Macrophage migration inhibitory factor boosts inflammatory processes in the aortic valve and is associated with the degree of aortic valve sclerosis and stenosis

Livia Baas (Tübingen)1, T. Harm (Tübingen)1, M. Sigle (Tübingen)2, A.-K. Rohlfing (Tübingen)1, K.-P. Kreisselmeier (Tübingen)1, M. Senel (Tübingen)1, D. Rath (Tübingen)1, T. Geisler (Tübingen)2, O. Borst (Tübingen)2, M. Droppa (Tübingen)1, T. Castor (Tübingen)1, 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


Background: Degenerative aortic stenosis (AS) is driven by progressive inflammatory and fibro-calcific processes regulated by pro-inflammatory mediators that play a critical role for phenotypic changes of valvular interstitial (VIC) and endothelial cells (VEC). Among those, macrophage migration inhibitory factor (MIF) boosts vascular und valvular inflammation. However, the role of MIF during the early stages of aortic sclerosis and stenosis are unknown.

Methods: We prospectively analyzed 129 consecutive patients and matched healthy controls (n=25) with either mild (n=17), moderate (n=24), or severe (n=63) AS undergoing cardiac check-up due to systolic heart murmur. Cardiac workup included physical examination, echocardiography, blood sampling for laboratory parameters, chemokine profiling, and phenotyping of monocytes and platelets as well as collection of plasma and immune cell samples for further analysis of protein and gene expression.

Results: We evaluated the MIF expression in platelets and monocytes along with MIF plasma levels in a prospective clinical study cohort of n=129 patients with different stages of aortic valve sclerosis and stenosis and in matched healthy controls. We found that plasma levels of MIF and monocytic MIF is enhanced to a greater extent as the degree of aortic valve stenosis advances (p<0.001). The systemic amount of MIF correlated significantly with the echocardiographic findings in transthoracic echocardiography comprising aortic valve area, peak velocity of the aortic valve (p<0.05, respectively). Linear regression analysis revealed that MIF plasma levels, MIF content in monocytes, increased numbers of intermediate and non-classical monocytes, female gender, age, and C-reactive protein levels were independently associated with peak velocity of the aortic valve and the degree of aortic stenosis.

Conclusion: Our findings suggest that changes in MIF levels occur during disease progression of aortic valve disease and play an important role as valvular inflammatory booster. However, our findings are rather observational and hypothesis-generating. Therefore, further studies are needed to elucidate underlying mechanisms of MIF-triggered valvular inflammation and its prognostic impact on disease progression.

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