Efficacy of High-Dose and Low-Dose Simvastatin on Vascular Oxidative Stress and Neurological Outcomes in Patient with Acute Ischemic Stroke: A Randomized, Double-Blind, Parallel, Controlled Trial

Abstract

Backgrounds
Stroke is the leading cause of death and long-term disability. Oxidative stress is elevated during occurrence of acute ischemic stroke (AIS). Soluble LOX-1 (sLOX-1) and NO are used as biomarkers for vascular oxidative stress that can reflect stabilization of atherosclerotic plaque. Previous study showed that simvastatin can reduce oxidative stress and LOX-1 expression.

Objectives
To evaluate neurological outcomes and serum sLOX-1 and NO levels in patients with AIS treatment with low dose 10 mg/day and high dose 40 mg/day of simvastatin.

Methods
65 patients with AIS within 24 hours after onset were randomized to treatment with simvastatin 10 mg/day or 40 mg/day for 90 days. Personal data and past history of all patients were recorded at baseline. The blood chemistries were measured by standard laboratory techniques. Serum sLOX-1 and NO levels and neurological outcomes including NIHSS, mRS, and Barthel index were tested at baseline and Day 90 after simvastatin therapy.

Results
Baseline characteristics were not significantly different in both groups except history of hypertension. Serum sLOX-1 and NO levels significantly reduce in both groups (sLOX-1 = 1.19 ± 0.47 and 0.98 ± 0.37 ng/ml; NO = 49.28 ± 7.21 and 46.59 ± 9.36 μmol/l) in 10 mg/day and 40 mg/day simvastatin groups, respectively. Neurological outcomes including NIHSS, mRS, and Barthel index significantly improve in both groups. However, no difference in NO level and neurological outcomes was found at 90 days after treatment as compared between low dose 10 mg/day and high dose 40 mg/day of simvastatin.

Conclusion
High-dose simvastatin might be helpful to reduce serum sLOX-1. But no difference in clinical outcomes was found between high- and low-dose simvastatin. Further more intensive clinical trial is needed to confirm the appropriate dosage of simvastatin in patients with acute ischemic stroke. This trial is registered with ClinicalTrials.gov ID: NCT03402204.

Full text

Clinical Study
Efficacy of High-Dose and Low-Dose Simvastatin on
Vascular Oxidative Stress and Neurological Outcomes in
Patient with Acute Ischemic Stroke:
A Randomized, Double-Blind, Parallel, Controlled Trial
Nattaphol Uransilp,1Pannawat Chaiyawatthanananthn,2and
Sombat Muengtaweepongsa 3
1Neurology, Faculty of Medicine, ammasat University, Pathum ani, ailand
2Department of Applied ai Traditional Medicine, Faculty of Medicine, ammasat University, Pathum ani, ailand
3Department of Internal Medicine, Faculty of Medicine, ammasat University, Pathum ani, ailand
Correspondence should be addressed to Sombat Muengtaweepongsa; sombatm@hotmail.com
Received 3 January 2018; Revised 26 February 2018; Accepted 13 March 2018; Published 18 April 2018
Academic Editor: Je Bronstein
Copyright ©  Nattaphol Uransilp et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Backgrounds. Stroke is the leading cause of death and long-term disability. Oxidative stress is elevated during occurrence of acute
ischemic stroke (AIS). Soluble LOX- (sLOX-) and NO are used as biomarkers for vascular oxidative stress that can reect
stabilization of atherosclerotic plaque. Previous study showed that simvastatin can reduce oxidative stress and LOX- expression.
Objectives. To evaluate neurological outcomes and serum sLOX- and NO levels in patients with AIS treatment with low dose
 mg/day and high dose   mg/day of simvastatin. Methods.  patients with AIS within  hours aer onset were randomized
to treatment with simvastatin mg/day or mg/day for  days. Personal data and past history of all patients were recorded at
baseline. e blood chemistries were measured by standard laboratory techniques. Serum sLOX- and NO levels and neurological
outcomes including NIHSS, mRS, and Barthel index were tested at baseline and Day  aer simvastatin therapy. Results. Baseline
characteristics were not signicantly dierent in both groups except history of hypertension. Serum sLOX- and NO levels
signicantly reduce in both groups (sLOX- = 1.19 ± 0.47 and 0.98 ± 0.37ng/ml; NO = 49.28 ± 7.21 and 46.59 ± 9.36𝜇mol/l)
in  mg/day and  mg/day simvastatin groups, respectively. Neurological outcomes including NIHSS, mRS, and Barthel index
signicantly improve in both groups. However, no dierence in NO level and neurological outcomes was found at  days aer
treatment as compared between low dose  mg/day and high dose  mg/day of simvastatin. Conclusion. High-dose simvastatin
might be helpful to reduce serum sLOX-. But no dierence in clinical outcomes was foundb etweenhig h- and low-dose simvastatin.
Further more intensive clinical trial is needed to conrm the appropriate dosage of simvastatin in patients with acute ischemic
stroke. is trial is registered with ClinicalTrials.gov ID: NCT.
1. Introduction
Ischemic stroke is the main etiology of disability in senile
population and remains the third most common cause of
death in the world []. Stroke has been the common cause
of mortality in ailand for decades [–]. e prevalence
of stroke is one percent in ai people aged more than 
years [] or . percent in ai people aged more than 
years []. Oxidative stress is dened as a disturbance in the
prooxidant-antioxidant balance in favor of the prooxidant,
leading to potential damage []. Oxidative stress is elevated
during occurrence of acute ischemic stroke (AIS) [, ].
Previous study found that oxidized-low density lipopro-
tein (ox-LDL) and oxidative stress induce production of
lectin-like oxidized low density lipoprotein receptor- (LOX-
) and cleavage some extracellular parts of LOX- into blood
circulation, and it is called soluble LOX- (sLOX-) []. e
sLOX- is used for biomarker in patients with myocardial
Hindawi
Neurology Research International
Volume 2018, Article ID 7268924, 6 pages
https://doi.org/10.1155/2018/7268924

