Abstract Body (Do not enter title and authors here): Introduction: Calcific aortic valve stenosis is the more frequent valvular disease, affecting more than 10% of patients >75 years old. Surgical or transcatheter aortic valve replacement is the only treatment available. There is an increase use of bioprosthetic valves, even if they present a limited durability with the progressive development of structural bioprosthetic deterioration (SVD). Recent clinical studies highlighted an association between circulating lipid factors, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), Lipoprotein (a) and LDL-cholesterol, and SVD. However, the underlying mechanisms remain unknown.

Objective: We aim at deciphering the role of hypercholesterolemia and/or PCSK9 on the early processes leading to SVD.

Methods: Subcutaneous implantation of bioprosthetic tissue was performed on 10-week old wild type (WT), PCSK9 knock-out (KO) and PCSK9 overexpressing C57BL/6J mice for 28 days. A qualitative anatomopathological score evaluating cell density, infiltration, and tissue degradation was developed. Infiltrated immune cells were characterized by IHC, with a focus on anti- (CD163+) and pro-inflammatory (F4/80+) macrophages, lymphocytes (CD3+) and polynuclear eosinophils (CCR3+).

Results: An important infiltration of mononuclear cells into the explanted punches was observed among the 3 groups (n=10 mice/group). Cell recruitment was more pronounced in mice overexpressing PCSK9 compared to WT and KO. The anatomopathological score of PCSK9 overexpressing mice was significantly higher as compared to WT and KO (7.0 [4.1-8.4] vs 4.0 [3.0-4.5] and 2.8 [2.0-3.9], respectively; p=0.008). The infiltrate was mainly composed of macrophages (CD163+ F4/80+) and polynuclear eosinophils, even if few lymphocytes were observed. Polynuclear eosinophils were more abundant in mice overexpressing PCSK9 compared to WT and KO (p=0.01 and p=0.002).

Conclusion: Hypercholesterolemia and/or high PCSK9 level promote the cellular response against the bioprosthetic tissue. It potentiates the infiltration of polynuclear eosinophils and macrophages, pointing out for an exacerbated inflammatory response, post implantation. Deeper cellular/molecular analyses are ongoing to provide mechanistic clues to better understand the link between hypercholesterolemia/PCSK9 and the early inflammatory processes leading to SVD.