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Page 2 of 15 Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69
[4]
including turbulent blood flow or low wall shear stress . Accumulating evidences indicate that symptomatic
≥ 70% CA stenosis should undergo expedited surgery, and most of the guidelines recommend carotid
endarterectomy (CEA) within 2 weeks of minor ischemic strokes or transient ischemic attacks (TIAs). In
contrast, some guidelines also recommend CEA for asymptomatic CA stenosis, but surgical or interventional
[5]
therapies for asymptomatic CA stenosis are a weaker recommendation . This is because recent advance in
medical therapies has reduced the stroke risk in an asymptomatic CA stenosis. Indeed, a large prospective
cohort study reported that asymptomatic ≥ 50% CA stenosis was associated with an annual rate of < 1%
[6]
ischemic strokes . According to meta-analyses, an annual rate of ischemic strokes in asymptomatic severe
CA stenosis was decreased to 1.13% after 2000 with medical therapy alone, while that was 2.83% before
[7]
2000 . The remarkable thing is that the time of decreases in ischemic stroke risks in CA stenosis overlaps
with that of increases in modern intensive medical treatment including statin medications and the improved
control of hypertension.

Several lipid-lowering agents such as a statin are well known to be effective for the primary or secondary
stroke prevention [8-10] . Statin exerts not only lipid-lowering effects but also pleiotropic effects including
the reduction of inflammatory reactions, endothelial cell (EC) activation, and smooth muscle cell (SMC)
[11]
proliferation . As for the association between statins and atherosclerotic CA stenosis, statins are well
known to decrease CA intima-media thickness (IMT) [12-15] , suppress CA plaque progression [16,17] , and
improve CA plaque vulnerability [18,19] .

This article focuses on mechanisms of CA atherosclerosis development, by which dyslipidemia induces,
and discusses potential therapeutic roles of stains as well as non-statin lipid-lowering agents and non-drug
therapies for atherosclerotic CA stenosis.

THE FORMATION OF ATHEROSCLEROTIC CA PLAQUE [Figure 1]
The mechanisms of atherosclerotic formation in CA are similar to those in other arteries. A hemodynamic
shear stress triggers EC dysfunction and induces SMC accumulations in the subendothelial space, initiating
atherosclerosis formation at arterial branch sites as intimal cell masses [20,21] . Physical or metabolic injury-
induced disturbance of EC integrity makes ECs transduce hemodynamic stress into biochemical signals,
which change the expressions of cell adhesion molecules (CAMs) and other cell surface receptors to
[20]
alter blood cell adhesion . Several mediators including reactive oxygen species induce CAMs such as
intercellular adhesion molecule (ICAM)-1, vascular CAM (VCAM)-1, and endothelial-leukocyte adhesion
[21]
molecules on ECs . The first step of atherogenesis is that low-density lipoprotein (LDL) cholesterol
(Cho) (LDL-C) enters into the subendothelial spaces, and is trapped by a high affinity to the glycoprotein
[22]
molecules at the lesion . Although LDL particles cannot penetrate the junctions between ECs due to
their too large molecular size, most of circulating LDLs can be transported across the EC by receptor-
mediated or nonspecific uptake into micropinocytic channels. Each EC has receptors for both LDLs and the
modified forms. A free receptor modifies and oxidizes LDL into modified forms of LDL such as oxidized
LDLs (ox-LDLs), and ox-LDLs promote transendothelial migration of monocytes into the subendothelial
spaces, which is guided by chemokines. Moreover, ox-LDLs induce the differentiation of monocytes into
macrophages. Macrophages develop receptors for ox-LDLs to become lipid-laden foam cells through the
[21]
receptor-mediated incorporation of ox-LDLs . Thus, Cho is trapped within the arterial walls, which is
the hallmark of early-stage atherosclerotic lesion formation. Macrophage also induces local inflammatory
reactions within the vessel walls, which are promoted by cytokines, activated helper T cells, and activators
[23]
of scavenger receptors . Accumulated lipid-laden foam cells in the tunica intima in the artery wall mature
fatty streaks and produce a lesion, which is covered with a fibrous cap consisting of macrophages, SMCs, and
[24]
extracellular matrix (ECM) components including collagen, elastin and proteoglycans . The fibrous cap
is a layer of connective tissues, and separates a lipid-rich core from arterial lumen, forming atherosclerotic
plaques. When chronic inflammation is present, foam cells are persistently recruited, and apoptosis and