Neurology Research International
infarction (MI), coronary artery diseases (CAD), metabolic
syndrome, or others [, ].It is known that oxidized-LDL can
lead to plaque instability by increasing vascular oxidative
stress and by upregulation of matrix metalloproteinases
(MMPs).
During  hours aer onset of ischemic stroke, nitric
oxide (NO) is mainly produced by activation of both induci-
ble nitric oxide synthase (iNOS) and neuronal nitric oxide
synthase (nNOS). ese two subtypes of NO are considered
as neurotoxic agents and supposed to become lower at 
months aer onset. In contrast, NO created by endothelial
nitric oxide synthase (eNOS) demonstrates neuroprotective
eect []. However, eNOS produces small amount of NO at
the ultraearly stage of ischemic stroke. Simvastatin shows
gainful eect for ischemic stroke by upregulation of eNOS
activity [].
Simvastatin is a cholesterol-lowering medication which
acts by inhibiting hydroxymethylglutaryl-coenzyme A (HMG-
CoA)reductase,henceusedfortheprimaryandsecondary
prevention of ischemic stroke. Simvastatin can inhibit activa-
tion of extracellular regulated kinase (ERK) / and prolifer-
ation of rat vascular smooth muscle cells [], attenuation of
inammation, oxidative stress and plaque stabilization, and
plaque thickness in type  diabetes patients []. Simvastatin
can reduce oxidative stress through inhibiting nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase and
reducing angiotensin type  (AT) receptor. erefore, overall
eect of simvastatin beyond lowering cholesterol includes
improving endothelial function, modulating thrombogene-
sis, attenuating inammatory, and oxidative stress damage,
and facilitating angiogenesis [].
is study aims to investigate outcomes of simvastatin
 mg/day and  mg/day on vascular oxidative stress and
neurological outcomes in patients with acute ischemic stroke.
We expect that the results of our study might have clinical
implications for ischemic stroke prevention in future.
2. Material and Methods
2.1. Study Population. We recruited patients with acute
ischemic stroke received at ammasat University Hospital
between April  and December . Patients who met
the following inclusion criteria were eligible:  to  years
old; diagnosis of an acute ischemic stroke; and ability to
start the study drug within  hours aer symptom onset.
Patients were excluded if they had any of the following:
contraindication to simvastatin; prestroke mRS score more
than ; conscious level > scores on question  of NIHSS;
hematocrit less than .; blood sugar (BS) less than  mg/dl
or more than  ml/dl or between  and  mg/dl and
treated with diabetes drug until the BS levels are less than
 mg/dl; acute myocardial infarction (AMI) or coronary
heart disease (CHD) within  weeks; patient who receives
lower-lipid level drug, that is, ezetimibe, fenobrate, gem-
brozil, and niacin, or statin drugs, that is, atorvastatin and
pitavastatin, and increasing liver enzyme level or liver disease.
e study was registered in ClinicalTrials.gov. e clinical
study registration number is NCT.
2.2. Study Design. Patients with acute ischemic stroke were
divided into  groups (simvastatin  mg/day and  mg/day).
Personal and past medical history were recorded aer the
patients signed informed consent. Blood samples were col-
lected from patients for measuring biomarkers in serum
related to vascular oxidative stress, that is, sLOX- and NO,
and neurological examination was done, that is, NIHSS, mRS,
and Barthel’s index scale at Day  and Day .
2.3. Blood Chemical Analysis. Peripheral venous blood sam-
ples of all  patients with acute ischemic stroke were
obtained not later than  hours aer onset. e sample
was centrifuged , rpm at ∘Cforminutes.Serum
samples were frozen at −∘C until analysis. Serum blood
sugar, cholesterol, triglycerides, high density lipoprotein
cholesterol (HDL-c), and low density lipoprotein cholesterol
(LDL-c)weremeasuredbystandardlaboratorytechniquesof
ammasat University Hospital. Serum sLOX- and NO lev-
els were determined using commercially available enzyme-
linked immunosorbent assay (ELISA) kits (R&D systems,
MN, USA).
2.4. Ethical Consideration. e clinical study protocol was
submitted to Ethical Committee of Faculty of Medicine,
ammasat University (number ) for approval before con-
ducting experiments. e number of approved protocol is
MTU-EC--/.
2.5. Data Analysis. SPSS version . for Windows (Chicago,
IL, USA) was used for statistical analysis. All data were
presented as mean ±standard deviation (SD). e possible
statistical dierences among groups were tested using Mann–
Whitney 𝑈test or Chi square test. e possible statistical
dierence among persons at Day  and Day  was tested
using Wilcoxon test. A probability value of less than . was
considered to be statistically signicant.
3. Results
3.1. Baseline Clinical Characteristics.  patients were treated
with simvastatin  mg/day and  patients were treated with
simvastatin  mg/day during the study period. Baseline
characteristics were shown in Table . ere were no signif-
icant dierences in age, systolic or diastolic blood pressure,
blood sugar, lipid prole, NIHSS score, and treatment with
IV rtPA between the two groups but there was signicant
dierence in medical history of hypertension.
As Table  showed there is no signicant dierence in
serum sLOX- and NO level at baseline in patients with AIS
between  groups.
3.2. Association of Serum sLOX-1, NO Levels, and Neurological
Outcomes aer Simvastatin erapy. Aer  days of simvas-
tatin treatment, serum sLOX- level was signicantly reduced
in simvastatin  mg/day group (𝑃 = 0.04)buttherewas
no dierence in NO level as compared between simvastatin
 mg/day and simvastatin  mg/day group (Table  and
Figure ). When compared between Day  and Day  within

