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ORIGINAL ARTICLE

Effects of Rosuvastatin vs. Simvastatin/ezetimibe on Arterial


Wall Stiffness in Patients with Coronary Artery Disease
Ban Liu 1, Wenliang Che 1, Hongwei Yan 2, Weidong Zhu 2 and Hongbao Wang 3

Abstract
Objective Statins prevent cardiovascular events in patients with coronary artery disease (CAD). However,
there is little information regarding the vascular effects of statins on arterial wall stiffness in CAD patients.
Methods A total of 36 patients were randomly assigned to receive rosuvastatin (10 mg per day) or simvastatin/ezetimibe (10/10 mg per day) for eight weeks. The aim of the present study was to determine the effects
of rosuvastatin or simvastatin/ezetimibe on arterial wall stiffness measured according to the brachial and ankle pulse wave velocity (baPWV) in CAD patients.
Results Both treatments significantly improved the levels of total cholesterol (TC), triglycerides (TGs), lowdensity lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP) (p<0.05). The
ROCK activity and baPWV were significantly improved in the rosuvastatin group compared with that observed in the simvastatin/ezetimibe group (p<0.05). The changes in baPWV were significantly correlated with
the changes in the ROCK activity (r=0.488, p<0.01), but not with the changes in the lipid profile or the hsCRP level.
Conclusion Compared with simvastatin/ezetimibe (10/10 mg), rosuvastatin (10 mg) appears to more effectively improve arterial wall stiffness that may be mediated by modulation of the ROCK activity.
Key words: statin, low-density lipoprotein cholesterol, coronary artery disease, pulse wave velocity, ROCK
activity
(Intern Med 52: 2715-2719, 2013)
(DOI: 10.2169/internalmedicine.52.0731)

Introduction
A relationship between the serum levels of low-density
lipoprotein cholesterol (LDL-C) and the incidence of coronary artery disease (CAD) has been demonstrated (1, 2).
Statins, which are inhibitors of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA), can reduce the LDL-C level and
are an established therapy in the primary and secondary prevention of CAD (3, 4). The overall benefits observed with
statins are mediated not only by their cholesterol-lowering
effects, but also by their pleiotropic anti-inflammatory effects (5). Cumulative evidence suggests that the ROCK
pathway is involved in many steps of the inflammatory atherosclerotic process (6-8). Inhibition of the ROCK activity

with Y-27632 limits early atherosclerotic plaque development in LDLr-/- mice fed a high-cholesterol diet (9). The
purpose of the present study was to determine the pleiotropic effects of statins on arterial wall stiffness and the correlations between arterial wall stiffness and inflammatory
markers in patients with CAD.

Materials and Methods


Study design
This study involved Chinese patients with 50%
stenosis in at least one major coronary artery who
ferred for coronary angiography. The patients were
ized to receive eight weeks of rosuvastatin (10 mg

or more
were rerandomper day)

Department of Cardiology, Shanghai Tenth Peoples Hospital, Tongji University School of Medicine, China, Key Laboratory of Arrhythmias,
Ministry of Education, Tongji University School of Medicine, China and Department of Cardiology, Shanghai Yangpu District Central Hospital,
China
Received for publication April 7, 2013; Accepted for publication August 5, 2013
Correspondence to Dr. Ban Liu, liuban@126.com

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Intern Med 52: 2715-2719, 2013

DOI: 10.2169/internalmedicine.52.0731
Table1.Patients Characteristic

or simvastatin/ezetimibe (10/10 mg per day). Rosuvastatin


was chosen because it has been proven to be the most effective hydrophilic statin in lowering cholesterol (10). Rosuvastatin (10 mg/day) and simvastatin/ezetimibe (10/10 mg) are
considered to equally decrease the LDL-C level (11). A total
of 36 CAD patients with 50% or more stenosis in at least
one major coronary artery were divided into a rosuvastatin
(n=18) and simvastatin/ezetimibe (n=18) group at random.
Rosuvastatin was administered at a dose of 10 mg/day and
simvastatin/ezetimibe was administered at a dose of 10/10
mg/day in order to lower the LDL-C level without the use
of any other lipid-lowering drugs. Patients with acute myocardial infarction (AMI), spastic angina pectoris, chronic
diseases of the liver or kidney (a serum creatinine level of >
2.0 mg/dL or elevation of the alanine transaminase level exceeding three times the upper limit of normal), anemia, neurological or endocrine diseases or malignancy were excluded. No subjects had taken any statins before this study.
All subjects were advised to continue their current medications and lifestyle for the duration of the study.

