John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.
John Paul II Hospital, Kraków, Poland.
Int J Cardiol. 2019 Jul 1;286:121-126. doi: 10.1016/j.ijcard.2019.03.047. Epub 2019 Mar 26.
An involvement of neutrophil extracellular traps (NETs) in the aortic stenosis (AS) pathogenesis is unknown.
We enrolled 50 patients, median age 66.5 years with isolated severe AS, after aortic valve replacement and 20 healthy sex/age-matched controls. Autopsy-derived aortic valves from 5 healthy donors served as controls. Valvular expression of citrullinated histone H3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) and macrophages (CD68) were evaluated by immunostaining. Plasma citH3 and interleukin 6 (IL-6) were also determined.
All stenotic and healthy valves expressed citH3 in the leaflets' endothelial and sub-endothelial layers at the aortic side. Amount of valvular citH3-positive cells was higher in AS patients compared with controls (53.5 [33-62]% vs. 5.7 [4.1-9.0]%, p < 0.0001) and correlated with aortic valve area (AVA; r = -0.69, p < 0.0001) and mean transvalvular gradient (r = 0.6, p < 0.0001). Double-staining revealed that in AS valves 27.2 ± 9.8% of cells were citH3/MPO- and 25.3 ± 8.9% citH3/NE-positive. Within stenotic valves, 6.4 ± 2.5% of cells showed citH3/CD68 double-positivity and were identified as macrophages. AS patients compared to controls had 83% higher plasma citH3 (p < 0.0001). In AS, plasma citH3 correlated with IL-6 (r = 0.39, p = 0.0054) levels and AVA (r = -0.45, p = 0.0009).
The presence of NETs in stenotic valves and association with AS severity suggest novel mechanisms involved in the disease progression.
中性粒细胞胞外诱捕网（NETs）是否参与主动脉瓣狭窄（AS）的发病机制尚不清楚。
我们纳入了 50 名年龄中位数为 66.5 岁的孤立性重度 AS 患者，这些患者在接受主动脉瓣置换术后，与 20 名性别和年龄匹配的健康对照者一起入组。5 名健康供体的尸检主动脉瓣用作对照。通过免疫染色评估瓣叶内皮和亚内皮层的瓜氨酸化组蛋白 H3（citH3）、髓过氧化物酶（MPO）和中性粒细胞弹性蛋白酶（NE）以及巨噬细胞（CD68）的表达。还测定了血浆 citH3 和白细胞介素 6（IL-6）的水平。
所有狭窄和健康的瓣膜在主动脉瓣侧的瓣叶内皮和亚内皮层均表达 citH3。与对照组相比，AS 患者的瓣 citH3 阳性细胞数量更高（53.5[33-62]% vs. 5.7[4.1-9.0]%，p<0.0001），且与主动脉瓣面积（AVA；r=-0.69，p<0.0001）和平均跨瓣梯度（r=-0.6，p<0.0001）相关。双重染色显示，在 AS 瓣膜中，有 27.2±9.8%的细胞 citH3/MPO 阳性，有 25.3±8.9%的细胞 citH3/NE 阳性。在狭窄的瓣膜内，有 6.4±2.5%的细胞 citH3/CD68 双阳性，被鉴定为巨噬细胞。与对照组相比，AS 患者的血浆 citH3 水平高出 83%（p<0.0001）。在 AS 中，血浆 citH3 与白细胞介素 6（IL-6）（r=0.39，p=0.0054）水平和 AVA（r=-0.45，p=0.0009）相关。
在狭窄瓣膜中存在 NETs 及其与 AS 严重程度的相关性表明，在疾病进展中涉及新的机制。
