The Effects of Previous Statin Treatment on Plasma MatrixMetalloproteinase-9 Level in Chinese Stroke Patients

Undergoing ThrombolysisHong-Dong Zhao, MD, and Ying-Dong Zhang, MDFrom the Department

ing Medical University, N

Received June 18, 2014

This study was funded

Address corresponden

Neurology, Affiliated Na

versity, 68 Changle Roa

China. E-mail: yingdong

1052-3057/$ - see front

2014 by National Strhttp://dx.doi.org/10.1

Journal of Stroke and CIt is unclear whether previous statin therapy influences the prognosis, hemorrhagic

transformation, and plasma matrix metalloproteinases (MMP)-9 levels in Chinese

stroke patients receiving intravenous thrombolysis. We conduct a prospective

cohort study of 193 patients treated with intravenous thrombolysis. All the enrolled

patients were divided into 2 groups (the control group and the statin group), accord-

ing to the previous history of statin use. The plasma MMP-9 levels were detected

before and at 6 hours, 12 hours, 24 hours, and 72 hours after intravenous thrombol-

ysis. The clinical outcome of strokewasmeasured in terms of the functional outcome

and occurrence of symptomatic intracerebral hemorrhage. The MMP-9 levels

increased after thrombolysis in statin group and control group. No significant inter-

group difference was found in the MMP-9 levels before and at 6 hours after throm-

bolysis, but the levels were significantly lower in the statin group than in the control

group at 12, 24, and 72 hours (P , .001) after thrombolysis. Similarly, no significantintergroup difference was noted in the occurrence of symptomatic intracranial

hemorrhage as was the case with the modified Rankin scale (assessed by

the MannWhitney U test) at 7 days (P 5 .428) and 90 days (P 5 .419) afterthrombolysis. Our results indicate that pretreatment with statin can inhibit the

thrombolysis-induced increase in plasma MMP-9 levels but does not significantly

affect the prognosis of acute ischemic stroke patients undergoing intravenous

thrombolysis. Key Words: Ischemic strokethrombolysisstatinmatrix

metalloproteinase-9prognosisprospective clinical cohort study.

2014 by National Stroke AssociationIntroduction

Statins, by virtue of their lipid-lowering and nonlipidic

properties, are recommended for the primary and sec-

ondary prevention of stroke in patients at high risk of ce-

rebrovascular events.1,2 The preferred treatment for acute

ischemic stroke is intravenous (IV) thrombolysis inducedof Neurology, Nanjing First Hospital, Nanj-

anjing, Jiangsu Province, PR China.

; accepted July 1, 2014.

by Nanjing Health Bureau (YKK11121).

ce to Ying-Dong Zhang, MD, Department of

njing First Hospital, Nanjing Medical Uni-

d, Nanjing, Jiangsu Province 210006, PR

zhang_njmu@163.com.

matter

oke Association

016/j.jstrokecerebrovasdis.2014.07.001

erebrovascular Diseases, Vol. -, No. - (---by the administration of recombinant tissue plasminogen

activator (rtPA).3 However, it is unclear whether the prior

use of statins has a positive or negative influence on the

outcome of IV thrombolysis for ischemic stroke because

the results of pertinent studies have been contradictory.

Two large observational studies have shown that previ-

ous treatment with statins is not an independent predictor

of the functional outcome or of the occurrence of intracra-

nial hemorrhage (ICH) in stroke patients.4,5 On the other

hand, a couple of recent meta-analyses showed that

prior statin use may be associated with increased risk of

symptomatic intracranial hemorrhage (sICH) during the

first 36 hours of the IV administration of rtPA, without

influencing the 3-month functional outcome.6,7

Matrix metalloproteinases (MMPs) are a group of zinc-

and calcium-dependent endopeptidases that degrade

type IV collagen, laminin, and fibronectin, which are the

major components of the extracellular matrix and the), 2014: pp 1-6 1

Delta:1_given nameDelta:1_surnamemailto:yingdongzhang_njmu@163.comhttp://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.001

Figure 1. Flowchart showing the selection of patients in this study We re-

cruited 4175 ischemic stroke patients; 3937 were excluded because they did

not receive intravenous thrombolysis therapy. Forty-five of the remaining pa-

tients were excluded because they had a history of stroke. Finally, 193 pa-

H.-D. ZHAO AND Y.-D. ZHANG2basal lamina around cerebral blood vessels. MMPs

possibly play important roles in the occurrence of brain

infarction, edema, and hemorrhagic transformation asso-

ciated with acute ischemic stroke.8,9 Previous studies 10,11

have shown that in patients with cerebral ischemic stroke,

the level of MMP-9 increased significantly after IV throm-

bolysis and that this increase was closely associated with

the prognosis of thrombolysis and bleeding. Furthermore,

studies on animal models have indicated that statins can

inhibit the rtPA-related raise in MMP-9 levels, thereby

protecting the integrity of cerebral vessels after thrombo-

lytic rtPA therapy for stroke,12 although clinical evidences

pertaining to humans are scarce.

