大劑量阿托伐他汀對(duì)急性腦梗死患者血清細(xì)胞因子及動(dòng)脈粥樣硬化斑塊的影響

李 強(qiáng),凌 芳,聶德云,熊 濤

(湖北省武漢市第五醫(yī)院神經(jīng)內(nèi)科 430050)

大劑量阿托伐他汀對(duì)急性腦梗死患者血清細(xì)胞因子及動(dòng)脈粥樣硬化斑塊的影響

李 強(qiáng),凌 芳,聶德云,熊 濤

(湖北省武漢市第五醫(yī)院神經(jīng)內(nèi)科 430050)

目的探討大劑量阿托伐他汀調(diào)脂治療對(duì)急性腦梗死患者血清超敏C反應(yīng)蛋白(hs-CRP)?白細(xì)胞介素-17(IL-17)及基質(zhì)金屬蛋白酶-8(MMP-8)的影響,觀察其對(duì)動(dòng)脈粥樣硬化斑塊的消退作用?方法 136例急性腦梗死患者根據(jù)頸動(dòng)脈超聲檢查結(jié)果分為頸動(dòng)脈穩(wěn)定斑塊組(n=68)和頸動(dòng)脈易損斑塊組(n=68)?抽血檢查后再隨機(jī)分為小劑量組68例(阿托伐他汀10mg/d,口服)和大劑量組68例(阿托伐他汀40mg/d,口服)?比較治療前后血脂?血清hs-CRP?IL-17和 MMP-8水平;觀察治療前后頸動(dòng)脈內(nèi)-中膜厚度(IMT值)?斑塊厚度及頸動(dòng)脈粥樣硬化斑塊回聲變化?結(jié)果治療前,兩組中血脂及血清hs-CRP?IL-17和MMP-8水平差異無(wú)統(tǒng)計(jì)學(xué)意義(均P0.05)?治療后2周及4周,大劑量組中血清LDL-C?TG?TC水平均低于小劑量組(P0.01),治療后4周,大劑量組血清hs-CRP?IL-17和MMP-8均低于小劑量組,且大劑量組下降幅度均大于小劑量組,差異具有統(tǒng)計(jì)學(xué)意義(P0.01);治療后6月,兩組IMT值和斑塊厚度較治療前降低,且大劑量組兩項(xiàng)指標(biāo)低于小劑量組,差異具有統(tǒng)計(jì)學(xué)意義(P0.01);大劑量組低回聲斑塊回聲增強(qiáng)例數(shù)較治療前明顯增加(P0.01)?結(jié)論大劑量阿托伐他汀調(diào)脂治療能迅速降低腦梗死患者的血清炎癥因子水平,具有更強(qiáng)的抗炎作用,可逆轉(zhuǎn)?穩(wěn)定斑塊?

腦梗死;白細(xì)胞介素17;基質(zhì)金屬蛋白酶類;動(dòng)脈粥樣硬化;阿托伐他汀

腦梗死是目前危害中老年人健康的主要疾病之一,而動(dòng)脈粥樣硬化(atherosclerosis,AS)是腦梗死的重要病因之一;在AS的基礎(chǔ)上,頸動(dòng)脈粥樣硬化粥樣易損斑塊不可預(yù)測(cè)地突然破損(破裂或潰瘍形成)?血小板被激活,繼之動(dòng)脈血栓形成等構(gòu)成了腦梗死的重要發(fā)病機(jī)制[1]?基質(zhì)金屬蛋白酶(marix metalloproteinase,MMP)是在細(xì)胞外基質(zhì)(extracellular matrix,ECM)降解中起主要作用的鋅離子依賴性蛋白酶超家族,可通過(guò)消化斑塊纖維帽成分破壞其結(jié)構(gòu),造成斑塊不穩(wěn)定性增加,加速斑塊破裂[2]?MMP-8又稱多形核細(xì)胞膠原酶,能降解ECM成分,具有調(diào)節(jié)可溶性細(xì)胞因子分泌和影響斑塊穩(wěn)定性

的作用[3]?目前國(guó)內(nèi)關(guān)于大劑量阿托伐他汀調(diào)脂治療對(duì)急性腦梗死患者血清炎癥因子——超敏C反應(yīng)蛋白(high sensitivity C-reactive protein,hs-CRP)?白細(xì)胞介素-17(interleukin-17,IL-17)?MMP-8水平的影響及頸動(dòng)脈粥樣硬化斑塊干預(yù)作用方面的報(bào)道不多,本組將就此進(jìn)行觀察,并探討其臨床意義?

