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.

Keywords: Lp(a); PCSK9; aortic valve; lipids; statins.

Figure 5

Off-target effects of statins. Statins act at different levels in skeletal muscle cells. First, they provoke the increased release of calcium from the sarcoplasmic reticulum to the cytoplasm and perturb the contractility of muscle fibers. In parallel, statins impair mitochondrial function, leading to the accumulation of ROS and to the activation of apoptosis. Finally, statins impair the function of Akt due to the impaired insulin signaling pathway and due to the impaired function of mTORC2. As a result, statins induce increased protein degradation and impaired protein synthesis, promoting skeletal muscle atrophy [95].

Figure 1

The implication of Ox-LDL in the calcification of the aortic valve. The infiltration of Ox-LDL into the aortic valve activates inflammation and, consequently, the release of PLA2G7 from macrophages, leading to the production of LysoPC. The activation of autotaxin leads to the preproduction of LPA, which amplifies the inflammation and the activation of the osteoblastic-like phenotype switch.

Figure 2

Statins’ mechanism of action. Statins inhibit the HMG-CoA reductase to block the synthesis of mevalonic acid and, consequently, the production of cholesterol.

Figure 3

The effects of statins at systemic levels. Statins increase the expression of LDL receptors on hepatocytes to increase LDL uptake and catabolism, leading to a systemic decrease in LDLs, vLDLs, and the production of HDL.

Figure 4

The effect of Lp(a) on aortic valve calcification. Lp(a) particles carry oxidized LDL, which stimulate aortic valve cells’ calcification. Targeting Lp(a) might inhibit valve inflammation and, consequently, reduce valve cell calcification.