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ORIGINAL RESEARCH
published: 08 December 2021
doi: 10.3389/fneur.2021.693397
Frontiers in Neurology | www.frontiersin.org 1December 2021 | Volume 12 | Article 693397
Edited by:
Anna Bersano,
Fondazione IRCCS Istituto Neurologio
Carlo Besta, Italy
Reviewed by:
Yuishin Izumi,
Tokushima University, Japan
Xiaodong Liu,
Beijing University of Chinese
Medicine, China
*Correspondence:
Honghua Gao
ghh_0710@sina.com
Specialty section:
This article was submitted to
Stroke,
a section of the journal
Frontiers in Neurology
Received: 19 April 2021
Accepted: 08 November 2021
Published: 08 December 2021
Citation:
Wu Y, Li F, Wang Y, Hu T and Gao H
(2021) Standard-Dose Atorvastatin
Treatment in Patients With
Symptomatic Middle Cerebral Artery
Atherosclerotic Stenosis: A Vessel
Wall Magnetic Resonance Imaging
Study. Front. Neurol. 12:693397.
doi: 10.3389/fneur.2021.693397
Standard-Dose Atorvastatin
Treatment in Patients With
Symptomatic Middle Cerebral Artery
Atherosclerotic Stenosis: A Vessel
Wall Magnetic Resonance Imaging
Study
Yejun Wu 1, Fangbing Li1, Yilin Wang 1, Tianxiang Hu 1and Honghua Gao 2
*
1Department of Radiology, Fourth Affiliated Hospital of China Medical University, Shenyang, China, 2Department of
Neurology, Fourth Affiliated Hospital of China Medical University, Shenyang, China
Background and Purpose: Ischemic stroke can be caused by atherosclerotic lesions
of the middle cerebral artery (MCA). Some studies have described the effects of statin
treatment on carotid artery plaques, but little is known about the effects of statin treatment
on MCA plaques. The purpose of this study was to validate the efficacy of standard-dose
atorvastatin (20 mg/day) in patients with symptomatic MCA atherosclerotic stenosis
(SMAS) in northern China.
Materials and Methods: This study is a prospective, single-arm, single-center,
12-month follow-up observational study monitoring imaging, and clinical outcomes of
standard-dose atorvastatin treatment among patients with SMAS. The primary outcomes
were changes in vessel wall magnetic resonance imaging (VWMRI) and serum lipid
profiles before and after (1, 3, 6, and 12 months) statin treatment.
Results: A total of 46 patients were recruited for this study, and 24 patients
completed the follow-up. During the follow-up period, serum non-high-density
lipoprotein cholesterol concentrations gradually decreased in the patients. Fourteen
patients (54.33%) had a reversal of MCA plaques and 10 patients (41.67%) had
no significant progression of MCA plaques and remained stable at the follow-up
endpoint. At the 12 months follow-up time-point, the treatment did not reverse vascular
remodeling or change the shape and distribution of plaques. Altered serum low-density
lipoprotein cholesterol (LDL-C) concentrations in patients were strongly associated with
plaque reversal.
Conclusion: Vessel wall magnetic resonance imaging could accurately characterize
changes in MCA plaques after lipid-lowering therapy. Standard-dose atorvastatin
treatment could stabilize and reverse plaques in northern Chinese patients with SMAS.
Keywords: vessel wall magnetic resonance imaging, middle cerebral artery, atorvastatin, stand-dose,
atherosclerotic stenosis
Wu et al. VWMRI Evaluate SMAS With Atorvastatin
INTRODUCTION
Intracranial atherosclerotic disease (ICAD) is one of the major
causes of ischemic stroke worldwide, and it is more common
in the Chinese population (1). The middle cerebral artery
(MCA) is an important branch of the intracranial carotid artery
and is most susceptible to atherosclerotic lesions. Intracranial
atherosclerotic disease can cause cerebral tissue ischemia, and
thus, a variety of neurological symptoms through the following
mechanisms: occlusion of blood vessels by thrombi, occlusion
of small penetrating arteries, artery-to-artery embolism due to
plaque rupture, and inadequate perfusion of brain tissue due to
intracranial arterial stenosis (2). Therefore, treatment strategies
for ICAD include the following: first, anti-thrombotic drugs (3).
Second, percutaneous transluminal angioplasty and stenting (4).
Third, the adoption of healthy lifestyle choices and aggressive
control of ICAD risk factors, such as low-density lipoprotein
cholesterol (LDL-C) control below 70 mg/dl and systolic blood
pressure control below 140 mm/Hg (5).
