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

项目摘要 预测不良心血管事件的更可靠和个性化的方法可以改善结果 1800多万患有稳定性缺血性心脏病(SIHD)的美国人的生活质量。当代风险 SIHD的分层评估临床危险因素和诱发心肌缺血和梗阻的测试 冠状动脉疾病。正如我们最近在NHLBI缺血试验中显示的那样，诱导性缺血可以 如果是慢性的，耐受性良好，CAD狭窄通常不会进展为心血管事件。在缺血后， 临床医生需要更好的工具来补充缺血和CAD的临床测试，以确定SIHD患者处于高水平 心血管事件的风险，并最终瞄准导致风险的途径。如果我们能用生物标记物和分子 为了更好地识别这些高危患者，我们可以更好地将资源密集型疗法对准正确的方向 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事件的根源-是预测SIHD事件的有力候选者。然而，这些标记 尚未根据最先进的诱发缺血和冠心病严重程度的临床测量进行评估 链接到集中裁决的简历事件。因此，仍然很难确定这些和其他检测方法是否 可改善临床危险因素，并检测为SIHD危险分层。 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群体。 SIHD的核心实验室确认为诱发性缺血、冠心病严重程度和集中判定的心血管事件 来自两个由NHLBI资助的具有强大生物库的大型策略试验：缺血试验和Promise 审判。我们将在NHLBI的TOPMed(Trans-Omics for 精准医学)计划。我们的中心假设是，用生物标记物加强临床测试 与临床测试相比，分析将更准确、更有效地预测SIHD的心血管事件 独自一人。在目标1中，我们将确定报告的预测心血管事件的生物标记物是否改善了对 当死亡或心肌梗死添加到SIHD患者的独特临床测试中时，可供我们使用。 在目标2中，我们将发现新的分子特征，改善对死亡或心肌梗死的预测 当添加到SIHD的详细临床测试中时。带着这些目标，我们将开发一个多维模型 改善患者预后和管理的生物标志物、新的分子特征和临床测试 使用SIHD。

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.