Clinical and Molecular Epidemiology of High Risk Coronary Plaque

尽管目前的实践主要集中在梗阻的检测和管理上 冠心病(CAD)与冠心病的关系存在明显的异质性 心血管(CV)事件的风险。一些患者，尽管有梗阻性冠心病，但没有 心血管事件，而其他非梗阻性冠心病患者则有。其作用机制 这种高危冠状动脉斑块(HRCP)的发生尚不完全清楚；应用 一系列新兴的成像和分子技术为同时 识别潜在的生物途径，早期非侵入性检测的标记，以及新的 HRCP的治疗靶点。因此，我们建议(1)确定炎症和 HRCP病理生理学中的其他候选生物学途径；(2)发现新的 通过机器学习分析介导HRCP发展的生物途径 综合代谢组、蛋白质组和转录组图谱；以及(3)确定 这些影像和分子生物标志物在临床上的增量预后价值 因素，并创建心血管事件风险预测的综合临床分子模型。我们会 通过首次集成先进的基于CTA的表型分析来实现这些目标 HRCP，具有分子分析和裁决的简历事件，利用强大的、现有的 一项由美国国立卫生研究院资助的大型、独特的胸痛患者影像临床试验资料 (承诺)。这项建议通过增加电流，具有重大的公共卫生意义 基于群体和缺血的方法以及更准确和更先发制人的识别 风险最高的患者。我们的发现将为发展提供一个重要的基础 针对特定的、罪魁祸首的动脉硬化表型的诊断和治疗 分子途径。

Although current practice focuses largely on the detection and management of obstructive coronary artery disease (CAD), there is marked heterogeneity in the relationship between CAD and risk for cardiovascular (CV) events. Some patients, despite having obstructive CAD, do not experience cardiovascular events, while others with non-obstructive CAD do. The mechanisms of this high risk coronary plaque (HRCP) development are incompletely understood; application of emerging imaging and molecular technologies holds great promise for simultaneously identifying underlying biological pathways, markers for early noninvasive detection, and novel therapeutic targets for HRCP. Thus, we propose to (1) determine the role of inflammation and other candidate biological pathways in the pathophysiology of HRCP; (2) identify novel biological pathways mediating development of HRCP through machine learning analyses of integrated metabolomic, proteomic and transcriptomic profiling; and (3) determine the incremental prognostic value of these imaging and molecular biomarkers over clinical factors and create an integrated clinico-molecular model of CV event risk prediction. We will accomplish these goals by, for the first time, integrating advanced CTA-based phenotyping of HRCP with molecular profiling and adjudicated CV events, leveraging the robust, existing resources of a large, unique NIH-funded clinical trial of imaging in chest pain patients (PROMISE). This proposal holds great public health significance by augmenting current population- and ischemia- based approaches and more precisely and preemptively identifying those patients at highest risk. Our findings will provide a critical foundation for the development of diagnostics and therapeutics targeted at specific, culprit atherosclerotic phenotypes and molecular pathways.