Previous studies have shown that statins can cause plaque
stabilization or reversal in carotid arteries by lowering the serum
LDL-C and triglyceride concentrations (6,7) and reducing plaque
lipid content (8,9). Moreover, statins have been shown to slow
down the progression of atherosclerosis and reduce the incidence
of cerebrovascular events in patients with stroke through
their effective lipid-lowering function (10). Several studies have
confirmed that high-dose statins stabilize plaques in patients
with ICAD (11,12). However, as the statin dose increases, the
risk of adverse effects in patients increases (13,14). To our
current knowledge, there are no detailed reports on whether
the stabilization and reversal of atherosclerotic plaques in the
brain occur after patients with symptomatic MCA atherosclerotic
stenosis (SMAS) are treated with standard doses of statins
(atorvastatin, 20 mg/day), and how early these changes occur.
Vessel wall magnetic resonance imaging (VWMRI) is currently
recognized as the best non-invasive method for evaluating the
vascular characteristics of intracranial atherosclerotic lesions.
This technique allows for the assessment of the intracranial
vascular lumen and the vessel wall (15). Therefore, we designed
and conducted this prospective, single-arm, 12-month follow-
up observational study using VWMRI to assess the correlation
between changes in lipid levels and changes in MCA plaques
in patients treated with standard doses of atorvastatin for
SMAS. We hypothesized that VWMRI would allow the precise
assessment of plaque changes during atorvastatin treatment in
patients with SMAS and provide rich information for evaluating
atorvastatin drug efficacy.
MATERIALS AND METHODS
Study Design
This study is a 12-month single-center, single-arm, prospective,
observational study focused on monitoring changes in imaging
and clinical outcomes in patients with SMAS who were
taking standard doses of atorvastatin (Lipitor, Pfizer, Inc.,
USA; 20 mg/day). The study protocol and informed consent
were reviewed and approved by the Ethics Committee of
our hospital, and the study was registered with the China
Clinical Trials Registry. All patients signed an informed
consent form.
Patients were recruited from the inpatients of the Department
of Neurology of our hospital from March 21 to December 31,
2019. Due to the lack of prior relevant literature, it was impossible
to determine the sample size required to observe the changes in
the responsible vascular imaging features of patients with SMAS
over 12 months of treatment with standard-dose atorvastatin.
Considering the study period and available study funding, we
planned to enroll 50 patients.
Inclusion criteria: (1) age 20–80 years (2) atorvastatin
treatment began upon enrollment in the study and the patients
had not previously taken atorvastatin (3) presence of one or more
atherosclerotic risk factors (4) confirmed diagnosis of SMAS
[diagnosis made by a neurologist according to the diagnostic
criteria for intracranial artery stenosis (16)] (5) recent (14 days)
ischemic stroke or transient ischemic symptoms (6) not treated
with angioplasty for intracranial artery stenosis.
Exclusion criteria: (1) contraindication to MRI (2) severe
hepatic or renal dysfunction or malignancy (3) extracranial artery
stenosis >50% (4) atrial fibrillation, severe cardiac insufficiency,
cardiogenic stroke risk factors (5) incomplete clinical data (6)
MCA stenosis due to non-atherosclerotic lesions.
All patients who met the inclusion criteria received 12 months
of standard-dose atorvastatin treatment. Clinical information
was recorded for all patients. All patients received VWMRI and
blood biochemistry analysis to determine baseline levels before
treatment, and VWMRI and blood analyses were repeated at
months 1, 3, 6, and 12 after treatment. In addition, all patients
received anti-platelet therapy, with blood pressure control in
patients with hypertension (target blood pressure below 140/90
mm/Hg; hypertension with diabetes, target blood pressure
below 130/80 mm/Hg), and active glycemic control in patients
with diabetes (fasting blood glucose control below 7 mmol/L
and postprandial blood glucose control below 11 mmol/L).
Clinical and home blood pressure and glucose monitoring were
performed to clarify blood pressure and glucose control during
the study period.
Follow-Up and Evaluation of Clinical
Outcomes
The main clinical indicators tested included (1) the vascular
characteristics and changes in the MCA by VWMRI before and
after atorvastatin treatment. The blood biochemical examination
included changes in serum triglycerides, total cholesterol,
LDL-C, and high-density lipoprotein cholesterol (HDL-C).
