From the Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Spain.
Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):892-902. doi: 10.1161/ATVBAHA.117.310597. Epub 2018 Feb 8.
Atrial fibrillation (AF) patients experience adverse cardiovascular events (ACEs) despite anticoagulant therapy. We reported that rs2431697 of miR-146a, a negative regulator of inflammation, predicts ACEs in patients with AF. The relationship between neutrophil extracellular traps and thrombogenesis is known. Thus, our aim was to evaluate the role of neutrophil extracellular trap compounds as prognostic markers of ACEs in AF and to study whether miR-146a affects NETosis.
We included 336 steadily anticoagulated AF patients with a median follow-up of 7.9 years (interquartile range, 7.3-8.1) and 127 healthy subjects. The reviewed ACEs included stroke (ischemic/embolic), acute coronary syndrome, acute heart failure, and global or vascular death. We quantified cell-free DNA and NE (neutrophil elastase) at diagnosis. Rs2431697 was genotyped. Neutrophils from human and mice were seeded to analyze shed cell-free DNA and H3cit (citrullinated histone 3) after activation. In human plasmas, higher NE levels (>55.29 ng/mL), but not cell-free DNA, were independently associated with higher risk of all-cause mortality (hazard ratio, 2.24; 95% CI, 1.36-3.68), cardiovascular mortality (hazard ratio, 4.77; 95% CI, 1.11-20.47), and composite cardiovascular events (hazard ratio, 1.84; 95% CI, 1.01-3.76). In patients, NE levels were associated with rs2431697 (TT: 51.82±2.73 versus CC: 40.01±3.05 ng/mL; =0.040). In vitro, both human (TT for rs2431697) and miR-146a mice neutrophils yielded higher levels of cell-free DNA and H3cit than CC or wild-type cells, respectively.
NE activity can provide new ACE prognostic information in AF patients. These findings provide evidence of a potential role of miR-146a in neutrophil extracellular trap generation and cardiovascular risk in AF.
尽管接受抗凝治疗，房颤（AF）患者仍会经历不良心血管事件（ACEs）。我们曾报道过，miR-146a 的 rs2431697 是炎症的负调节剂，可预测 AF 患者的 ACEs。中性粒细胞胞外诱捕网（NET）与血栓形成之间的关系是已知的。因此，我们的目的是评估中性粒细胞胞外诱捕网化合物作为 AF 中 ACEs 预后标志物的作用，并研究 miR-146a 是否影响 NETosis。
我们纳入了 336 例稳定抗凝的 AF 患者，中位随访时间为 7.9 年（四分位距，7.3-8.1），并纳入 127 名健康对照者。回顾性 ACEs 包括中风（缺血/栓塞）、急性冠脉综合征、急性心力衰竭以及全因或血管性死亡。我们在诊断时定量检测细胞游离 DNA 和中性粒细胞弹性蛋白酶（NE）。对 rs2431697 进行基因分型。在人类和小鼠的中性粒细胞中接种，以分析激活后释放的细胞游离 DNA 和 H3cit（瓜氨酸化组蛋白 3）。在人类血浆中，较高的 NE 水平（>55.29ng/mL），而不是细胞游离 DNA，与全因死亡率（危险比，2.24；95%可信区间，1.36-3.68）、心血管死亡率（危险比，4.77；95%可信区间，1.11-20.47）和复合心血管事件（危险比，1.84；95%可信区间，1.01-3.76）的风险升高独立相关。在患者中，NE 水平与 rs2431697 相关（TT：51.82±2.73 与 CC：40.01±3.05ng/mL；=0.040）。在体外，携带 rs2431697 的 TT 人类（和 miR-146a）小鼠中性粒细胞比 CC 或野生型细胞释放出更高水平的细胞游离 DNA 和 H3cit。
NE 活性可为 AF 患者提供新的 ACE 预后信息。这些发现为 miR-146a 在 AF 中中性粒细胞胞外诱捕网生成和心血管风险中的潜在作用提供了证据。