In this study, we sought to explore the effect of statin pre-

treatment on the prognosis and plasmaMMP-9 levels of pa-

tients undergoing IV thrombolysis for acute ischemic stroke.tients were enrolled and divided into the statin group and control group

based on whether they did or did not receive statin therapy.Methods

Study Design and Patient Selection

This investigation was designed as a prospective cohort

study. The study designwas approved by the Ethics Com-

mittee of Nanjing First Hospital. We screened 4175

consecutive patients treated at Nanjing First Hospital in

China for ischemic stroke between January 2011 and

September 2012. Among these patients, those meeting

the following criteria were included in the study: (1)

IV thrombolysis administered for indications cited by

the Safe Implementation of Thrombolysis in Stroke-

MOnitoring STudy13; (2) availability of complete medical

history; and (3) first episode of stroke. The exclusion

criteria for this studywere as follows: (1) refusal to receive

rtPA for IV thrombolysis; (2) history of stroke (hemor-

rhage or ischemic); (3) presence of contraindications for

statin therapy; and (4) refusal to provide consent for

participation in this study.

Of the 4175 patients screened, 238 had undergone IV

thrombolysis and 193 of them received the treatment for

their first-ever acute ischemic stroke. Among these 193

patients, 146 (control group) had no history of statin

use, whereas 47 (statin group) had previously received

statin therapy for the management of diseases other

than those of the cerebrovascular system (coronary heart

disease in 9 cases, hyperlipidemia in 26 cases, hyperten-

sion in 8 cases, and unknown causes in 4 cases; Fig 1).

Patients in the statin group had received atorvastatin

(20 mg per day) or rosuvastatin (10 mg per day) and

were maintained on the same drug dosage even after IV

thrombolysis. Patients in the control group received ator-

vastatin (20 mg per day) or rosuvastatin (10 mg per day)

at 72 hours after IV thrombolysis.Data Collection

Data regarding the following parameters were

collected for all the enrolled patients: (1) demographicfeatures, namely, age and sex; (2) time window for IV

thrombolysis; (3) systolic and diastolic blood pressure

levels; (4) the modified Rankin Scale (mRS) score for

assessment of functional dependence; (5) baseline

severity of stroke, defined using the National Institutes

of Health Stroke Scale (NIHSS); (6) laboratory data re-

corded within 24 hours of symptom onset; (7) cause of

stroke, namely, large artery atherosclerosis, cardioembo-

lism, small vessel occlusion, stroke of other determined

etiology, or stroke of undetermined etiology, as defined

by the modified Trial of ORG 10172 in Acute Stroke Ther-

apy criteria; and (8) type of stroke, defined as per the Ox-

fordshire Community Stroke Project classification system.Measurements

In addition to the collection of data mentioned previ-

ously, measurements of the plasma MMP-9 levels were

made at different time points. Peripheral blood samples

were obtained from all the enrolled 193 patients before

and at 6 hours, 12 hours, 24 hours, and 72 hours after

IV thrombolysis. The samples were collected in sodium

heparin sampling tubes, immediately placed on ice,

and centrifuged within 15 minutes at 2000 3 g for 10 mi-

nutes. The isolated plasma was transferred to cryovials

for storage at 280C until analysis. The plasma MMP-9concentrations were determined using a commercially

available sandwich enzyme-linked immunosorbent

assay kit (Invitrogen Co, Carlsbad, CA), as per the manu-

facturers instructions.

The clinical outcome of stroke was measured in terms

of the functional outcome and occurrence of symptomatic

intracerebral hemorrhage (sICH). The functional outcome

was evaluated using the mRS score recorded at 7 days

and 90 days after IV thrombolysis, and the outcome was

dichotomized as excellent (score, 0-1) and favorable

mailto:Images of Figure 1|tif

Table 1. Clinical characteristics in the statin group and control group

Characteristics All subjects, N 5 193 Statin group, N 5 47 Control group, N 5 146 P value*

Sex (women), % 35.7% 29.8% 37.7% .327

Age, y 65.3 6 10.3 65.1 6 8.9 65.34 6 10.8 .882Time window, min 179.2 6 46.9 174.8 6 44.5 180.6 6 47.9 .466Medical history, %