Phosphocreatine kinase and liver transaminases were evaluated
to determine if they were in the normal or abnormal range
and (2) whether clinical cerebrovascular events (including
cerebrovascular death, recurrent transient ischemic attack,
ischemic stroke) occurred during the study period. (3) Vital
signs and neurological-specific physical examination, dietary
status questioning, and medication compliance assessments
were conducted.
Frontiers in Neurology | www.frontiersin.org 2December 2021 | Volume 12 | Article 693397
Wu et al. VWMRI Evaluate SMAS With Atorvastatin
VWMRI Protocol
Vessel wall magnetic resonance imaging was performed on a
3.0T MRI (GE Discovery MR750; Milwaukee, WI, USA) with an
eight-channel head coil, and the scan parameters are shown in
Table 1. To localize the artery of interest, a three-dimensional
time-of-flight MRA (3D TOF MRA) of the circle of Willis was
performed. The 3D TOF-MRA images from each patient were
used as the positioning images to scan the 3D T1-weighted
imaging (T1WI)/2D T2-weighted imaging (T2WI). The MRI
scanning equipment, patient’s scanning position, range, and scan
parameters were consistent at each follow-up time point.
Definition of Different Features of VWMRI
The Warfarin Aspirin Symptomatic Intracranial Disease criteria
are widely used to measure MCA stenosis (stenosis rate, %) =[1
– (diameter of stenosis/diameter of normal) ×100%)] (17). The
vessel area and lumen area are measured at the narrowest part
of the MCA. Plaque burden is defined as (vessel area – lumen
area)/vessel area ×100%.
The ratio between the vascular area at the plaque and the
vascular area proximal to the plaque is defined as the remodeling
rate (RR). An RR >1.05 is positive remodeling, an RR <0.95
is negative remodeling, and an RR between 0.95 and 1.05 is
defined as no remodeling (18,19). Plaque surface irregularities
can be considered when the plaque surface is discontinuous
or poorly displayed. Plaque distribution was divided on the
cross-sectional images of the MCA (20) and averaged into four
distributions: ventral, dorsal, superior, and inferior quadrants.
The quadrant with the most significant proportion of plaque
was taken to determine the plaque distribution. The eccentricity
index (maximum vessel wall thickness – minimum vessel wall
thickness)/maximum vessel wall thickness) was used to evaluate
the shape of the plaque, with an eccentricity index ≥0.5 for
eccentric vessel wall thickening and otherwise for centripetal
(annular) vessel wall thickening (21).
Image Analysis
First, a radiologist assessed the image quality of the VWMRI.
The image quality was then divided into four levels based
on the clarity of the vessel wall structure in the analyzed
imaging sequence: level 1, non-diagnostic; level 2, not suitable
for diagnostic purposes; level 3, adequate for diagnostic purposes;
level 4, high quality for diagnostic purposes (22). Images with
quality below level 3 were excluded and were not used for
statistical analyses. Secondly, two other radiologists separately
and independently measured and evaluated the VWMRI images
using a blinded method according to the above criteria. The
patients’ information and follow-up times were not visible to
the radiologists during the measurement and evaluation. One
of the radiologists re-evaluated the VWMRI images 4 weeks
later to assess the inter-observer agreement. All measurements
were performed on a GE workstation. The measurements of two
radiologists were averaged and used for the final analyses.
Since continuous or diffuse lesions are widespread in MCA
stenosis, measurements of diffuse lesions in the MCA were made
for the most severe lesions. The lumen is manually outlined on
T1WI, the outer wall of the vessel is manually drafted on T2WI,
and the GE workstation automatically calculates the lumen and
vessel areas.
Laboratory Tests
The patients were examined between 8:00 to 10:00 a.m. Serum
was obtained by centrifugation (6 min at 4,000 rpm), and an
automatic biochemical analyzer (ADVIA2400, Siemens, Berlin,
Germany) was used to obtain the biochemical measurements.
An immune transmission turbidimetric method was used to
measure the serum triglycerides (normal: 0.38–2.83 mmol/l),
total cholesterol (normal: 3.50–5.18 mmol/l), LDL-C (normal:
2.60–3.40 mmol /L), HDL-C (normal 0.95–1.95 mmol /L)
concentration; phosphoric creatine kinase (normal: 32–294
units/l), and liver transaminase activity (glutamic–pyruvic
transaminase normal: 7–40 units/l; glutamic-oxaloacetic
transaminase normal: 19–35 units/l).
