Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail?

Abstract

Calcific Aortic Valve Disease (CAVD) is a fibrocalcific disease. Lipoproteins and oxidized phospholipids play a substantial role in CAVD; the level of Lp(a) has been shown to accelerate the progression of valve calcification. Indeed, oxidized phospholipids carried by Lp(a) into the aortic valve stimulate endothelial dysfunction and promote inflammation. Inflammation and growth factors actively promote the synthesis of the extracellular matrix (ECM) and trigger an osteogenic program. The accumulation of ECM proteins promotes lipid adhesion to valve tissue, which could initiate the osteogenic program in interstitial valve cells. Statin treatment has been shown to have the ability to diminish the death rate in subjects with atherosclerotic impediments by decreasing the serum LDL cholesterol levels. However, the use of HMG-CoA inhibitors (statins) as cholesterol-lowering therapy did not significantly reduce the progression or the severity of aortic valve calcification. However, new clinical trials targeting Lp(a) or PCSK9 are showing promising results in reducing the severity of aortic stenosis. In this review, we discuss the implication of lipids in aortic valve calcification and the current findings on the effect of lipid-lowering therapy in aortic stenosis.

Identification of HIBCH as a Fatty Acid Metabolism-Related Biomarker in Aortic Valve Calcification Using Bioinformatics

“…Surgical treatment is required in patients with serious symptoms and has a poor prognosis [19]. The pathogenesis of AVC is complex and similar to atherosclerosis, involving multiple pathological processes including chronic inflammation, lipid metabolism disorders, fibrosis, and calcification [20]. This is consistent with our analysis using publicly available databases and bioinformatic analysis that AVC may be closely associated with fatty acid metabolism.…”

Lipoprotein(a): Emerging insights and therapeutics

“…The pathophysiology leading to the development of AS is complex, resulting from the interplay of endothelial dysfunction, inflammation, and lipoprotein oxidation leading to aortic valve calcification as well as additional risk factors such as smoking and hypertension [38] , [39] , [40] . Lp(a) is thought to play a significant role in the development of AS, as a major lipoprotein carrier of the pro-inflammatory and pro-calcific oxidized phospholipids which can induce osteogenic differentiation of valvular interstitial cells [ 41 , 42 ]. Enzymes such as autotaxin have also been associated with calcific AS and concomitant elevations in Lp(a) and oxidized phospholipids strongly predict risk of calcific AS suggesting interconnected mechanisms that require further investigation [43] .…”

Focusing on the Native Matrix Proteins in Calcific Aortic Valve Stenosis

“… 77 Biglycan colocalized with phospholipid transfer protein and Toll-like receptor-2 receptor, suggesting an increased cellular absorption of the trapped lipid particles. 78 Furthermore, ECM protein fragmentation products can serve as a source of immune cell activation via the Toll-like receptors and integrins. Local macrophages can migrate into areas of collagen deformation, driven by mechanical stretching forces alone.…”