Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state.
Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state.
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DOI：
10.1161/atvbaha.113.301627
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发表时间：
2013-08
期刊：
影响因子：
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通讯作者：
Kietselaer BLJH
中科院分区：
文献类型：
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作者：
Borissoff JI;Joosen IA;Versteylen MO;Brill A;Fuchs TA;Savchenko AS;Gallant M;Martinod K;Ten Cate H;Hofstra L;Crijns HJ;Wagner DD;Kietselaer BLJH
异常的中性粒细胞活化发生在动脉粥样硬化的晚期阶段。一旦引发，中性粒细胞可以经历凋亡或释放中性粒细胞胞外陷阱（NET）。这种细胞外DNA发挥有效的促炎、促血栓形成和细胞毒性特性。本研究的目的是检查细胞外DNA形成，冠状动脉粥样硬化和血栓前状态的存在之间的关系。在一项前瞻性、观察性、横断面队列研究中，282例疑似冠心病（CAD）患者采用冠状动脉计算机断层血管造影（CCTA）检查冠状动脉粥样硬化的严重程度、范围和表型。建立了双链DNA、核小体、瓜氨酸化组蛋白H4和髓过氧化物酶（MPO）-DNA复合物，分别被认为是细胞死亡和NETosis的体内标志物。我们进一步测量了凝血激活和炎症的各种血浆标志物。血浆双链DNA、核小体和MPO-DNA复合物与凝血酶生成呈正相关，在严重冠状动脉粥样硬化或冠状动脉极度钙化的患者中显著升高。调整混杂因素后的多项式回归分析将高血浆核小体水平确定为严重冠状动脉狭窄的独立危险因素（OR：2.14，95%CI 1.26-3.63; p=0.005）。NET的标志物，如MPO-DNA复合物，预测冠状动脉粥样硬化血管的数量和主要不良心脏事件的发生。我们的报告提供的证据表明，细胞死亡和NET形成的标志物与CAD，血栓前状态和不良心脏事件的发生独立相关。这些生物标志物可能有助于预测胸部不适患者的心血管风险。
Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps (NETs). This extracellular DNA exerts potent pro-inflammatory, prothrombotic and cytotoxic properties. The goal of this study was to examine the relationships between extracellular DNA formation, coronary atherosclerosis and the presence of a prothrombotic state. In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease (CAD), we examined the severity, extent, and phenotype of coronary atherosclerosis by using coronary computed tomographic angiography (CCTA). Double-stranded DNA, nucleosomes, citrullinated histone H4 and myeloperoxidase (MPO)-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes and MPO-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (OR: 2.14, 95% CI 1.26-3.63; p=0.005). Markers of NETs, such as MPO-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events. Our report provides evidence demonstrating that markers of cell death and NET formation are independently associated with CAD, prothrombotic state and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.