Statistics
All statistical analyses were performed using a statistical software
(MedCalc v19.0.7; MedCalc Software Ltd., Ostend, Belgium).
The Shapiro-Wilk test was used to verify whether continuous
variables conformed to a normal distribution. Data with a
normal distribution were expressed as mean ±SD. Data with
a non-normal distribution were expressed as the median and
interquartile range (median spacing: 25–75%). For discrete
variables, data are expressed as counts and percentages. Intra-
and inter-observer agreement were evaluated using the intraclass
correlation coefficient (ICC), with good agreement for ICC >
0.80; 0.40 ≤ICC ≤0.80, fair agreement; and poor agreement for
ICC <0.4. Serum values and magnetic resonance measurements
at each follow-up time point were compared with baseline
time points using a signed rank-sum test or paired t-test.
Multiple linear regression analysis was further used to explore
independent clinical and imaging factors influencing changes
in plaque loading and stenosis, and variables with P<0.20 in
univariate analysis were considered explanatory variables and
evaluated in subsequent multivariate analysis. P<0.05 was
considered to be statistically significant for all statistical analyses.
RESULTS
Patient Clinical Information
A total of 46 patients were recruited during the study period,
and 24 completed the 12-month follow-up (14 missed visits,
1 discontinued intervention due to adverse drug reactions, 1
underwent MCA angioplasty during the follow-up period, 1 had
a sudden onset of other illnesses, and 5 were affected by the
COVID-19 epidemic). The clinical information for all patients
who completed follow-up at baseline time points is shown in
Tables 2,3. The lifestyle changes in patients who completed
follow-up included: low-fat diet (23), low-salt diet (15), diabetic
diet (9), smoking cessation (7), and alcohol cessation (5). Seven
people with a history of hypertension had blood pressure control
below 130/80 mm/Hg, four people had blood pressure control
below 140/90 mm/Hg, three people had average blood pressure
control, with blood pressure fluctuations ranging from 130 to
150/80 to 100 mm/Hg, and one person had poor blood pressure
Frontiers in Neurology | www.frontiersin.org 3December 2021 | Volume 12 | Article 693397
Wu et al. VWMRI Evaluate SMAS With Atorvastatin
TABLE 1 | Vessel wall imaging protocol.
Sequences TR (ms) TE (ms) Flip angle Slice thickness (mm) FOV (mm) NEX Locs per slab Matrix Acquisition time
3D TOF-MRA 23 2.5 20 1.4 220 3 32 320 ×256 4 min 1 s
3D CUBE T1WI 1,140 14 / 1 180 1 160 320 ×228 7 min 5 s
3D CUBE PDWI 2,500 35 / 1 180 1 160 320 ×228 9 min 46 s
2D FSE T2WI 4,000 42 125 2 130 4 16 256 ×224 6 min 8 s
3D, three dimensional; 2D, two dimensional; PDWI, proton density-weighted imaging; TR, repetition time; TE, echo time; FOV, field of view; NEX, number of excitations; Locs per slab,
total number of locations (slices) generated from a slab; min, minute; s, second; CUBE, variable-flip-angle turbo-spin-echo.
TABLE 2 | Patients’ baseline clinical information.
N=24
Age (year) 55.26 ±10.31
Sex
Male 11 (45.83%)
Female 13 (54.17%)
Body mass index (kg/m2) 24.86 ±0.48
Smoking (ever) 7 (29.17%)
Diabetes 9 (37.50%)
Hypertension 15 (62.50%)
Dyslipidemia 13 (54.16%)
Alcoholism (ever) 5 (20.83%)
NIHSS 1* (0–3)
Clinical events
Transient ischemic attack 3 (12.50%)
Ischemic stroke 21 (87.50%)
Serum lipoprotein concentration (mmol/L)
Total cholesterol 3.79 ±1.02
Triglycerides 1.77 ±0.97
Low-density lipoprotein cholesterol 2.17 ±1.00
High-density lipoprotein cholesterol 0.95 ±0.33
Phosphocreatine kinase and hepatic transaminase activity
Normal 24 (100.00%)
Abnormal 0 (0.00%)
Anti-platelet drug
Aspirin (100 mg/day) 19
Clopidogrel (75 mg/day) 5
NIHSS, National Institutes of Health Stroke Scale; *21 patients with ischemic stroke.
control. All nine people with a history of diabetes mellitus
attained glycemic control. The follow-up endpoint National
Institute of Health Stroke Scale (NIHSS) score was 0 (0–1), and
there were no new abnormal neurological symptoms, ischemic
stroke, or recurrence of transient ischemic attack during the
follow-up period. All patients who completed the follow-up had
good compliance with drug therapy. No adverse drug reactions
occurred during the follow-up period, except for one person with
abnormal phosphocreatine kinase metabolism.
