High-Intensity Statins Promote PCSK9 Secretion and aortic valve calcification in patients with severe aortic stenosis: In vitro and clinical evidence

Aortic stenosis (AS) is the most common valvular disease, characterized by progressive fibro-calcific remodeling of the aortic leaflets, leading to increased morbidity and mortality. It is now well known that statins influence the production of proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn is linked to calcification. Here, we found that statins significantly increased, in a dose dependent manner, both PCSK9 secretion and valve interstitial cell (VIC) calcification, in vitro. These effects were blunted by PCSK9 genetic knock-down or by PCSK9 antibody neutralization. In AS patients, contrast-enhanced computed tomography evaluation showed a higher aortic valve calcium (AVC) content in patients on high-intensity statins compared to low-intensity ones, with no significant difference between low-intensity statin and non-users. At follow-up, high-intensity statin users exhibited a higher annual AVC accumulation compared to low-intensity statins and non-users. In a real-world scenario, high-intensity statin therapy was associated with a 30 % increased rate of hospitalization for non-rheumatic aortic valve disease. Our findings highlight the need for further investigation into the intricate relationship between statin therapy and aortic valve health to identify the optimal lipid-lowering strategy in the management of patients at risk of developing or afflicted by AS.