Hypertension 72.5 66.0 74.7 .245

Diabetes mellitus 26.4 29.8 25.3 .548

CAD 19.7 19.1 19.9 .915

Atrial fibrillation 25.9 23.4 26.7 .653

Valvular heart disease 7.8 8.5 7.5 .828

Cardiac insufficiency 6.2 8.5 5.9 .775

Systolic pressure, mm Hg 149.6 6 22.4 148.8 6 19.1 149.9 6 23.5 .776Diastolic pressure, mm Hg 86.3 6 11.7 87.9 6 10.5 85.8 6 12.1 .298NIHSS score at admission 8.8 6 6.4 8.9 6 6.2 8.7 6 6.5 .846Laboratory test results

WBC, 3109/L 7.8 6 2.6 8.3 6 3.0 7.6 6 2.5 .111Blood glucose, mmol/L 7.3 6 2.8 7.0 6 2.0 7.3 6 3.0 .414Cr 84.0 6 40.5 86.9 6 45.9 83.0 6 38.9 .567BUN 6.2 6 2.6 6.5 6 2.2 6.1 6 2.8 .376INR 1.02 6 .10 1.03 6 .10 1.02 6 .10 .774APTT, s 26.7 6 4.4 26.7 6 5.0 26.8 6 4.2 .884

TOAST classification, %

LA 50.8 57.4 48.6 .487

CE 17.6 12.8 19.2

SA 31.6 29.8 32.2

OCSP classification, %

TACT 18.1 19.2 17.8 .179

PACT 55.4 55.3 55.5

LACT 16.1 8.5 18.5

POCI 10.4 17.0 8.2

Abbreviations: APTT, activated partial thromboplastin time; BUN, blood urea nitrogen; CAD, coronary atherosclerotic heart disease; CE,

cardioembolism; Cr, creatinine; INR, international normalized ratio; LA, large artery atherosclerosis; LACT, lacunar infarct; OCSP, Oxfordshire

Community Stroke Project; PACT, partial anterior circulation infarct; POCI, posterior circulation infract; SA, small artery occlusion lacunar;

TACT, total anterior circulation infarct; TOAST, Trial of ORG 10172 in Acute Stroke Therapy; WBC, white blood cell.

*The comparison of statin group with control group.

THE EFFECTS OF PREVIOUS STATIN ON MMP-9 3(score, 1-2). The occurrence of sICH was defined by an in-

crease of greater than or equal to 4 points from the base-

line NIHSS score or the occurrence of death with

computed tomography evidence of brain hematoma

within 24-36 hours of treatment.

Statistical Analyses

Categorical and continuous data were presented as

percentages and mean 6 standard deviation, respec-

tively. Intergroup differences were assessed using the

chi-square test for categorical variables, and statistical

significance was set at a P value of less than .05. The

repeated 2-way analysis of variance test was performed

to determine intergroup differences in the plasma MMP-

9 levels at the various time points. Additionally, the

MannWhitney U test was used for the stratified anal-

ysis of the mRS score distribution. All data were entered

into and calculated using the software SPSS, version 17.0

(SPSS, Chicago, IL).Results

Baseline Clinical Characteristics

Among the 193 patients, 35.6% were women. The

average age of the patients was 65.3 6 10.3 years. The

time window for the administration of thrombolytic ther-

apy was 179.2 6 46.9 minutes. The average NIHSS score

at admission was 8.8 6 6.4 before the initiation of IV

thrombolysis. Among the 193 patients who underwent

IV thrombolysis, the causes of the stroke were large artery

atherosclerosis, cardioembolism, and small artery occlu-

sion, at frequencies of 50.8%, 17.6%, and 31.6%, respec-

tively. Further, the most common type of stroke was

partial anterior circulation infarct (55.4%), followed by to-

tal anterior circulation infarct (18.1%), lacunar infarct

(16.1%), and posterior circulation infract (10.4%), in that or-

der. The 2 groups did not show any significant differences

in age, sex, medical history, laboratory test results, severity

of stroke, cause of stroke, or type of stroke (Table 1).

Figure 2. Plasma matrix metalloproteinase (MMP)-9 levels in both

groups after thrombolysis. Plasma MMP-9 levels were assessed at 0 hours,

6 hours, 12 hours, 24 hours, and 72 hours after thrombolysis. Repeated mea-

sures analysis of variance was used to compare the intergroup differences in

plasma MMP-9 levels (*P , .001).

