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Background: Treatment with non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran (a direct thrombin inhibitor) or rivaroxaban (a direct inhibitor of factor [F] Xa) attenuates atherosclerotic plaque progression in hypercholesterolemic mice., Purpose: To evaluate the effect of NOACs application on the expression of coagulation proteins in loco within stenotic aortic valves and in valve interstitial cells (VICs) from patients with severe aortic stenosis (AS)., Methods: Primary cultures of VICs obtained from 90 patients undergoing aortic valve replacement were stimulated with TNF-α (50 ng/mL) and pre-treated with rivaroxaban (1 and 10 ng/mL) or dabigatran (25 and 250 ng/mL). The expression of coagulation proteins was analyzed by immunofluorescence. Cytokine levels were measured by ELISA., Results: FX, FXa, FVII, thrombin and PAR1/2 were present in loco within human aortic stenotic valves. Cultured VICs exhibited constant expression of FX, TF, PAR1/2. Exposure of VICs to TNF-α caused the upregulated expression of TF, PAR1/2 and induced expression of thrombin, FVII and FXa. FX was expressed by 80% of VICs, regardless of stimulation. Cultured VICs were able to synthesize metalloproteinases 1-3, IL-6, IL-32, IL-34, osteopontin and osteocalcin, the levels of which increased under TNF-α stimulation. NOACs added to culture inhibited coagulation factor and PAR1/2 expression. Moreover, NOACs down-regulated VIC-derived proteins responsible for valve calcification and extracellular matrix remodeling., Conclusions: NOACs at therapeutic concentrations may inhibit the effects of FXa and thrombin at in vitro level. It might be speculated that long-term treatment with rivaroxaban or dabigatran could attenuate the progression of AS in humans., Competing Interests: Declaration of Competing Interest AU received lecture honoraria from Bayer, Boehringer Ingelheim, and Pfizer. Other authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Aortic stenosis (AS) is the most common acquired valvular heart disease in adults. Immune system involvement becomes evident during AS development. We sought to investigate the role of different circulating lymphocyte and monocyte subpopulations, with focus on CD4 + CD8 + and natural killer T (NKT) cells, in AS., Material and Methods: Blood samples and aortic valves were obtained from patients undergoing elective aortic valve surgery. Valves were dissected and underwent genetic analyses and calcium content assessment. Lymphocytes and monocytes subsets were assessed by flow cytometry., Results: Thirty-eight AS patients were studied. Maximal transvalvular pressure gradient (PG max ) as well as mean transvalvular pressure gradient (PG mean ) correlated with the CD4 + CD8 + lymphocyte count (r=0.35, P=.03 and r=0.43, P=.006, respectively) and fraction (r=0.43, P=.007 and r=0.48, P=.002, respectively). PG max and PG mean correlated with CD16 + CD56 + CD3 + NKT cell count (r=0.39, P=.01 and r=0.43, P=.007, respectively) and fraction (r=0.49, P=.002 and r=0.47, P=.003, respectively). The classical monocyte subpopulation increased after the surgery by 68% (P<.0001). Patients after mini-sternotomy surgery had 47% lower nonclassical monocyte counts than those with full-sternotomy (P=.03). Patients treated with statins had significantly lower postoperative levels of both classical (-25%, P=.04) and nonclassical monocytes (-37%, P=.004) than nontreated individuals., Conclusions: In patients with severe isolated AS, CD4 + CD8 + T cells and CD16 + CD56 + CD3 + NKT cells are associated with AV pressure gradients. Postoperative monocyte levels are affected by procedure invasiveness and use of statins., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Valve calcification is well estimated by ex-vivo micro-computed tomography (micro-CT). The objective of this study was to investigate the associations between micro-CT findings and biological indices of calcification in aortic stenosis (AS), as well as differences between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV)., Methods and results: Aortic valves and plasma were obtained from patients undergoing valve surgery. Valves were dissected and underwent micro-CT, genetic analyses, and calcium content assessment. Plasma levels of calcification markers were measured. Forty-two patients with isolated severe AS, including 22 with BAV, were studied. BAV patients had a lower median CT value (140.0 [130.0-152.0] vs. 157.0 [147.0-176.0], P=0.002) and high-density calcification (HDC) fraction (9.3 [5.7-23.3] % vs. 21.3 [14.3-31.2] %, P=0.01), as compared with TAV. Calcification fraction (CF) correlated with AS severity (measured as maximal transvalvular pressure gradient [r=0.34, P=0.03], maximal flow velocity [r=0.38, P=0.02], and indexed aortic valve area [r=-0.37, P=0.02]). For TAV patients only, mRNA expression of integrin-binding sialoprotein correlated with CF (r=0.45, P=0.048), and the receptor activator of the nuclear factor κ-B ligand transcript correlated with HDC corrugation (r=0.54, P=0.01)., Conclusions: TAV patients with AS present more mineralized calcifications in micro-CT than BAV subjects. The relative volume of calcifications increases with the AS severity. In TAV patients, upregulated expression of genes involved in osteoblastogenesis in AS correlates with leaflet mineralization in micro-CT.