Macrophage migration inhibitory factor is a game-changing trigger in fast progressive, inflammation-driven aortic stenosis

Tobias Harm (Tübingen)1, M. Sigle (Tübingen)2, A.-K. Rohlfing (Tübingen)1, L. Baas (Tübingen)1, M. Senel (Tübingen)1, D. Rath (Tübingen)1, K.-P. Kreisselmeier (Tübingen)1, T. Castor (Tübingen)1, S. Autenrieth (Heidelberg)3, M. Gawaz (Tübingen)2, K. A. L. Müller (Tübingen)2

1Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Angiologie Tübingen, Deutschland; 2Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland; 3Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Deutschland

 


Background:
Aortic stenosis (AS) is driven by progressive inflammatory and fibro-calcific processes regulated by pro-inflammatory and pro-osteogenic mediators. An enhanced systemic and local inflammatory response at the site of the aortic valve leads to specific differentiation of valve resident endothelial and interstitial cells. The impact of proinflammatory components like macrophage migration inhibitory factor (MIF) on the progress of aortic inflammation and calcification are of utmost clinical interest, as MIF can be addressed by established MIF inhibitors, however is not yet fully understood.

Methods: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve (AV) replacement. Patients were stratified into slow (SP-) and fast progressive (FP-) AS by repetitive transthoracic echocardiography. Cardiac workup included physical examination, echocardiography, blood sampling for laboratory parameters, chemokine profiling, and phenotyping of monocytes as well as collection of explanted valve tissue for further analysis of protein and gene expression.

Results: Macroscopic and immuno-histological analysis of AVs revealed substantially enhanced infiltrating inflammatory cells, mainly monocytes and macrophages along with T cells (p<0.001) with less calcification in FP-AS compared to SP-AS (p<0.0001). Local MIF expression in valvular tissue was significantly enhanced in cell- and collagen-rich samples of FP-AS and correlated significantly with infiltration of platelets and monocyte/macrophages (p<0.001). Immunohistological analysis revealed that platelet infiltration determined by CD42b expression significantly co-localizes with MIF expression in the aortic valve tissue and is predominant in FP-AS (p<0.001). In-depth analysis of platelets and monocytes also uncovered phenotype-specific changes in monocyte and platelet marker profiles in FP- and SP-AS (p<0.05). Most interestingly, MIF plasma levels, MIF content in platelets and MIF expression in monocytes correlated significantly with FP-AS (p<0.05). MIF-associated gene expression was significantly enhanced in FP-AS accompanied by significantly elevated MIF plasma levels (mean ± SEM; 6877±379.1 vs 9959±749.1, p=0.0003), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation [CD62P; %; median, IQR; 16.8 (11.58-23.8) vs 20.55 (12.48-32.28), p=0.0045; MIF; %; 4.85 (1.48-9.75) vs 2.3 (0.78-5.9), p<0.0001]. Furthermore, regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. Here, we also tested for possible confounding effects of cardiovascular risk factors, comedication, and comorbiditiesm on the progression rate of AS using PLS-DA and OPLS-DA. Here, we confirmed that MIF plasma levels and MIF expression in platelets and monocytes remained the strongest independent predictor of the progression rate of AS in our studied cohort.

Conclusion: We report a game-changing role of MIF as key component in inflammation-driven, fast progressive aortic valve stenosis. Our findings suggest a key role for platelet- and/or monocyte-derived MIF and its interplay with circulating immune cells and valve resident cells in local and systemic thrombo-inflammation during accelerated disease progression of the aortic valve stenosis. MIF levels serve as biomarkers to predict an accelerated course of AS.

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