H.-D. ZHAO AND Y.-D. ZHANG4Plasma MMP-9 Level

The patients in both groups showed an increase in the

plasmaMMP-9 levels soon after IV thrombolysis; the levels

peaked at 24 hours after thrombolysis. Before the initiation

of IV thrombolysis, the plasma MMP-9 levels in the statin

group and the control group showed no significant differ-

ence (P 5 .055) at 68.7 6 20.8 ng/mL and 76.6 6 25.4 ng/

mL, respectively. The plasma MMP-9 levels in the statin

group and control group were comparable at 6 hours

(121.96 29.4 vs. 135.46 35.5,P..05), but lower in the statin

group than in the control group at 12 hours (131.0 6 40.6

vs. 191.2 6 40.0, P , .001), 24 hours (157.4 6 28.9 vs.

214.6 6 49.5, P , .001), and 72 hours (86.1 6 29.0 vs.

110.56 29.7, P, .001) after thrombolysis (Fig 2).Prognosis

At 7 days after thrombolysis, the outcomes were excel-

lent and favorable in 12 (25.5%) and 23 (48.9%) of the pa-

tients in the statin group, respectively and in 33 (22.6%)

and 65 (44.5%) of those in the control group. The differ-

ence between the 2 groups in the number of patients

with excellent (P 5 .247) and favorable outcomes

(P 5 .579) was not statistically significant. Similarly, at

90 days, no significant difference was noted between the

statin and control groups in the frequencies of excellent

(46.8% vs. 45.9%, P 5 .913) and favorable (63.8% vs.

61.6%, P 5 .788) outcomes. In addition, sICH occurred

in 2 cases (4.3%) of the statin group and 6 cases of the con-

trol group (4.1%), with no statistical intergroup difference

(P5 .965; Table 2). Furthermore, analysis using theMann

Whitney U test revealed no significant intergroup differ-

ences for the mRS scores recorded for 7 days (P 5 .428)

and 90 days (P 5 .419) after IV thrombolysis (Fig 3).Discussion

This prospective clinical cohort study revealed that the

plasma MMP-9 levels in acute stroke patients increasedgradually during the first 6 hours of IV thrombolysis,

reaching peak levels at 24 hours and that the plasma

MMP-9 levels in the statin group were significantly lower

than those in the control group at 12 hours, 24 hours, and

72 hours after IV thrombolysis. This implies that previous

statin therapy inhibits the thrombolysis-induced raise in

MMP-9 levels. However, we found that previous statin

therapy did not exert any significant effect on the prog-

nosis at 7 days and 90 days after IV thrombolysis or on

the occurrence of hemorrhagic transformation after

stroke.

Clinical studies have suggested that acute ischemic

stroke triggers a series of inflammatory cascades that

induce the expression and activation of MMP-9. Studies

have also shown that increased plasma levels of MMP-9

are correlated with the infarct volume, severity of stroke

symptoms, hemorrhagic transformation, stroke progres-

sion, and death; MMP-9 level can serve as a biochemical

marker for acute ischemic stroke, predicting cerebral

hemorrhage after IV thrombolysis.14,15 rtPA is a serine

protease that restores blood supply by dissolving clots

through fibrin degradation, and it is the only

thrombolytic medication approved by the Food and

Drug Administration. However, in vitro studies have

shown that rtPA may induce neutrophil degranulation

and release of MMP-9, which reaches its peak levels

within 10-30 minutes of the administration of rtPA. Clin-

ical and animal studies have confirmed that in acute

ischemic stroke patients, the rtPA-induced activation of

MMP-9 is mediated by a signaling pathway involving

the lipid-preferred partner protein, which also increases

the levels of MMP-9.16,17 This may explain the initial

increase in the MMP-9 levels observed in both the statin

group and control group in this study.

A previous study has shown that ICH occurred in 7.7%

of the patients administered rtPA for IV thrombolysis

within 36 hours of stroke onset.18 ICH is the major cause

of early disease progression and death in patients

receiving IV thrombolysis treatment for stroke manage-

ment. Excessive disruption of the bloodbrain barrier

mediated by MMP-9 plays a key role in the development

of brain edema and cerebral hemorrhage after IV throm-

bolysis. Therefore, some investigators have suggested

the administration of MMP-9 inhibitors along with rtPA

to improve the efficacy and safety of the latter.19,20

MMP-9 inhibitors, such as minocycline and Batimastat

(BB-94), are reported to reduce the size of the ischemic

infarct and alleviate bleeding complications in the rat

model of IV thrombolysis for stroke management.21,22

This therapeutic approach has generated widespread

interest in the field of research on IV thrombolytic

therapy. Statins are inhibitors of hydroxymethyl acid

coenzyme A reductase and exhibit lipid-lowering, anti-in-

flammatory, and antioxidative effects. They are the main

components of antiatherosclerotic therapy and are widely

used to prevent ischemic cerebrovascular disease in

mailto:Images of Figure 2|tif

Table 2. Comparison of the prognosis in the statin group with control group

Prognosis All subjects, N 5 193 Statin group, N 5 47 Control group, N 5 146 P value*

