Department of Cardiology and Angiology (K.A.L.M., C.L., T.H., M.S., M.D., O.B., A.-K.R., S.G., H.J., D.R., K.-P.K., T.C., I.I.M., M.P.G.), University Hospital Tuebingen, Eberhard Karls University Tuebingen, Germany.
Institute for Experimental Biomedicine, Chair I University Hospital Würzburg, Germany (K.M., H.S.).
Arterioscler Thromb Vasc Biol. 2024 Sep;44(9):2118-2135. doi: 10.1161/ATVBAHA.124.321000. Epub 2024 Jul 11.
BACKGROUND: 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. METHODS: 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. RESULTS: 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]; <0.001) with less calcification (calcification area, mm: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; <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; <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], =0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], <0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: 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.
背景：主动脉瓣狭窄（AS）是由循环炎症和瓣膜驻留的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、血小板衍生的介质以及血小板-单核细胞相互作用对加速局部瓣膜炎症和矿化的影响目前尚不清楚。
方法：我们前瞻性地招募了 475 名患有严重症状性 AS 并接受主动脉瓣置换术的连续患者。临床检查包括重复超声心动图检查、血小板、单核细胞分析、趋化因子分析、主动脉瓣组织样本进行免疫组织化学分析和基因表达分析。
结果：通过超声心动图确定的每年 0.45 m/s 的 ∆Vmax 中位数，将患者分为快速进展性 AS。快速进展性 AS 的主动脉瓣免疫组织学分析显示细胞增多（缓慢进展性 AS 与快速进展性 AS 相比；中位数[四分位数范围]，247 [142.3-504] 与 717.5 [360.5-1234]；<0.001），钙化减少（钙化面积，mm：33.74 [27.82-41.86] 与 20.54 [13.52-33.41]；<0.001）。快速进展性 AS 中 MIF（巨噬细胞移动抑制因子）相关基因表达显著增强，同时血浆 MIF 水平显著升高（平均值±SEM；6877±379.1 与 9959±749.1；<0.001），血小板激活增加，细胞内 MIF 表达减少，表明血小板激活时 MIF 释放增加（CD62P，%：中位数[四分位数范围]，16.8 [11.58-23.8] 与 20.55 [12.48-32.28]；=0.005；MIF，%：4.85 [1.48-9.75] 与 2.3 [0.78-5.9]；<0.001）。回归分析证实，MIF 相关生物标志物与 AS 加速过程中局部和全身血栓炎症密切相关。
结论：我们的研究结果表明，血小板衍生的 MIF 及其与循环和瓣膜驻留的单核细胞/巨噬细胞的相互作用在加速 AS 期间局部和全身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，代表了一种减弱 AS 进展的新型药物靶点。
Arterioscler Thromb Vasc Biol. 2024-9
Thromb Haemost. 2017-1-26
Int J Cardiol. 2013-10-3
J Am Coll Cardiol. 2019-5-7
Atherosclerosis. 2015-3
JACC Cardiovasc Imaging. 2009-8
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