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

Figures

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  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].

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  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.

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  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.

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  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.

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  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.