Changes in VWMRI in Patients
A total of 120 images were obtained from patients at all follow-
up time points, and the image quality met the criterium of
level 3 or higher (level 3: 27, level 4: 93). Data were collected
for: stenosis rate [intra- and inter-observer: 0.94 (0.90–0.95),
0.93 (0.87–0.96)], plaque burden [intra- and inter-observer: 0.96
(0.91–0.98), 0.95 (0.93–0.97)], RR [intra- and inter-observer: 0.97
(0.87–0.99),0.95 (0.86–0.97)], and eccentricity index [intra- and
inter-observer: 0.97 (0.89–0.99),0.98 (0.90–0.99)]. All data had
good intra- and inter-observer agreement.
There were 12 cases of severe MCA stenosis (stenosis
rate: 75.35 ±6.35%), 11 cases of moderate stenosis (stenosis
rate: 61.25 ±5.07%), and 1 case of mild stenosis (stenosis
rate: 31.23%) in patients atbaseline at the commencement
of the study. Vessel remodeling observed: there were 7
cases of negative remodeling (RR: 0.91 ±0.02), 6 cases of
positive remodeling (RR: 1.11 ±0.04), and 11 cases of no
remodeling (RR:1.01 ±0.01). Plaque shape and distribution
observed: there were 22 cases of eccentric thickening (10
cases of plaque distribution in the ventral wall, 6 cases in
the inferior wall, 2 cases in the superior wall, and 4 cases
in the dorsal wall), and 2 cases of centripetal thickening
(circumferential wall: 2 cases). The mean plaque burden was
81.30 ±16.38%. Eleven patients (11/24, 45.83%) had rough
plaque surfaces.
After lipid-lowering treatment, no significant changes in
VWMRI were observed at the 1- and 3-month follow-up time
points compared with baseline levels; at the 6-month follow-up
time point, a total of five patients (20.83%) had a reversal of MCA
plaque; at the 12-month follow-up point, a total of nine patients
(37.50%) had a reversal of MCA plaque (Figure 1), with a mean
time to plaque reversal of 9.85 months. A total of 10 patients
(41.67%) had stable MCA plaques with no significant changes
during the follow-up period.
At the follow-up endpoint, MCA stenosis (71.91 ±15.91
vs. 66.66 ±14.08%, P=0.00) and plaque burden (80.01
±11.98 vs. 73.39 ±13.46%, P=0.00) were reduced in
the 14 patients with plaque reversal. Although plaque reversal
brought about a reduction in vessel area, it did not reverse
positive vessel remodeling, and the change in RR was not
significant (1.11 ±0.04 vs. 1.08 ±0.15, P=0.29). Plaque
reversal was mainly reflected in a reduction of plaque volume,
which was dominated by a reduction in the internal lipid
core of the plaque and an increase in fibrous cap thickness
(Figure 2). Atorvastatin treatment for 12 months reversed
plaques but did not change the shape and distribution of plaques.
The plaque surfaces became smooth in seven patients (7/11,
63.63%) after 12 months of continuous atorvastatin treatment
(Figure 3).
Frontiers in Neurology | www.frontiersin.org 4December 2021 | Volume 12 | Article 693397
Wu et al. VWMRI Evaluate SMAS With Atorvastatin
TABLE 3 | Patients’ serum lipid concentrations during the follow-up.
Serum lipids (mmol/L) Baseline 1 month 3 month 6 month 12 month
(N=24) (N=24) (N=24) (N=24) (N=24)
Total cholesterol 3.79 ±1.20 3.60 ±0.97 3.50 ±1.07 3.37 ±0.97 3.09 ±0.78
Triglycerides 1.77 ±0.97 1.66 ±0.89 1.43 ±0.62 1.35 ±0.58 1.23 ±0.50
Low-density lipoprotein cholesterol 2.17 ±1.00 2.04 ±0.73 1.93 ±0.78 1.89 ±0.72 1.68 ±0.59
High-density lipoprotein cholesterol 0.95 ±0.33 1.00 ±0.22 1.06 ±0.42 1.09 ±0.43 0.96 ±0.31
FIGURE 1 | Vessel wall magnetic resonance imaging (VWMRI) of plaque
changes in the right middle cerebral artery (MCA) of a patient during the
follow-up period. VWMRI and MRA show no significant changes in plaque
volume and luminal stenosis at baseline, 1, 3, and 6 months. The plaque
volume and luminal stenosis degree were reduced at the 12-month follow-up
time point. Baseline, 1-, 3-, 6-, and 12-month 3D CUBE T2 images (A1–E1),
3D CUBE T1 sequence images (A2–E2), and 3D TOF MRA images (A3–E3).
