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Page 6 of 15 Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69

hemorrhage [56,57] . In a previous meta-analysis study, an inverse dose-response association was shown
[56]
between TC levels and hemorrhagic stroke risks [odds ratio (OR), 0.85 per 1 mmol/L increase] . A more
recent systematic review also showed that hemorrhagic stroke was increased under low TC conditions: East
Asian ethnic status favors the development of subarachnoid hemorrhage, and non-East Asian ethnic status is
[57]
predisposed to intracerebral hemorrhage .

As to the relationships between dyslipidemia and the subtypes of ischemic strokes, dyslipidemia has a
stronger association with ischemic stroke due to atherosclerotic large artery diseases: it was reported that
[51]
the association between Cho levels and risks of atherosclerotic stroke was the highest (OR, 3.2) , and
[49]
the findings were confirmed in other studies . On the other hand, there are no or obscure associations
between dyslipidemia and other ischemic stroke subtypes: an association between dyslipidemia and lacunar
[51]
strokes was shown in some studies but not all studies , and most studies failed to show any association of
dyslipidemia with cardioembolic infarction [49,51] .

DYSLIPIDEMIA AND CA STENOSIS
The risk factors for CA stenosis are similar to those for other vascular diseases, and the relationship between
[58]
dyslipidemia and CA stenosis is well known. Mathiesen et al. reported that TC, HDL-C (inversely),
fibrinogen, systolic blood pressure, and current smoking were independent factors for the development of
CA stenosis. The determinants of CA IMT were LDL-C levels, systolic blood pressure, body mass index and
[59]
smoking in childhood, and systolic blood pressure, body mass index and smoking in adulthood . Other
previous studies reported that the progression of CA atherosclerosis was associated with a higher level of TC,
[60]
LDL-C, or a lower level of HDL-C . In patients with type 2 diabetes, regression of CA IMT was observed
[61]
when LDL-C and systolic blood pressure were reduced to a lower target .
Several studies investigated if TG can be a risk factor for the progression of CA stenosis [60,62] . In patients
with diabetes, the CA atherosclerosis progression tended to occur more frequently when fasting TG levels
[60]
[62]
were higher . Recently, Kitagami et al. reported that a higher level of TG was an independent risk
factor for the progression of CA atherosclerosis in patients with moderate to severe CA stenosis who were
treated with CA stenting (CAS), CEA, or other treatments under well-controlled LDL-C levels. The findings
suggest that to control TG levels at least within the normal limits is an important management strategy for
[62]
CA stenosis . However, to our knowledge, no studies have revealed the relationships between the degree
of changes in TG levels and the rate of CA IMT progression. It is expected that some studies investigate if
therapeutic reduction of TG levels can suppress the risks of progression of CA atherosclerosis or stenosis.

LIPID-LOWERING AGENTS AND CA STENOSIS [Figure 2]
Statin
Statin inhibits the synthesis of Cho in liver and thereby increases the uptake of Cho by liver, resulting in a
decrease in circulating lipid levels: thus, statin has been extensively reported to exert a lipid-lowering effect.

Experimental studies have demonstrated protective effects of statins on ischemic stroke [63-65] . For example,
rosuvastatin upregulated eNOS and protected ischemic brain in middle cerebral artery occlusion (MCAO)
[63]
[64]
mice ; atorvastatin reduced brain edema via the suppression of aquaporin 4 expression in MCAO rats ;
and simvastatin protected cerebrum from ischemic and reperfusion injury by decreasing the expressions of
[65]
Ca /calmodulin-dependent protein kinase II and aquaporin 4 in MCAO rats .
2+
In clinical settings, there are good evidences that statin reduces risks of ischemic strokes by about 30%,
and that statins are effective for the primary prevention of ischemic strokes in the elderly and patients with
[8]
diabetics, or hypertension . In addition, statins are reported to have beneficial effects on the secondary
prevention for TIAs and ischemic strokes: statin administration significantly reduced the risk of fatal or