Variables

Simvastatin/ezetimibe
(n=18)

Rosuvastatin
(n=18)

Age(yrs)
Male(%)
Body mass index (kg/m2)
Waist circumstance (cm)
Total cholesterol (mmol/L)
Triglycerides (mmol/L)
HDL-C (mmol/L)
LDL-C (mmol/L)
hsCRP (mg/L)
Multi vessel disease, n(%)
Hypertention, n(%)
Diabetes, n(%)
Smoking, n(%)
ROCK activity, %
baPWV (cm/s)

6513
11(61.1)
24.33.1
96.14.7
3.950.2
1.420.28
1.110.08
2.400.10
2.00.38
9(50)
12(66.7)
11(61.1)
6(33.3)
83.2
1769421

6718
10(55.6)
25.13.5
96.04.7
4.010.17
1.430.29
1.100.12
2.420.15
2.10.35
9(50)
11(61.1)
12(66.7)
6(33.3)
86.1
1772430

HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density


lipoprotein cholesterol, hsCRP: high-sensitivity C-reactive protein,
baPWV: brachial and ankle pulse wave velocity. No differences
were observed among the 2 treatment groups (all p>0.05).

Measurement of the lipid profiles, hsCRP levels and


ROCK activity
Blood samples were collected in citrate-treated tubes two
times in all patients: 1) immediately before coronary angiography after an overnight fast and 2) after eight weeks of
lipid-lowering treatment. The concentrations of highsensitivity C-reactive protein (hsCRP) were measured using
an immunoturbidimetric assay on a modular system randomaccess analyzer (Dade Behring, Deerfield, IL, USA).
To evaluate the ROCK activity, the Rho kinase-dependent
phosphorylation of the myosin binding subunit (MBS) at
threonine 853 (phospho-Thr853-MBS) was assayed in peripheral blood leukocytes, as previously described (12). The
blood was collected at room temperature in heparinized
tubes (20 U/mL). The leukocytes were isolated from the peripheral blood samples (15 mL), suspended and diluted, as
previously described (13). After the proteins were precipitated, a Western blot analysis was performed, as previously
described (13). The ROCK activity was expressed as the ratio of phospho-Thr853-MBS/total MBS normalized to the
positive controls.
Measurement of baPWV
The patients were examined using a volume plethysmographic instrument (PWV/ABI; Colin Co, Komaki, Japan) in
the morning following an overnight fast at the time of enrollment and at end of the study. The brachial and ankle
pulse wave velocity (baPWV) was measured after allowing
the patient to rest in the supine position for 10 minutes in a
24-26 air conditioned room. The baPWV was calculated
using a time-phase analysis of the right brachial artery pressure and volume waveforms at both ankles at the beginning
of the study, and a repeated analysis was performed on the
same side in each patient during the study (14).

Statistical analysis
All statistical analyses were conducted using the Statistical Package for Social Sciences version 17.0 software package (SPSS Inc., Chicago, IL). The baseline characteristics of
the two groups were analyzed using Students t-test or the
Mann-Whitney U test for continuous variables and the chisquare for discrete variables. Paired Students t-test or the
Wilcoxon test was performed to analyze the effects of the 8week rosuvastatin or simvastatin/ezetimibe treatment. The
Pearson correlation test was used to analyze the correlation
between changes in baPWV and the other parameters. The
data were expressed as the mean standard deviation (SD)
or median, and p<0.05 was considered to be statistically significant.

