Clinical, Genetic, and Proteomic Risk Factors for Pulmonary Hypertension in Heart Failure

心力衰竭肺动脉高压的临床、遗传和蛋白质组学危险因素

• 批准号: 10163899
• 负责人: Evan L Brittain
• 金额: $ 78.78万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163899
• 关键词: Address; Affect; African American; American; Automobile Driving; Bioinformatics; Biological; Biometry; Blood Vessels; Clinical; Clinical Practice Guideline; Code; Cohort Studies; Consumption; DNA Repository; Data; Development; Echocardiography; Electronic Health Record; Epidemiology; Event; Financial compensation; Functional disorder; Funding; Genetic; Genetic Risk; Genetic Variation; Genotype; Goals; Gold; Guidelines; Health; Heart failure; Heritability; Incidence; Individual; Inflammatory; Insulin Resistance; Knowledge; Laboratories; Left; Letters; Link; Lung; Measurement; Measures; Medical; Medical Genetics; Metabolic; Molecular; Natural History; Obesity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Population; Prospective cohort; Proteins; Proteomics; Pulmonary Hypertension; Pulmonary artery structure; Reporting; Resources; Right Ventricular Dysfunction; Right Ventricular Function; Risk; Risk Factors; Specificity; System; Systolic Pressure; Time; United States Department of Veterans Affairs; Ventricular; Veterans; Woman; base; biobank; cardiometabolism; care seeking; clinical risk; cohort; comorbidity; cost; cost effective; demographics; design; epidemiologic data; genetic association; genome-wide; improved; improved outcome; insight; modifiable risk; mortality; new therapeutic target; precision medicine; preservation; pressure; prevent; programs; protein H(3); protein biomarkers; pulmonary arterial hypertension; racial diversity; trait

PROJECT SUMMARY At least 50% of people with HF develop pulmonary hypertension (HF-PH). The fact that all people with HF have elevated left ventricular filling pressures suggests that there must be additional factors that drive the development of PH. Identifying these factors is important because HF-PH carries a 50% increase in mortality and no treatments exist to improve outcomes or prevent PH development. Epidemiologic data on the risk factors and natural history of HF-PH are lacking. Similarly, the biological mechanisms underlying HF-PH are unknown because no molecular studies have been performed in this population. In addition to establishing incidence rates and clinical risk factors, an important goal of this application is to identify molecular features associated with HF-PH and right ventricular (RV) compensation (i.e. preserved RV function in the setting of PH). We hypothesize that (1) HF-PH incidence rates using echocardiographic data are higher than previously reported rates based on medical codes (2) HF-PH and RV compensation are genetically influenced, and (3) protein biomarkers will be associated with prevalent HF-PH and RV function. These hypotheses are based on our preliminary showing: 1) higher rates of incident HF-PH using echo data than rates based on medical codes alone; 2) association of poor metabolic health with HF-PH and RV dysfunction; 3) high genetic heritability of pulmonary pressure; 4) shared genetic risk between obesity and pulmonary pressure; 5) a genetic association between insulin resistance and PH; and 6) elevation of inflammatory and vascular tone proteins in HF-PH patients. Developing large, prospective cohorts designed to study the natural history of HF-PH would be prohibitively expensive and inefficient. Leveraging electronic health record (EHR)-based cohorts linked to biobanks presents a scientifically valid, cost-effective, and efficient pathway for studying HF-PH epidemiology and pathophysiology. In Aim 1, we will establish HF-PH incidence rates and examine the importance of modifiable risk factors for HF-PH (e.g. obesity, insulin resistance) by extracting echocardiographic PASP values on ~425,000 individuals in the Veterans Affairs and Vanderbilt EHRs (64,000 African Americans and 85,000 women). Approximately 100,000 of these individuals have repeat PASP measurements, and 65,000 have gold standard RHC data. Both cohorts are well phenotyped with detailed data on demographics, comorbidities, medication exposure, laboratory, and clinical events. In Aim 2, we will leverage the VA-funded Million Veterans Program and Vanderbilt's BioVU to analyze genome-wide genotyping data in a total of 25,000 subjects with HF at no cost to this application. In Aim 3, we will perform proteomic profiling (1129 proteins) in discovery (800 subjects) and replication (600 subjects) HF cohorts collected through BioVU. We have combined existing resources with new phenotypic, genotypic, and proteomic data and assembled a team with the specific expertise to execute our aims. If our hypotheses are correct, the results could improve clinical guidelines for HF-PH and identify new therapeutic targets for HF-PH and RV dysfunction.

项目总结