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@ARTICLE{Mueller:291568,
author = {K. A. L. Mueller and C. Langnau and T. Harm and M. Sigle
and K. Mott and M. Droppa and O. Borst and A.-K. Rohlfing
and S. Gekeler and M. Günter$^*$ and N. Goebel and U. F. W.
Franke and M. Radwan and C. Schlensak and H. Janning and S.
Scheuermann and C. M. Seitz and D. Rath and K.-P.
Kreisselmeier and T. Castor and I. I. Mueller and H. Schulze
and S. Autenrieth$^*$ and M. P. Gawaz},
title = {{M}acrophage {M}igration {I}nhibitory {F}actor {P}romotes
{T}hromboinflammation and {P}redicts {F}ast {P}rogression of
{A}ortic {S}tenosis.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {44},
number = {9},
issn = {0276-5047},
address = {Stanford, Calif.},
publisher = {HighWire},
reportid = {DKFZ-2024-01453},
pages = {2118-2135},
year = {2024},
note = {#LA:D431# / 2024 Sep;44(9):2118-2135},
abstract = {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.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.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.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.},
keywords = {aortic valve stenosis (Other) / biomarkers (Other) / blood
platelets (Other) / chemokines (Other) / inflammation
(Other)},
cin = {D431},
ddc = {610},
cid = {I:(DE-He78)D431-20160331},
pnm = {314 - Immunologie und Krebs (POF4-314)},
pid = {G:(DE-HGF)POF4-314},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38989580},
doi = {10.1161/ATVBAHA.124.321000},
url = {https://inrepo02.dkfz.de/record/291568},
}