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Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69 Page 7 of 15

Figure 2. Metabolic pathways for cholesterol (Cho) and the main acting points of lipid-lowering agents. Statin is a 3-hydroxy-3-
methylglutaryl coenzyme A (HMG-CoA) inhibitor, and exerts lipid-lowering effects by inhibiting the synthesis of Cho in liver and
pleiotropic effects such as anti-inflammation and improvement of endothelial dysfunction. Niacins modify plasma lipid levels by inhibition
of lipolysis in adipose tissues. Fibrates reduce triglyceride (TG) levels and increase high-density lipoprotein (HDL) Cho (HDL-C) levels
via various mechanisms including the inactivation of peroxisome proliferator activated receptor (PPAR) α, which increases the oxidation
of free fatty acid (FFA) in liver and reduces the hepatic synthesis of TG and expression of lipoprotein lipase. Omega-3 polyunsaturated
fatty acids (PUFAs), the major component of fish oil, are widely used as a TG-lowering therapy and have been found against oxidative
stress and inflammation. Ezetimibes reduce low-density lipoprotein (LDL) Cho (LDL-C) levels by inhibition of the absorption of Cho
from intestines. Cho ester (CE) transfer protein (CETP) inhibitors increase HDL-C levels by the inhibition of CETP, which promotes the
net effects on the equilibration of both CE and TG among all lipoprotein particles. Proprotein convertase subtilisin-kexin type 9 (PCSK9)
inhibitors remove LDL-C from plasma by the inhibition of PCSK9, which is a hepatic protease that decreases hepatic LDL receptor (LDL-R)
leading to an increase in the plasma concentration of LDL-C. CM: chylomicron; ICAM: intercellular adhesion molecule; Ox-LDL: oxidized
LDL; ROS: reactive oxygen species; SMC: smooth muscle cell; TGRL: TG-rich lipoprotein; VCAM: vascular cell adhesion molecule; VLDL:
very LDL; VLDL-R: VLDL receptor

[9]
nonfatal strokes by 16% and prevented the development of atherothrombotic infarction even after adjusting
[10]
LDL-C levels at baseline [adjusted hazard ratio (HR), 0.39] . The American Heart Association guideline
states that statin treatment is reasonable for reducing LDL-C levels to less than or equal to 70 mg/dL in a
patient with an atherosclerotic disease at the extracranial CA or vertebral artery who has sustained ischemic
[66]
strokes .

Statins are well known not only to decrease IMT and to suppress plaque progression in the CA, but also
to improve plaque vulnerability in the CA as described below. These effects might be exerted by their
pleiotropic effects, which include the inhibition of subclinical systemic inflammation, EC activation, and
[11]
intra-plaque infiltrations of leukocytes, as well as an increase in protective SMC migration into plaques .
Statin and CA IMT
Stains were for the first time reported to play a role in reducing CA IMT in coronary heart disease patients
[12]
with hypercholesterolemia . After that, several randomized clinical trials revealed that statins have