1 資料與方法

1.1 一般資料 2007年1月至2010年10月期間本院神經(jīng)內(nèi)科的住院患者中,對(duì)所有符合要求且發(fā)病48h之內(nèi)的腦梗死患者行頸動(dòng)脈彩超檢查?根據(jù)參考文獻(xiàn)[4]中B超下頸動(dòng)脈粥樣硬化斑塊的分類標(biāo)準(zhǔn),將頸動(dòng)脈斑塊呈低回聲的患者納入易損斑塊組,共68例,其中,男性36例,女性32例;年齡37～75歲,平均61.56歲?頸動(dòng)脈斑塊呈高回聲的患者納入穩(wěn)定斑塊組,共68例,其中,男性35例,女性33例;年齡35～76歲,平均年齡61.75歲?兩組間一般臨床資料差異無(wú)統(tǒng)計(jì)學(xué)意義?穩(wěn)定斑塊組和易損斑塊組中隨機(jī)各抽取34例患者分別給予小劑量阿托伐他汀(10mg/d,口服)和大劑量阿托伐他汀(40mg/d,口服)治療?腦梗死的診斷符合1996年全國(guó)腦血管病學(xué)術(shù)會(huì)議修訂的診斷標(biāo)準(zhǔn),經(jīng)頭顱CT和(或)MRI確診,均為前循環(huán)腦梗死,除外無(wú)癥狀性腦梗死?梗死后出血和腦出血?全部研究對(duì)象既往無(wú)腦卒中史,均為湖北武漢地區(qū)的漢族人,彼此無(wú)血緣關(guān)系,排除患有肝臟疾病?腎臟疾病?2型糖尿病?血液病?自身免疫系統(tǒng)疾病?甲狀腺疾病?結(jié)核?惡性腫瘤?嚴(yán)重感染及妊娠者;排除接受溶栓治療者,近3個(gè)月來(lái)服用各類降脂藥及抗血小板聚集藥者?

1.2 方法

1.2.1 治療方法 小劑量和大劑量治療組均應(yīng)用阿司匹林和維生素E?C及對(duì)癥治療如脫水?調(diào)控血壓等基礎(chǔ)治療?于發(fā)

病48h內(nèi),小劑量組加用阿托伐他汀(即立普妥,輝瑞制藥,10mg/晚,口服)和大劑量組(阿托伐他汀40mg/晚,口服),連服6月?用藥1?2周后復(fù)查肝?腎功能及心肌酶學(xué),若轉(zhuǎn)氨酶超過(guò)正常值的3倍則停用此藥,如出現(xiàn)肌肉酸痛?橫紋肌溶解現(xiàn)象等不良反應(yīng),立即退出治療?

1.2.2 頸動(dòng)脈超聲檢查 采用飛利浦IU22型彩色多普勒超聲診斷儀測(cè)定頸動(dòng)脈內(nèi)-中膜厚度(intima-media thickness,IMT),雙側(cè)各測(cè)量3次,取平均值?本組將粥樣硬化斑塊定義為IMT≥1.3mm?

1.2.3 檢測(cè)方法 于服藥前?用藥后2周和4周清晨空腹抽取肘靜脈血6mL,離心后分離血清?采用直接法測(cè)定總膽固醇(total cholesterol,TC)?三酰甘油(triacylglycerol,TG)?低密度脂蛋白膽固醇(low density lipoprotein cholestorol,LDL-C)?高密度脂蛋白膽固醇(high density lipoprotein cholestorol,HDL-C)水平?采用免疫散射比濁法測(cè)定hs-CRP水平,采用雙抗體夾心酶聯(lián)免疫吸附試驗(yàn)(enzyme-linked immunosorbent assay,ELISA)法測(cè)定IL-17和 MMP-8水平,試劑盒由武漢博士德生物試劑有限公司提供,操作嚴(yán)格按照說(shuō)明書(shū)進(jìn)行?

1.3 統(tǒng)計(jì)學(xué)方法 應(yīng)用SPSS13.0統(tǒng)計(jì)軟件,所有計(jì)量資料以±s表示,組間比較采用t檢驗(yàn)?治療前后指標(biāo)比較采用配對(duì)t檢驗(yàn),P0.05為差異有統(tǒng)計(jì)學(xué)意義?

2 結(jié) 果

2.1 治療前?后血脂水平的比較(見(jiàn)表1?2) 兩組治療前血脂水平差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05);治療后2周和4周,除

HDL-C外,大劑量組TG?TC?LDL-C水平均低于小劑量組,差異有統(tǒng)計(jì)學(xué)意義(P0.01)?