7 d mRS 0-1, n (%) 45 (23.3) 12 (25.5) 33 (22.6) .247

7 d mRS 0-2, n (%) 88 (45.6) 23 (48.9) 65 (44.5) .597

90 d mRS 0-1, n (%) 89 (46.1) 22 (46.8) 67 (45.9) .913

90 d mRS 0-2, n (%) 120 (62.2) 30 (63.8) 90 (61.6) .788

SICH, n (%) 8 (4.1) 2 (4.3) 6 (4.1) .965

Abbreviations: mRS, modified Rankin scale; sICH, symptomatic intracranial hemorrhage.

*Comparison of the statin group with control group.

THE EFFECTS OF PREVIOUS STATIN ON MMP-9 5high-risk patients. Basic research has revealed that statins

reduce the expression and activity, as well as the release,

of MMPs in different cell types.23 Studies on animal

models of ischemic stroke have shown that the combined

use of atorvastatin and IV thrombolytic agents can effec-

tively reduce the post-thrombolysis increase in blood

MMP-9 levels, thereby protecting the integrity of the

bloodbrain barrier and promoting the efficacy of IV

thrombolysis. For the first time in a clinical setting, our

study shows that the administration of statins to patients

with ischemic stroke before the initiation of IV thrombol-

ysis may inhibit the post-thrombolysis increase in the

MMP-9 levels.

At present, the combined effects of statin therapy and IV

thrombolysis on the prognosis of ischemic stroke are

largely unclear. Our finding that previous treatment with

statin therapy had no significant benefit on the prognosis

of acute stroke patients managed with IV thrombolysis is

not in agreement with those reported previously. Studies

have indicated that the combined use of statins and IV

thrombolysis improved the short- and long-termprognosis

of stroke patients.5,24-26 However, our findings are in line

with those of clinical studies by Miedema et al6 and Engel-

ter et al,4 which showed no significant benefit of statin ther-Figure 3. Comparison of mRS score between

the statin group and control group. (A) Distri-

bution of mRS score at 7 days and (B) distribu-

tion of mRS score at 90 days.apy on the prognosis of stroke patients. Engelter et al4

suggested that the efficacy of statin therapy may be influ-

enced by several factors, including the patients age, co-

morbidities (such as diabetes and coronary heart

disease), and history of antiplatelet medications. In this

study, we recruited only patients with first-ever stroke,

thereby precluding the impact of the prior medical treat-

ment for stroke on the results, allowing for the comparison

between the 2 patient groups, and ensuring reliable study

results. Moreover, Cappellari et al25 indicated that the

timing of statin administration influences the efficacy of

statin therapy on the prognosis of stroke patients managed

with IV thrombolysis. Our results could also provide a ba-

sis for determining the optimal timing for the administra-

tion ofMMP-9 inhibitors in combinationwith rtPA therapy

for patients with acute ischemic stroke.

Our study has a couple of limitations. The size of the

study population was small. More large-scale studies

are warranted to test the clinical applicability of our find-

ings. Furthermore, in this study, we were unable to ac-

count for the duration of previous statin treatment; in

the future, we intend to investigate the effect of statin pre-

treatment on patients with different types and severities

of ischemic stroke.

H.-D. ZHAO AND Y.-D. ZHANG6In summary, the present study shows that among pa-

tients undergoing IV thrombolytic therapy for acute

ischemic stroke, those who were already receiving statin

therapy had lower levels of rtPA-induced increase in

MMP-9 levels. This implies that statin therapymight miti-

gate the thrombolysis-induced increase in MMP level.

However, we did not find any significant effect of prior

statin therapy on the prognosis of acute ischemic stroke

patients managed with IV thrombolysis.

Acknowledgment: We thank Medjaden Bioscience

Limited for editing the article.References

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The Effects of Previous Statin Treatment on Plasma Matrix Metalloproteinase-9 Level in Chinese Stroke Patients Undergoing T ...IntroductionMethodsStudy Design and Patient SelectionData CollectionMeasurementsStatistical Analyses

ResultsBaseline Clinical CharacteristicsPlasma MMP-9 LevelPrognosis

DiscussionReferences