■主动脉瓣狭窄(AS)是由循环炎症和瓣膜驻留内皮细胞和间质细胞调节的进行性炎症和纤维钙化过程驱动的。血小板的影响,血小板衍生介质,和血小板-单核细胞相互作用对局部瓣膜炎症和矿化的加速作用目前尚不清楚。
■我们前瞻性纳入475例重度症状性AS患者行主动脉瓣置换术。临床检查包括重复超声心动图,血小板分析,单核细胞,趋化因子分析,用于免疫组织化学的主动脉瓣组织样本,和基因表达分析。
■通过超声心动图确定的每年的中位Vmax为0.45m/s,将患者分类为快速进展性AS。免疫组织学主动脉瓣分析显示,快速进展性AS的细胞增多(缓慢与快速进展性AS;中位数[四分位距],247[142.3-504]与717.5[360.5-1234];P<0.001),钙化较少(钙化面积,mm2:33.74[27.82-41.86]vs.20.54[13.52-33.41];P<0.001)。MIF(巨噬细胞移动抑制因子)相关基因表达在快速进展的AS中显著增强,同时伴有显著升高的MIF血浆水平(平均±SEM;6877±379.1对9959±749.1;P<0.001),血小板活化增加,和细胞内MIF表达降低,表明血小板活化后MIF释放增强(CD62P,%:中位数[四分位数范围],16.8[11.58-23.8]对20.55[12.48-32.28],P=0.005;MIF,%:4.85[1.48-9.75]对2.3[0.78-5.9],P<0.001)。回归分析证实MIF相关的生物标志物与AS的加速进程密切相关。
■我们的研究结果表明,血小板源性MIF及其与循环和瓣膜驻留单核细胞/巨噬细胞的相互作用在加速AS期间的局部和全身性血栓炎症中起关键作用。基于MIF的生物标志物可预测AS的加速进程,并代表了一种新的药理靶标以减轻AS的进展。
UNASSIGNED: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown.
UNASSIGNED: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis.
UNASSIGNED: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS.
UNASSIGNED: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.