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.

总结