Results
Patient characteristics
The baseline characteristics of the patients are summarized in Table 1. The patients in both treatment groups were
matched for age, gender and cardiac risk factors (p>0.05).
Changes in the lipid profiles, hsCRP levels and
ROCK activity
The patients in both groups had similar lipid profiles and
hsCRP levels at randomization (Table 1). Both treatments
produced similar reductions in the total cholesterol (TC), triglyceride (TG) and LDL-C levels compared to the baseline
values (both p<0.05). Both treatments increased the highdensity lipoprotein cholesterol (HDL-C) levels slightly compared with the baseline values; however, no statistical significance was observed (p>0.05) (Table 2). Both treatments

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Intern Med 52: 2715-2719, 2013

DOI: 10.2169/internalmedicine.52.0731

Table2.Effects of Treatment on Lipid Profiles, hsCRP, and baPWV


Simvastatin/ezetimibe
day0
day56

Rosuvastatin
day0
day56

Total cholesterol (mmol/L)

3.950.25

2.200.32*

4.010.17

1.870.28*

Triglycerides (mmol/L)

1.420.28

1.200.22*

1.430.29

1.210.23*

HDL-C (mmol/L)

1.110.08

1.130.08

1.100.12

1.150.10

LDL-C (mmol/L)

2.400.10

1.430.17*

2.420.15

1.330.19*

hsCRP (mg/L)

1.680.38

1.020.28**

1.720.35

0.980.25**

baPWV (cm/s)

1,769421

1,722386

1,772430

1,603398*

HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, hsCRP: high-sensitivity
C-reactive protein, baPWV: brachial and ankle pulse wave velocity.
*p<0.05 indicates comparison of measured values before and after 8-week treatment within individual group.
**p<0.01 indicates comparison of measured
values before and after 8-week treatment within individual group.
indicates difference between the simvastatin/ezetimibe 10/10mg vs. rosuvastatin 10mg group.

Table3.Correlations between Changes in baPWV


and Changes in Lipid and Inflammation Parameters

Total cholesterol (mmol/L)


Triglycerides (mmol/L)
HDL-C (mmol/L)
LDL-C (mmol/L)
hsCRP (mg/L)
ROCK Activity(%)

p value

0.106
0.089
0.168
-0.172
0.263
0.488

NS
NS
NS
NS
NS
<0.01

HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density


lipoprotein cholesterol, hsCRP: high-sensitivity C-reactive protein,
baPWV: brachial and ankle pulse wave velocity,
NS: not significant

tatin/ezetimibe did not (p>0.05) (Table 2).

Figure.Effects of rosuvastatin 10 mg/d and simvastatin/ezetimibe 10/10 mg/d on leukocyte ROCK activity. ROCK activity
in leukocytes was measured as percentage of phosphorylated
(phospho-) MBS of myosin light-chain phosphatase (pThr853MBS) relative to the total (t-) MBS.

decreased the hsCRP levels compared with the baseline values (p<0.01 for both groups).
The baseline ROCK activity did not differ between the
two treatment groups (Table 1). No changes were observed
in the ROCK activity over time in the patients randomized
to the simvastatin/ezetimibe group (86.1% vs. 69.8%; p>
0.05, Figure). Rosuvastatin (10 mg/day) decreased the
ROCK activity (83.2% vs. 39.7%; p<0.01, Figure); this reduction in the ROCK activity was significant compared with
that observed in the simvastatin/ezetimibe group after eight
weeks of treatment (p<0.05, Figure).
Changes in baPWV
The baseline baPWV values were not different between
the two treatment groups (Table 1). Rosuvastatin significantly decreased the baPWV values (p<0.05), while simvas-

Correlations between the metabolic parameters,


hsCRP levels, ROCK activity and baPWV values
No correlations were found between the changes in the
LDL-C levels and the changes in the ROCK activity (r=
0.197, p>0.05). We further analyzed whether any correlations existed between the changes in the baPWV values,
lipid profiles, hsCRP levels or ROCK activity in the two
treatment groups. No correlations were found between the
changes in the baPWV values and the changes in the total
cholesterol, triglyceride, LDL-C, HDL-C or hsCRP levels in
either group (p>0.05). However, a strong association was
observed between the changes in the baPWV values and the
changes in the ROCK activity (r=0.488, p<0.01) in the subjects receiving rosuvastatin and simvastatin/ezetimibe (Table 3).

