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

基本信息

批准号：
9913572
负责人：
Evan L Brittain
金额：
$ 79.06万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9913572
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 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

项目摘要

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.

项目概要至少 50% 的心力衰竭患者会出现肺动脉高压 (HF-PH)。事实上，所有心力衰竭患者左心室充盈压升高表明一定还有其他因素驱动 PH 的发展。确定这些因素很重要，因为 HF-PH 会使死亡率增加 50% 并且没有治疗方法可以改善结果或预防肺动脉高压的发展。有关风险的流行病学数据缺乏 HF-PH 的影响因素和自然史。同样，HF-PH 的生物学机制是未知，因为尚未对该人群进行分子研究。除了建立发病率和临床危险因素，该应用的一个重要目标是识别分子特征与 HF-PH 和右心室 (RV) 代偿相关（即在以下情况下保留 RV 功能） PH）。我们假设 (1) 使用超声心动图数据的 HF-PH 发病率高于以前基于医疗代码的报告率 (2) HF-PH 和 RV 补偿受遗传影响，以及 (3) 蛋白质生物标志物将与普遍的 HF-PH 和 RV 功能相关。这些假设基于我们的初步显示：1) 使用回波数据的 HF-PH 发生率高于基于医疗代码的发生率独自的; 2) 代谢健康状况不佳与 HF-PH 和 RV 功能障碍有关； 3）遗传力高肺压； 4) 肥胖和肺动脉压有共同的遗传风险； 5) 遗传关联胰岛素抵抗和 PH 之间； 6) HF-PH 中炎症和血管张力蛋白的升高患者。开发旨在研究 HF-PH 自然史的大型前瞻性队列将是极其昂贵且低效。利用基于电子健康记录 (EHR) 的队列生物样本库为研究 HF-PH 流行病学提供了一条科学有效、具有成本效益且高效的途径和病理生理学。在目标 1 中，我们将确定 HF-PH 的发病率并检查以下因素的重要性：通过提取超声心动图 PASP 可改变 HF-PH 的危险因素（例如肥胖、胰岛素抵抗）退伍军人事务部和范德比尔特电子病历中约 425,000 名个人（64,000 名非裔美国人和 85,000 名女性）。其中大约 100,000 人重复进行了 PASP 测量，65,000 人进行了重复 PASP 测量。拥有黄金标准 RHC 数据。这两个群体的表型都很好，有详细的人口统计数据，合并症、药物暴露、实验室和临床事件。在目标 2 中，我们将利用 VA 资助的百万退伍军人计划和范德堡大学 BioVU 将分析总共 25,000 个全基因组基因分型数据患有 HF 的受试者对此应用程序免费。在目标 3 中，我们将进行蛋白质组分析（1129 个蛋白质）通过 BioVU 收集的发现（800 名受试者）和复制（600 名受试者）心力衰竭队列。我们有将现有资源与新的表型、基因型和蛋白质组数据相结合，并组建了一个团队执行我们目标的具体专业知识。如果我们的假设是正确的，结果可以改善临床 HF-PH 指南并确定 HF-PH 和 RV 功能障碍的新治疗靶点。