High-dose statins are associated with increased aortic valve calcium load in patients with severe stenosis

Abstract Background AS represents the predominant valvular pathology, marked by the progressive fibro-calcific remodeling of aortic valve leaflets. This condition poses a significant clinical burden due to its association with increased morbidity and mortality. In recent years, emerging research has shed light on the potential role of statins in influencing the pathogenesis of AS. Statins, known primarily for their lipid-lowering properties, have been found to modulate the production of proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. This novel avenue of investigation into the interplay between statins, PCSK9, and aortic valve calcification holds considerable therapeutic implications and warrants further exploration for the development of targeted interventions in the management of AS. Purpose To investigate the dose-dependent impact of statins on aortic valve calcification in patients with AS. Methods We enrolled 194 AS patients (87 no, 34 low-dose, and 73 high-dose statins) who underwent contrast-enhanced computed tomography (CT). Atorvastatin (A:0.1uM and 1uM) and pravastatin (P:1uM and 100uM) treatments were used to evaluate valve interstitial cells (VIC) calcification potential and PCSK9 secretion. Results CT quantifications showed that patients taking high-dose statins had significantly higher AVC content compared to low-dose (903.8±601 vs.526.8±403 mm3/cm2, respectively; p0.0001), while no difference in AVC was observed between patients with low-dose statins and no-statins (p=0.226). Of note, low-density lipoprotein cholesterol (LDL-C) levels were comparable between low- and high-dose statins’ groups (p=0.255). We confirmed our observation in vitro, showing that treatment with low-dose satins did not stimulate calcification nor PCSK9 secretion. While high-dose statins significantly increased VICs extracellular calcification (A:+4.3±2.6 fold-change (FC), P:+3.2±1.2FC, respectively; p0.0001) and PCSK9 secretion (A:+3.3±1.9FC, P:+2.5FC, respectively; p0.0001). Conclusion Patients with severe AS who receive high-dose statins compared with those receiving low-dose statins, both of whom achieve the target for LDL-C, had higher AVC load. An in vitro model confirms increased intracellular calcification and PCSK9 secretion upon treatment with high-dose statins only. To achieve lipid targeting in AS patients, it is important to consider this phenomenon, giving preference to other types of drugs, which do not exhibit similar effects.