Background: Aortic stenosis (AS) is driven by progressive inflammatory and fibro-calcific processes regulated by circulating inflammatory cells like monocytes. An enhanced inflammatory response leads to specific differentiation of valve resident endothelial and interstitial cells. The impact of proinflammatory monocytes on the progress of aortic stenosis has not been fully understood.

Methods: We prospectively enrolled 283 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). In-depth phenotyping uncovered disease-specific changes in monocyte marker profiles in FP- and SP-AS (p<0.05). Most interestingly, intracellular expression of several proinflammatory mediators were increased in intermediate and non-classical monocytes in patients with FP- compared to SP-AS (p<0.05). Finally, linear regression analysis confirmed that monocytic biomarkers are strongly associated with progression of aortic stenosis. Thus, patients with FP-AS are characterized by significant alterations of systemic inflammation triggered by monocytes, which can be linked to accelerated inflammation of AV tissue in FP-AS.

Conclusion: Our findings suggest a key role for circulating pro-inflammatory monocyte phenotypes on the differentiation of valve resident cells leading to an “inflammatory” valvular phenotype associated with fast progression of AS. These monocytic markers may help to identify patients at risk for fast progressive AS already at an early stage of the disease.