表1 兩組患者治療前?后血脂水平比較(±s)

表1 兩組患者治療前?后血脂水平比較(±s)

TG(mmol/L)組別 n TC(mmol/L)治療前 治療后2周 治療后4周 治療前 治療后2周 治療后4周小劑量組 68 1.81±0.53 1.56±0.37 1.38±0.32 5.98±0.39 3.93±0.81 3.61±0.89大劑量組 68 1.83±0.49 1.41±0.31 1.11±0.29 6.03±0.46 3.12±0.79 2.79±0.86

表2 兩組患者治療前?后血脂水平比較(±s)

表2 兩組患者治療前?后血脂水平比較(±s)

LDL-C(mmol/L)組別 n HDL-C(mmol/L)治療前 治療后2周 治療后4周 治療前 治療后2周 治療后4周小劑量組 68 3.94±0.63 2.83±0.46 2.69±0.48 0.97±0.31 0.98±0.41 0.97±0.36大劑量組 68 3.98±0.76 1.79±0.54 1.31±0.32 0.98±0.29 0.99±0.41 0.97±0.32

表3 治療前?后hs-CRP?IL-17和 MMP-8水平比較(±s)

表3 治療前?后hs-CRP?IL-17和 MMP-8水平比較(±s)

*:P0.05,**:P 0.01,與治療前比較;△:P0.05,△△:P 0.01,與小劑量組比較;#:P0.05,##:P 0.01,與相應(yīng)的穩(wěn)定班塊組比較?

hs-CRP(mg/L)組別 n IL-17(pg/mL)MMP-8(ng/μL)治療前 治療后 下降易損斑塊組 68 9.86±4.64# 3.54±1.75** 6.32±3.51## 150.16±37.41## 45.80±20.43** 104.36±30.14## 19.80±3.30## 7.20±1.90**治療前 治療后 下降 治療前 治療后 下降12.60±2.70小劑量組 34 9.59±4.82# 4.47±1.89** 5.12±3.61## 151.76±38.49## 59.91±22.34** 91.85±31.47## 19.70±3.20## 9.90±1.70** 9.80±2.60大劑量組 34 10.13±4.63# 2.96±1.59**△△ 7.17±3.16△△## 148.56±36.51## 31.68±18.32**△△ 116.88±28.75△△##19.90±3.40## 4.40±2.10** 14.60±2.80△△穩(wěn)定斑塊組 68 7.41±3.61 3.78±1.94** 3.63±2.90 115.58±30.98 37.06±17.51** 78.52±25.16 14.70±3.00 6.40±2.20** 8.30±2.60小劑量組 34 7.19±3.53 4.83±1.96** 2.36±2.86 118.51±29.63 47.69±19.86** 70.82±25.22 14.50±2.90 8.90±1.40** 5.60±2.30大劑量組 34 7.62±3.69 2.72±1.91**△△ 4.90±2.94△△ 112.65±32.28 26.43±14.79**△△ 86.22±25.11△ 14.80±3.10 3.80±2.70** 11.00±2.90△△

表4 治療前?后IMT值及斑塊厚度變化(±s)

表4 治療前?后IMT值及斑塊厚度變化(±s)

*:P0.05,**:P 0.01,與同組治療前比較;△:P0.05,△△:P 0.01,與小劑量組比較?

IMT值(mm)組別 n斑塊厚度(mm)治療前 治療后6月 治療前 治療后6月小劑量組 68 1.26±0.19 1.08±0.36** 2.68±0.11 2.49±0.24**大劑量組 68 1.24±0.20 0.91±0.23**△△ 2.71±0.17 1.93±0.16**△△

2.2 治療前?后血清hs-CRP?IL-17和 MMP-8水平比較 見(jiàn)表3?治療前,同一種性質(zhì)斑塊兩治療組間血清hs-CRP?IL-17和 MMP-8水平差異均無(wú)統(tǒng)計(jì)學(xué)意義,具可比性(P0.05),但兩種性質(zhì)斑塊間無(wú)論是小劑量組或大劑量組3項(xiàng)指標(biāo)易損斑塊組均高于穩(wěn)定斑塊組,P0.05或P0.01;同性質(zhì)斑塊組無(wú)論小劑量還是大劑量治療,治療后3項(xiàng)指標(biāo)均下降,但大劑量組下降幅度均大于小劑量組,P0.01?

