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.

项目摘要 至少有50％的HF患者会出现肺动脉高压（HF-PH）。所有患有HF的人 左心室填充压力升高表明，必须有其他因素驱动 PH的发展。确定这些因素很重要，因为HF-PH的死亡率增加了50％ 并且没有治疗可改善结果或防止pH发展的治疗方法。关于风险的流行病学数据 缺乏HF-PH的因素和自然历史。同样，HF-PH的生物学机制是 未知，因为在该人群中没有进行分子研究。除了建立 发病率和临床风险因素，该应用的重要目标是识别分子特征 与HF-PH和右心（RV）补偿相关（即保留的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 根据医疗法规（2）HF-PH和RV补偿的报告率受到遗传影响，（3） 蛋白质生物标志物将与普遍的HF-PH和RV功能有关。这些假设是基于 我们的初步显示：1）使用ECHO数据比基于医疗代码的速率更高的事件HF-PH率更高 独自的; 2）不良的代谢健康与HF-PH和RV功能障碍的关联； 3）高遗传性的遗传力 肺压； 4）肥胖和肺部压力之间有遗传风险； 5）遗传关联 在胰岛素抵抗和pH之间； 6）HF-PH中炎症和血管张力蛋白的升高 患者。发展旨在研究HF-PH自然历史的大型，前瞻性的队列将是 过于昂贵且效率低下。利用电子健康记录（EHR）的同伙 生物库提出了研究HF-PH流行病学的科学有效，成本效益和有效的途径 和病理生理学。在AIM 1中，我们将建立HF-PH发病率并研究的重要性 通过提取超声心动图PASP的HF-PH（例如肥胖症，胰岛素抵抗）的可修改风险因素 在退伍军人事务和范德比尔特EHR中，约有425,000个人的价值观（64,000名非裔美国人和 85,000名妇女）。这些人中约有100,000个具有重复测量值，65,000个 具有金标准RHC数据。两个队列都经过很好的表现，并有有关人口统计数据的详细数据， 合并症，药物暴露，实验室和临床事件。在AIM 2中，我们将利用VA资助 百万退伍军人计划和范德比尔特的BIOVU分析全基因组基因分型数据总计25,000 本申请无费用的HF受试者。在AIM 3中，我们将执行蛋白质组学分析（1129蛋白） 通过BIOVU收集的发现（800名受试者）和复制（600名受试者）HF队列。我们有 将现有资源与新的表型，基因型和蛋白质组学数据相结合，并与一个团队组合在一起 执行我们目标的具体专业知识。如果我们的假设正确，结果可以改善临床 HF-PH的指南，并确定HF-PH和RV功能障碍的新治疗靶标。