Role of hypercholesterolemia and PSCK9 in bioprosthetic aortic valve degeneration

Abstract

Calcific aortic valve stenosis (CAVS) is one of the most frequent cardiovascular diseases affecting more than 10% of the population over 70 years old. There is currently no pharmacological treatment to stop this process, and the only solution remains to replace the diseased valve with a prosthesis. A shift toward the use of biological prosthesis occurred in the last 10 years, as these protheses presented better hemodynamic profile without lifelong anticoagulation treatment. However, the main disadvantage of the bioprostheses is their limited durability overtime, with the development of a gradual structural bioprosthetic degeneration (SVD) in the following years post intervention. Our objective is to test the role of hypercholesterolemia and/or PCSK9, a well-know modulator of the cholesterol metabolism, on the early process leading to SVD. As the currently gold standard technic to test calcification potential of biological tissue from bioprosthetic valve, we implanted subcutaneously 5 mm punches of biological matrix from bovine pericardium, in 3 groups of mice: PCSK9 KO, WT and overexpressing hepatic PCSK9 (with AAV injection). After 28 days, punches werehandled and analyzed. Histology and molecular screening were performed. As compared to WT, KO PCSK9 mice presented a 25% to 50% reduction in cholesterol, and mice overexpressing hepatic PCSK9 a 2-time higher circulating cholesterol over the course of the protocol (all P < 0.003). PCSK9 circulating level was not detectable in KO and was significantly increased in mice overexpressing hepatic PCSK9 (fold change > 10 vs. WT; all P < 0.001). Preliminary histological analysis of explanted punches after 28 days revealed an important infiltration of mononuclear cells into the pericardial matrix, consistent over the 3 groups of mice. However, the quantity and degree of infiltration of these cells appeared to be exacerbated in mice overexpressing hepatic PCSK9. Further molecular screening is ongoing. We successfully developed an animal model allowing us the investigation of PCSK9 and hypercholesterolemia roles in SVD. Preliminary analyses suggest that high PCSK9 and/or cholesterol can potentiate cell infiltration post-implantation of bovine pericardial matrix. Further molecular analyses will provide key elements to decipher the mechanisms related to PCSK9 and cholesterol in the development of SVD.