Neurology Research International 
T : Baseline characteristics of patients with acute ischemic stroke receiving simvastatin therapy.
Characteristic Simvastatin  mg (N=) Simvastatinmg(N=) 𝑃value
Mean ±SD Mean ±SD
Age (years) . ±. . ±. .
Female, n(%)  ()  () .
SBP (mmHg) . ±. . ±. .
DBP (mmHg)  ±. . ±. .
Blood Sugar (mg/dl) . ±. . ±. .
Cholesterol (mg/dl) . ±. . ±. .
Triglyceride (mg/dl) . ±. . ±. .
HDL-c (mg/dl) . ±. . ±. .
LDL-c (mg/dl) . ±. . ±. .
NIHSS . ±. . ±. .
rtPA therapy
IV rtPA, n(%)  (.)  (.) .
Medical history, n(%)
Ischemic stroke  ()  () .
Atrial brillation or utter  ()  () .
Valvular heart disease  ()  () .
Hypertension  ()  () .
Diabetes mellitus  ()  () .
Dyslipidemia  ()  () .
Others  ()  () .
Note. Systolic blood pressure (SBP), diastolic blood pressure (DBP), recombinant tissue plasminogen activator (rtPA), and intravenous route (IV).
T : Serum sLOX- and NO levels in patients with acute ischemic stroke at baseline.
Parameter Simvastatin  mg (N=)
Mean ±SD
Simvastatin  mg (N=)
Mean ±SD 𝑃value
sLOX- levels (ng/ml) . ±. . ±. .
NO levels (𝜇mol/l) . ±. .  ±. .
each group (Table ), both sLOX- and NO were signicantly
declined at Day  in both groups. NIHSS, mRS, and Barthel
index were improved at Day  in both groups (Table , all
𝑃 < 0.05). However, there was no dierence in NIHSS, mRS,
and Barthel index at Day  as compared between simvastatin
 mg/day and simvastatin  mg/day group (Table ).
4. Discussion
Acuteischemicstrokepatientsreceivingsimvastatinand
 mg/day for  days signicantly decreased serum sLOX-
 and NO levels and improved neurological outcome. Sim-
vastatin  mg/day group signicantly reduced sLOX- level
compared to simvastatin  mg/day at  days aer treatment.
According to the previous study of statin in patients with
ischemic stroke, age did not aect any outcomes []. Patients
aged between  and  years were included in our study.
e involvement of LOX- is a factor that aects devel-
opment of atherosclerosis from several factors; for example,
dyslipidemia played the major role in the upregulation
of LOX- through ox-LDL stimulation [], hyperglycemia
increased LOX- upregulation in human endothelial cells
via activation of reactive oxygen species (ROS) [], and
hypertension upregulated the expression of LOX- by induc-
tion of angiotensin II []. Previous studies have also found
that sLOX- are signicantly increased in obesity [] and
type  DM. e activation of LOX- aects atherosclerotic
plaque formation and progression through dysfunction of
endothelial cells [], apoptosis of vascular smooth muscle
cells [], accumulation of lipids in macrophages [], and
production of matrix metalloproteinases []. Schwarz et
al. reported that LOX- expression was induced -fold at
ischemic core sites during experimental stroke []. us,
activation of LOX- might facilitate the pathophysiological
conditions leading to stroke.
e major ndings of this study show that simvastatin
signicantly reduces serum sLOX- levels aer  days of
treatment. But only higher dose of simvastatin ( mg/day)
can decrease serum sLOX- at Day  of treatment. is
nding reects higher doses of simvastatin may be more
useful in improving plaque stability and reduce risk for
recurrent ischemic stroke than lower doses of simvastatin.
As mentioned above, serum NO demonstrates not only
prosbutalsoconseectsonpatientswithischemicstroke.
NO produced by iNOS and nNOS is among the cons while
NO produced by eNOS is among the pros. From temporal