The clinical information of patients who experienced plaque
reversal and plaque stabilization is shown in Table 4. There
were no statistically significant differences in clinical outcomes
between the two except for a statistically significant difference
FIGURE 2 | Typical VWMRI of MCA plaque changes after 12 months of
atorvastatin treatment in a patient. (A) At baseline, the MCA plaques have a
large lipid core with a thin fibrous cap and poorly displayed fibrous cap edges.
(B) MCA plaque volume reduction at the 12-month follow-up time point. The
image depicts plaque lipid core volume reduction, accompanied by fiber cap
thickening, with the fiber cap edge showing more clearly.
FIGURE 3 | VWMRI of plaque surface changes in the MCA of a patient after
receiving 12 months of atorvastatin treatment. (A) 2D FSE T2WI at baseline
level showing the rough surface of the MCA plaque. (B) 2D FSE T2WI at the
12-month follow-up time point shows a smooth and well-defined MCA
plaque surface.
in the change in serum LDL-C concentration during the follow-
up period.
Correlation Analysis of Changes in VWMRI
in Patients
Based on these results, we performed multiple linear regression
analyses to identify independent influences on changes in
plaque burden in patients treated with atorvastatin. Among the
clinical and imaging variables of interest, changes in LDL-C
concentration (coefficient = −0.35, SE =0.11, P=0.01) were
strongly associated with changes in plaque load (Table 5).
Frontiers in Neurology | www.frontiersin.org 5December 2021 | Volume 12 | Article 693397
Wu et al. VWMRI Evaluate SMAS With Atorvastatin
TABLE 4 | Clinical information of patients with different plaque properties at the follow-up endpoint.
Patients with plaque
reversal (N=14)
Patients with plaque
stabilization (N=10)
P
Age (year) 57.14 ±10.23 55.00 ±10.83 0.81
Sex 0.28
Male 8(57.14%) 3 (30.00%)
Female 6(42.85%) 7 (70.00%)
Body mass index (kg/m2) 24.89 ±0.89 24.86 ±0.48 0.69
Smoking (ever) 5 (21.42%) 2 (20.00%) 0.54
Diabetes 6 (42.85%) 3 (30.00%) 0.62
Hypertension 9 (64.28%) 6 (60.00%) 0.88
Dyslipidemia 8 (57.14%) 5 (50.00%) 0.79
Alcoholism (ever) 3 (21.42) 2 (20.00%) 0.97
Final NIHSS 0* (0–2) 0# (0–1) 0.37
Changes in final serum lipid concentrations (mmol/L)
Total cholesterol −0.71 ±0.91 −0.70 ±1.02 0.97
Triglycerides −0.41 ±0.80 −0.59 ±0.91 0.61
LDL-C −0.67 ±1.02 −0.36 ±0.28 0.03
HDL-C 0.02 ±0.18 0.00 ±0.41 0.82
Achieved LDL-C target (2017 AACE) 8 (57.14%) 6 (70.00%) 0.93
Achieved LDL-C target (2018 AHA) 9 (64.28%) 3(30.00%) 0.17
NIHSS, National Institutes of Health stroke scale; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; 2017 AACE, American Association of Clinical
Endocrinologists, LDL-C target<70 mg/dl, for very high-risk patients (24); 2018 AHA, American Heart Association; HDL, LDL-C target>50% reduction, for secondary atherosclerotic
cardiovascular disease prevention (23).
*13 patients with ischemic stroke.
#8 patients with ischemic stroke.
TABLE 5 | Univariate and multiple linear regression analysis of plaque burden changes in vessel wall magnetic resonance imaging (VWMRI).