Discussion
In this randomized controlled study, we found that both
rosuvastatin (10 mg) and simvastatin/ezetimibe (10/10 mg)
similarly reduced the LDL-C, TC, TG and hsCRP levels after eight weeks. The PWV values are significantly decreased
after 4-12 weeks of statin treatment (15, 16). The results of
this study also demonstrate that rosuvastatin significantly

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DOI: 10.2169/internalmedicine.52.0731

ameliorated arterial wall stiffness after eight weeks of treatment in correlation with a reduced ROCK activity in the patients with CAD. Although rosuvastatin (10 mg) and simvastatin/ezetimibe (10/10 mg) have comparable lipid-lowering
effects, only the rosuvastatin group achieved a significant
improvement in arterial stiffness and inhibition of the
ROCK activity, compared with that observed in the simvastatin/ezetimibe group.
Increased arterial stiffness is thought to act as a risk factor for cardiovascular events via an impaired coronary blood
flow, direct atherogenic actions, increased cardiac afterload
and microvascular damage (17-19). Epidemiologic and clinical studies have shown that measuring the PWV is the gold
standard for assessing impaired aortic stiffness, and reducing the PWV levels is potentially beneficial in the management of patients with CAD (2, 4). BaPWV measurement is
a simple and effective tool in clinical practice (20). The
benefits of statin therapy extend beyond lipid-lowering effects (21). The pleiotropic effects of statins suggest that
the improvements in outcomes are related as much to the
anti-inflammatory actions as to the LDL-C-lowering effects
of the drugs (5). Inflammatory responses in the vascular
wall are thought to stiffen the arteries, both functionally and
structurally (22). Considerable evidence suggests that the
CRP level is an independent predictor of future cardiovascular events; however, the direct involvement of CRP in atherosclerosis remains controversial (21, 23). Data from the
1999-2000 National Health and Nutrition Examination Survey (NHANES) indicated that 47.1% of respondents 20
years of age or older had a high CRP level (24). Approximately one-third of the population has a CRP level above 3
mg/L (25).
Studies have demonstrated that ROCK is a critical contributor to many steps of the inflammatory atherosclerotic
process (6-8). Treatment with the ROCK inhibitor fasudil
causes a decrease in arterial intima medial thickness, maximum flow velocity and macrophage accumulation in atherosclerotic lesions (26). Statins prevent the synthesis of important isoprenoid intermediates of the cholesterol biosynthetic
pathway that serve as important lipid attachments for the
posttranslational modification of small GTPases, such as
Rho, Ras and Rac (27). By inhibiting mevalonate synthesis,
statins prevent the membrane targeting of Rho and its downstream effector ROCK (27). It is difficult to separate the
cholesterol-lowering effects of statins from their pleiotropic
effects. Ezetimibe, which inhibits intestinal cholesterol absorption, was introduced in this study. Treatment with
ezetimibe combined with a statin did not alter the progression of carotid artery intima-media thickening, despite a further reduction in the LDL-C and hsCRP levels, compared
with that achieved with statins alone (28). Despite achieving
equivalent reductions in the LDL-C and hsCRP levels with
both treatments, rosuvastatin, not simvastatin/ezetimibe, was
shown to improve arterial wall stiffness and reduce the
ROCK activity in the present study. Our data also indicate
that the ROCK activity may provide further predictive infor-

mation regarding arterial wall stiffness in patients with


CAD. In this study, we found that the hsCRP level is not
the best predictor of vascular stiffness. We also found no
significant correlations between arterial wall stiffness assessed according to the baPWV and aging, obesity, diabetes
mellitus, hypertension and lipid profile abnormalities.
Several limitations remain in this study. This study was a
single-center study with a small number of patients. A placebo group was not included due to the ethical implications
of withdrawing statin therapy in patients with CAD. Statins
may exert their anti-inflammatory effects via the Ras superfamily of small GTPases, including Ras, Rac and Cdc-42,
which may also play a role in mediating vascular abnormalities (29). This study did not assess the effects of rosuvastatin on other members of the Ras superfamily. The mechanism underlying the improvement of arterial stiffness due to
the inhibition of the ROCK activity by rosuvastatin is intriguing and requires further study.

Conclusion
This study demonstrates that rosuvastatin inhibits the
ROCK activity in patients with CAD, independent of cholesterol reduction, and that rosuvastatin therapy has significant vascular benefits, likely due to the suppression of the
ROCK pathway in the arterial wall.
The authors state that they have no Conflict of Interest (COI).
Ban Liu, Wenliang Che, and Hongwei Yan contributed equally
to this work.

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