Neurology Research International
T : Serum sLOX- and NO levels in patient with acute ischemic stroke received simvastatin therapy for  days.
Parameter Simvastatin  mg (N=)
Mean ±SD
Simvastatin  mg (N=)
Mean ±SD 𝑃value
sLOX- levels (ng/ml) . ±. . ±. .
NO levels (𝜇mol/l) . ±. . ±. .
T : Compare serum sLOX- and NO levels in patient with acute ischemic stroke at  days and  days aer simvastatin therapy.
Parameter
Simvastatin  mg (N=)
Mean ±SD 𝑃value
Simvastatin  mg (N=)
Mean ±SD 𝑃value
Day  Day  Day  Day 
sLOX-
levels (ng/ml) . ±. . ±. <. . ±. . ±. <.
NO levels (𝜇mol/l) . ±. .  ±. . . ±. . ±. .
T : Compare neurological outcome in patient with acute ischemic stroke  days and  days aer simvastatin therapy.
Parameter
Simvastatin  mg (N=)
Mean ±SD 𝑃value
Simvastatin  mg (N=)
Mean ±SD 𝑃value
Day  Day  Day  Day 
NIHSS . ±. . ±. <. . ±. . ±. <.
mRS . ±. . ±. <. . ±. . ±. .
Barthel Index . ±. . ±. <. . ±. . ±. .
Note. NIHSS, National Institutes of Health Stroke Scale; mRS, Modied Rankin Scale.
T : Compare neurological outcome in patient with acute ischemic stroke at  days aer simvastatin therapy.
Parameter Simvastatin  mg (N=)
Mean ±SD
Simvastatin  mg (N=)
Mean ±SD 𝑃value
NIHSS . ±. . ±. .
mRS . ±. . ±. .
Barthel Index . ±. . ±. .
Note. NIHSS, National Institutes of Health Stroke Scale; mRS, modied Rankin Scale.
Simvastatin 10 ＧＡ Simvastatin 40 ＧＡ
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
serum sLOX-1 levels (ng/ml)
(a)
Simvastatin 10 ＧＡ Simvastatin 40 ＧＡ
0
10
20
30
40
50
60
serum NO levels (mol/l)
(b)
F : Serum sLOX- (a) and NO (b) levels of patients with acute ischemic stroke that compare simvastatin  mg/day and  mg/day at
Day  aer simvastatin treatment. ∗𝑃< 0.05.

