Molecular predictors of resistance and vulnerability to cardiovascular events in stable ischemic heart disease

稳定型缺血性心脏病中心血管事件抵抗力和易感性的分子预测因子

• 批准号: 10298820
• 负责人: JONATHAN D NEWMAN
• 金额: $ 49.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10298820
• 关键词: American; Atherosclerosis; Atherosclerosis Risk in Communities; Biological Assay; Biological Markers; Blood specimen; Cardiac; Cardiovascular system; Caring; Cessation of life; Chronic; Clinical; Clinical Data; Clinical Trials; Coronary Arteriosclerosis; Coronary Artery Ischemia; DNA Methylation; Data; Data Store; Dietary Intervention; Evaluation; Event; Funding; Future; Gene Expression; Inflammation; Interleukin-6; Ischemia; Life Style; Link; Measures; Modeling; Molecular; Myocardial Infarction; Myocardial Ischemia; National Heart, Lung, and Blood Institute; Outpatients; Pathway interactions; Patient Rights; Patients; Performance; Pharmacotherapy; Phenotype; Plant Roots; Process; Prognosis; Quality of life; Reporting; Resistance; Resources; Risk; Risk Factors; Severity of illness; Stable Populations; Stress Tests; Structure; Testing; Thrombosis; Time; Trans-Omics for Precision Medicine; Troponin; United States National Institutes of Health; Whole Blood; adjudicate; biobank; cardiovascular risk factor; clinical phenotype; clinical risk; clinically relevant; cohort; design; disease phenotype; ethnic diversity; heart disease risk; high risk; improved; improved outcome; molecular marker; multiple omics; myocardial injury; novel; novel marker; patient population; programs; prospective; protein metabolite; racial diversity; research clinical testing; risk stratification; tool; transcriptomics

PROJECT ABSTRACT More reliable and personalized ways to predict adverse cardiovascular (CV) events could improve outcomes and quality of life for over 18 million Americans with stable ischemic heart disease (SIHD). Contemporary risk stratification in SIHD assesses clinical risk factors and tests for inducible myocardial ischemia and obstructive coronary artery disease (CAD). As we recently showed in the NHLBI ISCHEMIA trial, inducible ischemia can be chronic and well-tolerated, and CAD stenoses often do not progress to CV events. After ISCHEMIA, clinicians need better tools to supplement clinical testing of ischemia and CAD to identify SIHD patients at high risk for CV events and ultimately target the pathways conferring risk. If we could use biomarkers and molecular assays to better identify these high-risk patients, we could better target resource-intensive therapies to the right patient, at the right time. Molecular markers of thrombosis, inflammation, and myocardial injury – processes at the root of SIHD and CV events – are strong candidates to predict events in SIHD. However, these markers have not been evaluated against state-of-the-art clinical measures of inducible ischemia and CAD severity linked to centrally adjudicated CV events. As a result, it remains difficult to determine if these and other assays can improve on clinical risk factors and testing for SIHD risk stratification. To overcome this limitation, we will leverage a population of stable outpatients representing the risk spectrum of SIHD, with core-lab confirmed inducible ischemia, CAD severity, and centrally adjudicated CV events drawn from two large, NHLBI-funded strategy trials with robust biorepositories: the ISCHEMIA trial and the PROMISE trial. We will validate our findings in the multi “omics” cohorts of the NHLBI’s TOPMed (Trans-Omics for Precision Medicine) program. Our central hypothesis is that augmenting clinical testing with biomarker analysis will predict CV events in SIHD more accurately and with greater efficiency than clinical testing alone. In Aim 1, we will determine whether biomarkers reported to predict CV events improve prediction of death or myocardial infarction when added to unique clinical testing of patients with SIHD available for our use. In Aim 2, we will discover novel molecular features that improve prediction of death or myocardial infarction when added to detailed clinical testing in SIHD. With these aims, we will develop a multi-dimensional model of biomarkers, novel molecular features and clinical testing to improve the prognosis and management of patients with SIHD.

项目摘要 更可靠和个性化的方法来预测不良心血管（CV）事件可以改善结局 超过1800万患有稳定型缺血性心脏病（SIHD）的美国人的生活质量。当代风险 SIHD分层评估临床危险因素和诱发性心肌缺血和阻塞性心肌炎的试验 冠状动脉疾病（CAD）。正如我们最近在NHLBI ISCHEMIA试验中所显示的，诱导性缺血可以 慢性且耐受性良好，CAD狭窄通常不会进展为CV事件。缺血后， 临床医生需要更好的工具来补充缺血和CAD的临床测试，以识别高血压的SIHD患者。 CV事件的风险，并最终靶向产生风险的途径。如果我们能用生物标记和分子标记 通过更好地识别这些高风险患者的检测，我们可以更好地将资源密集型疗法用于正确的治疗， 耐心，在正确的时间。血栓形成、炎症和心肌损伤的分子标志物- SIHD和CV事件的根-是预测SIHD中事件的强候选者。然而，这些标记 尚未根据诱导性缺血和CAD严重程度的最新临床指标进行评价 与中心裁定的CV事件相关。因此，仍然很难确定这些和其他测定是否 可以改善临床风险因素和SIHD风险分层测试。 为了克服这一限制，我们将利用代表风险谱的稳定门诊患者人群 的SIHD，核心实验室确认的诱导性缺血、CAD严重程度和中心裁定的CV事件 从两个大型的，NHLBI资助的战略试验与强大的生物储存库：缺血试验和承诺 审判我们将在NHLBI的TOPMed的多“组学”队列中验证我们的发现（ 精准医学）计划。我们的中心假设是用生物标志物增强临床测试 分析将比临床检测更准确地预测SIHD中的CV事件，且效率更高 一个人在目标1中，我们将确定报告用于预测CV事件的生物标志物是否能改善对 死亡或心肌梗死时，添加到独特的临床试验的患者与SIHD可供我们使用。 在目标2中，我们将发现新的分子特征，以提高死亡或心肌梗死的预测 当添加到SIHD的详细临床试验中时。有了这些目标，我们将开发一个多维模型， 生物标志物、新分子特征和临床测试，以改善患者的预后和管理 关于SIHD