率较低表明免疫恢复特别容易受到 HFpEF 的影响 存在从高血压到与脱靶相关的特定 ART 类别等“第二次打击”的情况 合并症（例如体重增加）。第一个目标是，我们将调查临床风险因素和相互作用 其中与 PWH 的 HFpEF 事件密切相关。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 小组 – 我们在非 HIV HFpEF 患者中拥有大量试点数据 – 来定义免疫学和 PWH 中 HFpEF 的炎症因素。在目标 3 中，我们将使用一种新颖的方法来确定， 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志物 PWH 异常和 HFpEF；我们将在目标 4 中验证心脏组织中的这些发现。我们有数据可以 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 作为心脏病专家，他最近担任美国心脏协会关于艾滋病毒科学声明的撰写主席 CVD，这是一份具有里程碑意义的文件，需要广泛的多学科协调。我们的团队由 PI 领导 拥有成功执行分析所需的方法和内容专业知识。通过完成 为了实现这一目标，我们打算生成有关 HIV 相关心力衰竭的关键临床和病理生理学知识 这将为改善感染者中 HFpEF 的预防、诊断和最终治疗提供信息。