2.3 治療前后IMT值?斑塊厚度及斑塊數(shù)量的比較(見(jiàn)表4?5) 治療前,兩組IMT值和斑塊厚度比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05);治療后,兩組IMT值及斑塊厚度均下降,差異有統(tǒng)計(jì)學(xué)意義(P0.01),且大劑量組兩項(xiàng)指標(biāo)均低于小劑量組,差異有統(tǒng)計(jì)學(xué)意義(P0.01)?治療后,大劑量組低回聲斑塊數(shù)量較小劑量組明顯減少,兩組間比較,差異有統(tǒng)計(jì)學(xué)意義(P0.01)?

表5 兩組治療前?后斑塊數(shù)量的比較[n(%)]

2.4 不良反應(yīng) 小劑量組2例?大劑量組5例患者在服藥1周左右轉(zhuǎn)氨酶輕度升高,后復(fù)查正常;小劑量組和大劑量組各1例出現(xiàn)消化道反應(yīng),對(duì)癥治療后緩解,無(wú)嚴(yán)重不良反應(yīng)?所有隨訪病例腎功能均正常,沒(méi)有諸如肌痛?無(wú)力?發(fā)熱等癥狀?

3 討 論

腦卒中是在AS的基礎(chǔ)上發(fā)生的,大量研究表明,AS是一個(gè)血管受損后的慢性炎癥反應(yīng)過(guò)程,后者是AS的發(fā)生?發(fā)展及其并發(fā)腦缺血-再灌注損傷的主要原因[5]?目前研究顯示,高脂血癥是AS的重要促進(jìn)因素,LDL-C是AS的啟動(dòng)因子,尤其LDL-C升高和HDL-C降低,是高血壓和腦卒中的重要危險(xiǎn)因素[6]?他汀類藥物是目前臨床使用最廣泛的一類調(diào)脂藥,它可抑制體內(nèi)膽固醇的生物合成,刺激細(xì)胞表面的LDL受體合成增加從而降低血清LDL-C水平?本研究發(fā)現(xiàn),治療后2周及4周,大劑量組患者血清LDL-C均值低于2.1mmol/L,說(shuō)明大劑量阿托伐他汀治療可快速降低血清LDL-C水平,達(dá)到指南要求的降脂標(biāo)準(zhǔn)[7]?

在AS形成過(guò)程中,中性粒細(xì)胞在炎癥部位的募集過(guò)程包括邊集?滾動(dòng)?黏附和移行等階段,每個(gè)階段都有相關(guān)炎癥介質(zhì)參與?hs-CRP是一種測(cè)量低水平炎癥反應(yīng)的靈敏指標(biāo),可作為AS患者發(fā)生心?腦血管事件風(fēng)險(xiǎn)癥的有效預(yù)測(cè)因子[8]?在本研究中,治療前,易損斑塊組患者血清hs-CRP水平高于穩(wěn)定斑塊組,提示hs-CRP水平與斑塊的不穩(wěn)定性有一定關(guān)系?IL-17是近年來(lái)新發(fā)現(xiàn)的一種白介素家族成員,是一種強(qiáng)大的致炎因子和炎癥反應(yīng)的微調(diào)因子,在它的刺激下,成纖維細(xì)胞和內(nèi)皮細(xì)胞可釋放白介素-6等細(xì)胞因子放大炎癥反應(yīng),從而加重卒中后神經(jīng)元損傷?已有研究證明,炎癥是AS斑塊破裂的關(guān)鍵因素[9]?如何積極有效降低血清hs-CRP和IL-17水平,減輕缺血性卒中和AS斑塊的炎性反應(yīng)顯得尤其重要?在本研究中,治療前,易損斑塊組患者血清IL-17水平高于穩(wěn)定斑塊組;治療后,大劑量組患者血清hs-CRP和IL-17水平均明顯低于小劑量組,說(shuō)明大劑量阿托伐他汀調(diào)脂治療有助于快速降低血清炎癥因子hs-CRP和IL-17水平,證實(shí)阿托伐他汀具有抗炎作用;同時(shí),對(duì)于頸部血管存在易損斑塊的患者,采用大劑量他汀類藥物治療可獲得更強(qiáng)的抗炎效果?

從某種意義上來(lái)講,急性腦梗死的發(fā)生與AS易損斑塊不可預(yù)測(cè)的破裂有關(guān),如何使用藥物逆轉(zhuǎn)和穩(wěn)定斑塊是目前治療的熱點(diǎn)和難題?已有研究發(fā)現(xiàn),激活的MMP-8可能部分參與動(dòng)脈粥樣硬化斑塊纖維帽的降解,可作為易破裂斑塊藥物治療的靶點(diǎn)?本研究中,治療前,易損斑塊組血清 MMP-8水平高于穩(wěn)定斑塊組,提示血清MMP-8水平可作為預(yù)測(cè)AS斑塊穩(wěn)定性的血清學(xué)指標(biāo);治療后,大劑量組患者血清該指標(biāo)下降幅度大于小劑量組,提示大劑量阿托伐他汀可快速降低MMP活性,提高易損斑塊的穩(wěn)定性,證實(shí)阿托伐他汀具有降低 MMP活性的作用?