Neurology Research International 
ischemic stroke in our study, majority of NO is produced by
iNOSandnNOS[].DecrementofNOatdaysaeronset
should be a natural course of ischemic stroke. Simvastatin
may upregulate eNOS leading to rising NO. However, eNOS
usually produces a small amount of NO. Simvastatin may not
be able to aect NO level in our study.
e mechanisms by which statins provide benet to pa-
tients with acute ischemic stroke remain unclear and are
likely multifactorial. Previous study indicates that statin
has multiple eect beyond cholesterol lowering including
improving endothelial function, modulating thrombogene-
sis, attenuating inammatory and oxidative stress damage,
and facilitating angiogenesis []. In animal model of stroke,
statin shows benets to reduction in infarct size [] and
improves neurological function and cerebral blood ow [].
Recent study shows patients who take statin have . times
greater probability of discharge home compared to untreated
patients []. Our results are in agreement with previous
studies that have shown improvement in functional outcome
in stroke patients treated with statins.
ere are several limitations to this study. First, this study
was cross-sectional, thereby allowing the determination of
associations but not formulation of risk predictions. In addi-
tion, the study populations were relatively small. erefore,
our ndings need further investigation in prospective studies
with larger sample size. Last, sLOX- and NO levels might be
higher or lower in patients with ICAS than in general popula-
tion. erefore, a normal control group should be included in
future studies to evaluate the degree of impact of the presence
and severity of acute ischemic stroke. e low proportion of
patients with neurological progression could be secondary to
a selection bias because of the admission of patients with less
severe symptoms. Last, neurological improvement in stroke
patient could be from other factors than statin: age, NIHSS
scaleonadmission,HbAclevel,andlocationofstroke[].
5. Conclusion
Our study showed that high-dose simvastatin signicantly
reduced serum sLOX-. However, no dierence in clinical
outcome between high-dose and low-dose simvastatin was
found at  days aer treatment. Further more intensive
clinical trial is needed to conrm the appropriate dosage of
simvastatin in patients with acute ischemic stroke.
Abbreviations
SBP: Systolic blood pressure
DBP: Diastolic blood pressure
rtPA: Recombinant tissue
plasminogen activator
IV: Intravenous route
AIS: Acute ischemic stroke
LOX-: Lectin-like oxidized low density
lipoprotein receptor-
sLOX-: Soluble LOX-
MI: Myocardial infarction
CAD: Coronary artery diseases
MMPs: Matrix metalloproteinases
iNOS: Inducible nitric oxide synthase
NO: Nitric oxide
HMG-CoA: Hydroxymethylglutaryl-coenzyme A
ERK: Extracellular regulated kinase
NADPH: Nicotinamide adenine
dinucleotide phosphate
AT1: Angiotensin type 
BS: Blood sugar
CHD: Coronary heart disease
HDL-c: High density lipoprotein cholesterol
LDL-c: Low density lipoprotein cholesterol
ELISA: Enzyme-linked immunosorbent assay
NIHSS: National Institutes of Health
Stroke Scale
mRS: Modied Rankin Scale.
Disclosure
e manuscript was presented at World Congress of Neu-
rology (WCN ): https://www.sciencedirect.com/science/
article/pii/SX.
Conflicts of Interest
e authors declare that there are no conicts of interest re-
garding the publication of this paper.
Acknowledgments
is work was supported by the Center of Excellence in
Stroke, ammasat University Hospital, ammasat Univer-
sity. Finally, the authors thank all patients in the study and
stas of stroke unit in ammasat University Hospital.
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