Univariate analysis Multivariable analysis
Coefficient SE P Coefficient SE P
Age (year) −0.10 0.26 0.69
Sex 4.61 5.38 0.40
Malel −2.10 5.67 0.71
Female −5.61 5.87 0.65
Body mass index (kg/m2)−8.87 5.30 0.11 −0.04 0.19 0.82
Smoking (ever) −3.07 5.59 0.58
Diabetes −5.19 5.35 0.34
Hypertension −1.84 6.69 0.78
Changes in final serum lipid concentrations (mmol/L)
Total cholesterol −1.59 2.95 0.59
Triglycerides 2.28 3.42 0.51
Low-density lipoprotein cholesterol 8.76 2.74 0.00 −0.35 0.11 0.01
High-density lipoprotein cholesterol −1.81 9.63 0.85
Initial stenosis rate −0.41 0.15 0.01 0.01 0.01 0.09
VWMRI, vessel wall magnetic resonance imaging.
DISCUSSION
This study used VWMRI evaluation of plaques in patients
in northern China with SMAS. It was a single-center, single-
arm, prospective observational study that monitored imaging
outcomes and clinical parameters in patients treated with
standard doses of atorvastatin over a 12-month follow-up period.
Based on the data from this study, we found that standard-dose
atorvastatin consistently reduced non-HDL-C and stabilized and
reversed MCA atherosclerotic plaques.
Frontiers in Neurology | www.frontiersin.org 6December 2021 | Volume 12 | Article 693397
Wu et al. VWMRI Evaluate SMAS With Atorvastatin
We determined that VWMRI is a valid and non-invasive
method for the reliable evaluation of ICAD, which may provide
additional information for clinical treatment planning.
It has been shown that disorders of lipid metabolism are major
risk factors for various forms of atherosclerosis (25). Carvalho
concluded that elevated serum non-HDL concentrations and
reduced HDL concentrations are highly associated with the onset
and progression of atherosclerosis (26). Therefore, statins have
been recommended for the primary and secondary prevention
of this disease as an effective form of atherosclerosis risk
factor management (27). In the present study, we found that
standard doses of atorvastatin consistently reduced overall
serum non-HDL-C in patients. Our findings suggest that
changes in LDL-C concentrations are highly correlated with
plaque reversal and are an independent influence, with plaque
reversal at months 6 and 12 of lipid-lowering therapy and
mean LDL-C concentrations of 1.89 and 1.68 mmol/L during
the same period. These concentrations are similar to the
LDL-C attainment concentrations recommended by the 2017
American Association of Clinical Endocrinologists guidelines
(24). Moreover, the decrease in LDL-C concentrations was
higher in patients who experienced plaque reversal than
in those who experienced plaque stabilization. Based on
the above findings, we support the clinical use of LDL-C
concentration and its alteration as key reference indicators for
evaluating the effect of atorvastatin therapy and its therapeutic
dose adjustment.
Our study showed that at a mean of 9.85 months of
standard-dose atorvastatin treatment, 41.67% of patients had
stable plaques, and 58.33% had plaque reversal, similar to
the results of studies using vessel wall imaging and digital
subtraction angiography as evaluation tools (11,28). The causes
of the different outcomes of plaque stabilization and reversal are
complex. We analyzed common clinical features that were not
statistically significantly different except for LDL-C alterations.
The reasons for the different clinical outcomes may include
subject-specific differences, differences in genetic diversity, and
differences in associated lipid metabolism levels. The degree
of lumen stenosis and plaque burden is one of the important
indicators for evaluating ICAD. The greater the degree of stenosis
and plaque burden, the greater the risk of ischemic stroke
(29). Our study showed a mean decrease in plaque burden
and lumen stenosis of 14.38 and 11.32% with 12 months of
lipid-lowering treatment with atorvastatin, a change that may
reduce the risk of inadequate perfusion of brain tissue distal
to the responsible vessel due to lumen stenosis in patients
with ICAD. According to the current evidence (30), intracranial
atheromatous plaque intensification, positive remodeling, and
unsmooth plaque surfaces are associated with an increased risk of
ischemic stroke events, which can lead to plaque instability and
increased risk of artery-to-artery embolism. Although our study
confirmed that lipid-lowering therapy could reverse plaque,
it could not reverse positive vascular remodeling, and there
was no significant change in plaque distribution and shape.
This is likely because the degree of plaque volume reduction
is not sufficient to change the overall morphology of the
vessel, and plaque reduction is not continuous and remains
stable after a certain degree of volume reduction. In addition,
positive remodeling is a compensatory mechanism made by
the vessel itself, and the specific influencing factors are not
yet fully clarified. In both patients with plaque reversal and
those with plaque stabilization, we observed a change in plaque
surface from unstable to stable and an increase in fibrous
cap thickness, which would stabilize the plaque and reduce
the risk of plaque rupture. This implies that even without
plaque reversal, patients could benefit from long-term lipid-
lowering therapy, and reduce their risk of ischemic stroke due
to plaque rupture.