頸動(dòng)脈超聲檢查是目前診斷AS的重要手段之一,而IMT值可作為心?腦血管事件發(fā)生的有效預(yù)測(cè)因子?本研究中,治療后6月,兩組IMT值和斑塊厚度均下降,且大劑量組患者兩項(xiàng)指標(biāo)均低于小劑量組,低回聲斑塊超聲信號(hào)增強(qiáng)例數(shù)高于小劑量組,提示大劑量阿托伐他汀治療可逆轉(zhuǎn)AS斑塊,提高易損斑塊的穩(wěn)定性?此外,采用大劑量調(diào)脂治療,僅5例患者出現(xiàn)輕度轉(zhuǎn)氨酶升高,僅1例出現(xiàn)消化道反應(yīng),未見(jiàn)橫紋肌溶解現(xiàn)象,提示該治療方法不良反應(yīng)發(fā)生率低,安全性良好?綜上所述,大劑量阿托伐他汀調(diào)脂治療可快速降脂達(dá)標(biāo),有助于快速降低血清炎癥因子hs-CRP?IL-17和 MMP-8的水平,具有更強(qiáng)的抗炎作用,可逆轉(zhuǎn)和穩(wěn)定斑塊,不失為一種良好的治療方法,尤其在腦梗死合并頸部血管易損斑塊患者中值得推廣?

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Effect of high-dose atorvastatin on serum interleukin-17,marix metalloproteinases-8 and atheromatous plaque resolution of carotid artery in patients with acute cerebral infarction

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ObjectiveTo investigate the effect of high-dose atorvastatin on the inflammatory factors such as high sensitivity C-reactive protein(hs-CRP),interleukin-17(IL-17)and marix metalloproteinases-8(MMP-8)in the patients with acute stroke,and to observe its degrading role on atherosclerosis plaque.Methods136patients with acute cerebral infarction were divided into the carotid vulnerable plaque group and the carotid stable plaque group according to theResultsof carotid B-mode ultrasonography.After collecting blood for detection,they were randomly redivided into the low-dose group(n=68)and the high-dose group(n=68).The low-dose group

oal atorvastatin 10mg daily,whereas the high-dose group received atorvastatin 40mg daily.Blood lipoproteins were measured in all patients before treatment,in 2 ,4weeks after treatment.Levels of serum hs-CRP,IL-17and MMP-8 were measured in all patients before treatment and in 4weeks after treatment.The intima-media thickness,plaque thickness and echogenicity of carotid plaques were evaluated by Doppler ultrasonography during a 6-month follow-up period.ResultsBefore treatment,there were no significantly differences in blood lipoprotein,hs-CRP,IL-17and MMP-8between the low-dose group and the high-dose group(P0.05).No matter what treatment accepted,levels of hs-CRP,IL-17and MMP-8were obviously higher in the patients with unstable plaques than those with stable plaques.After 2-week and 4-week treatment,the levels of LDL-C,TG and TC were obviously lower in the patients treated with high-dose atorvastatin than those treated with low-dose atorvastatin(P0.01).Compared with before treatment,the levels of hs-CRP,IL-17and MMP-8were significantly decreased in the patients treated with high-dose atorvastatin for 4weeks,as well as in the patients treated with low-dose atorvastatin(P0.01).In comparison of drop scope,the decrease in the level of of hs-CRP,IL-17and MMP-8in the high-dose group was obviously higher than that in the low-dose group(P0.01).Whether the high-dose or the low-dose group,significant increases in echogenicity of carotid plaques and decreases in plaque thickness and intima-media thickness were noted after statin therapy.However,the value of IMT and plaque thickness in the high-dose group were significantly lower than those in the low-dose group(P0.01).Compared with before treatment,the number of echogenic cases of hypoechoic plaques in the high-dose group was increased significantly(P0.01).ConclusionHigh-dose atorvastatin could rapidly reduce serum inflammatory factors in the patients with acute cerebral infarction,might have the stronger anti-inflammation function,might reverse and stabilize the atherosclerosis plaque.

brain infarction;interleukin-17;matrix metalloproteinases;atherosclerosis;atorvastatin

10.3969/j.issn.1671-8348.2012.16.014

A

1671-8348(2012)16-1598-03

2011-10-17

2011-12-13)

?短篇及病例報(bào)道?