Several previous clinical studies using large samples have
shown that the clinical benefit of intensive lipid-lowering
therapy with 80 mg ator vastatin daily is significantly greater
than low or moderate doses in reducing cardiovascular risk
(31). However, Asians may respond more to statins than
Caucasians due to genetic differences in the rate of drug
metabolism (32,33). In a recently published clinical trial,
Chung et al. used 10–20 and 40–80 mg/day atorvastatin for
symptomatic intracranial atherosclerotic plaques, and there were
no significant differences between the two different doses in
terms of stenosis, RR, and wall index (34). Therefore, we
chose the atorvastatin dose of 20 mg/day for our study,
and this dose is also the more commonly used treatment
dose for Chinese patients with ICAD. In the evaluation of
adverse effects, only one subject discontinued treatment due to
failure to recover from phosphocreatine kinase elevation after
discontinuation of the drug. We did not observe any other
serious adverse reactions, suggesting that atorvastatin at 20
mg/day has a good safety profile and is well-tolerated for long-
term use.
There are some limitations to this study: first, this is a
single-center study; the patients included in this study were
limited to residents of Liaoning province in northern China. It
is known that genetic polymorphisms affect patients’ responses
to statins (35). Therefore, the generalizability of the results of
this study may be limited, and the results need to be further
validated in studies that include larger samples from multi-
ethnic populations. Second, although this was a prospective
study, the duration of follow-up in this study was only 1 year
due to study funding and periodicity. Since plaque changes
correlated with the duration of statin treatment, we plan to
conduct a longer follow-up study of statins for SMAS to
provide more study data. Third, this was a single-arm study
of patients receiving standard doses of atorvastatin, and it
was not possible to determine the natural course of change
in SMAS plaques and the number of patients who completed
the experimental design in this study was small. To verify
the long-term efficacy of atorvastatin for ICAD, a multicenter,
randomized, double-blind clinical trial with larger sample size
and longer follow-up time is the goal of our future work. Fourth,
treatment with anti-platelet, anti-hypertensive, and glucose drugs
in addition to atorvastatin may interfere with the progression
of atherosclerotic plaques in SMAS, and because of the small
number of patients in this study, this issue needs to be
further addressed in studies that include larger numbers of
patients. Fifth, only the T1/T2 sequence was selected for the
Frontiers in Neurology | www.frontiersin.org 7December 2021 | Volume 12 | Article 693397
Wu et al. VWMRI Evaluate SMAS With Atorvastatin
study. The T1-enhanced sequence may provide a more accurate
display of the vascular lumen and plaques (36). However,
injection of contrast medium is invasive, and there is a risk of
gadolinium deposition in the brain (37), and the vast majority
of patients were not willing to undergo enhanced MRI scans.
Finally, although all patients in this study received anti-platelet
therapy, we did not perform platelet agglutination tests to
assess the effect of anti-platelet drug therapy. All patients were
monitored for plasma prothrombin time, plasma fibrinogen,
activated partial thromboplastin time, and plasma prothrombin
time and did not show any abnormalities during the follow-
up period.
In conclusion, VWMRI can accurately characterize changes
in MCA plaques after lipid-lowering therapy and provide a
reliable basis for the clinical diagnosis and treatment of ICAD.
In patients with SMAS in northern China, long-term regular
treatment with standard doses (20 mg/day) of atorvastatin was
effective in stabilizing and reversing plaque, while changes in
LDL-C were an independent factor affecting plaque stabilization
and retraction.
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Ethics Committee of the Fourth Hospital of China
Medical University (EC-2019-KS-016). The patients/participants
provided their written informed consent to participate in
this study.
AUTHOR CONTRIBUTIONS
YWu: guarantor of integrity of the entire study, study concepts
and design, literature research, clinical studies, experimental
studies, data analysis, statistical analysis, manuscript preparation,
and manuscript editing. FL: clinical studies, experimental studies,
data analysis, and statistical analysis. YWa: clinical studies,
experimental studies, and data analysis. TH: experimental
studies and data analysis. HG: manuscript preparation and
manuscript editing. All authors contributed to the article and
approved the submitted version.
FUNDING
The project was funded by Natural Science Foundation of
Liaoning Province (2019-ZD-0762).
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
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