董梅,任法新,牟楠,張傳煥,李建平,陶志剛,楊軍
急性心肌梗死患者經(jīng)皮冠狀動(dòng)脈介入治療術(shù)后慢血流發(fā)生與梗死相關(guān)動(dòng)脈病變局部白細(xì)胞介素-6水平的關(guān)系*
董梅,任法新,牟楠,張傳煥,李建平,陶志剛,楊軍
目的:探討ST段抬高型心肌梗死(STEMI)患者經(jīng)皮冠狀動(dòng)脈介入治療(PCI)術(shù)后慢血流發(fā)生風(fēng)險(xiǎn)與梗死相關(guān)動(dòng)脈管病變局部白細(xì)胞介素-6(IL-6)水平的關(guān)系。
方法:共納入STEMI行急診PCI的患者56例,其中男性34例,女性22例,平均年齡(63.5±10.3)歲。PCI術(shù)前應(yīng)用6F Diver CE抽吸導(dǎo)管在導(dǎo)絲支持下,于冠狀動(dòng)脈病變的遠(yuǎn)端局部取樣,采用酶聯(lián)免疫吸附法測定IL-6水平。
結(jié)果:共計(jì)21例(37.5%)患者發(fā)生慢血流。多因素Logistic回歸分析表明糖尿?。∣R=0.124,95%CI:0.019-0.804,P=0.029)、血栓負(fù)荷評(píng)分(OR=0.080,95%CI:0.007-0.909,P=0.042)、局部 IL-6(OR=0.623,95%CI:0.441-0.881,P=0.007)是慢血流發(fā)生的獨(dú)立危險(xiǎn)因素。ROC曲線表明局部IL-6(ROC面積0.824,OR=1.704,95%CI: 1.274-2.281,P=0.001;理想閾值:≥11.3pg/ml)對(duì)慢血流的發(fā)生具有重要預(yù)測價(jià)值(敏感性為73%,特異性為71%)。
結(jié)論:梗死相關(guān)動(dòng)脈病變局部IL-6水平升高與STEMI患者行急診PCI術(shù)后慢血流的發(fā)生密切相關(guān)。
白細(xì)胞介素-6;慢血流;炎癥反應(yīng);急性心肌梗塞
(Chinese Circulation Journal, 2014,29:185.)
慢血流是指病變冠狀動(dòng)脈雖經(jīng)造影證實(shí)未見機(jī)械性阻塞造成的血管閉塞,但仍存在心肌灌注不良的現(xiàn)象[1-3]。它與經(jīng)皮冠狀動(dòng)脈介入治療(PCI)術(shù)后左心室功能恢復(fù)不佳、不良的臨床預(yù)后密切相關(guān)[4-6]。雖然近年來人們對(duì)慢血流的發(fā)病機(jī)制進(jìn)行深入研究,但具體機(jī)制仍不是很清楚,且目前尚未發(fā)現(xiàn)可靠的預(yù)測因子。
白細(xì)胞介素-6(IL-6)是一種多效能細(xì)胞因子,在慢性炎癥性疾病的發(fā)病中表現(xiàn)為促炎作用[7],在急性炎癥反應(yīng)中則表現(xiàn)為抗炎作用[8]。研究已證實(shí)IL-6水平升高是急性冠狀動(dòng)脈綜合征患者死亡率增加的獨(dú)立預(yù)測因子[9,10]。IL-6是否通過促進(jìn)慢血流的發(fā)生而對(duì)ST段抬高型心肌梗死(STEMI)患者產(chǎn)生不利影響,目前尚不清楚。因此,本研究主要探討STEMI患者梗死相關(guān)動(dòng)脈病變局部IL-6水平與PCI術(shù)后慢血流發(fā)生之間的關(guān)系。
對(duì)象: 2011-07至2012-07期間,在煙臺(tái)毓璜頂醫(yī)院就診的STEMI患者60例。納入標(biāo)準(zhǔn):持續(xù)性胸痛(>30min),且對(duì)硝酸甘油反應(yīng)差;12導(dǎo)標(biāo)準(zhǔn)心電圖示兩個(gè)或兩個(gè)以上相鄰導(dǎo)聯(lián)ST段抬高≥0.2 mV;肌酸激酶(CK)、肌酸激酶MB同工酶(CK-MB)或相對(duì)指數(shù)≥正常值上限2倍;發(fā)病12小時(shí)內(nèi)行急診PCI。入選患者均為初次診斷的STEMI,成功行PCI術(shù)。既往無慢性冠狀動(dòng)脈性疾病或心力衰竭病史。4例患者因發(fā)?。?2小時(shí)(n=3)或無IL-6檢測結(jié)果(n=1)被排除。本研究最終納入56例患者。
PCI治療:所有的冠狀動(dòng)脈造影診斷使用5F和6F動(dòng)脈鞘管(Cordis公司)通過右股動(dòng)脈或橈動(dòng)脈路徑操作。所有入選患者術(shù)前均給予阿司匹林300 mg、氯吡格雷300 mg雙聯(lián)抗血小板聚集治療,靜脈給予普通肝素5000 IU,必要時(shí)給予糖蛋白Ⅱb/Ⅲa受體拮抗劑。術(shù)者根據(jù)病變情況決定是否應(yīng)用抽吸導(dǎo)管抽吸血栓。病變?cè)试S,直接置入支架或者球囊擴(kuò)張后再置入支架。
冠狀動(dòng)脈血流評(píng)估:冠心病的冠狀動(dòng)脈造影評(píng)價(jià)應(yīng)用QCA系統(tǒng)。采用心肌梗死溶栓治療臨床試驗(yàn)(TIMI)血流分級(jí)[11]、校正的TIMI計(jì)幀數(shù)(cTFC)[12]和心肌呈色分級(jí)(MBG)[13]評(píng)估冠狀動(dòng)脈血流。慢血流定義為TIMI血流分級(jí)≤2或TIMI3且MBG≤2。2名術(shù)者分別對(duì)造影結(jié)果進(jìn)行分析,如對(duì)結(jié)果分析不一致,則協(xié)商解決。56例患者中21例發(fā)生慢血流(慢血流組),另外35例為成功復(fù)流(復(fù)流組)。
血漿IL-6測定方法:測定IL-6的血樣均采集于患者動(dòng)脈系統(tǒng),每次取樣時(shí)前3 ml血樣棄去。PCI術(shù)前動(dòng)脈鞘管采血,術(shù)中應(yīng)用6F Diver CE抽吸導(dǎo)管在導(dǎo)絲支持下于狹窄病變的遠(yuǎn)端局部取樣。采用酶聯(lián)免疫吸附法(試劑盒Biosource,Camarillo,CA,USA)分別測定系統(tǒng)和局部IL-6水平。IL-6測定下限為0.35 pg/ml。采用高度敏感的免疫比濁法(DADE Behring,Milan,Italy)測定高敏C反應(yīng)蛋白(hs-CRP)水平。
統(tǒng)計(jì)學(xué)處理:所有數(shù)據(jù)均以SAS 8.1(SAS Institute Inc.,Cary,NC,USA)軟件包進(jìn)行統(tǒng)計(jì)學(xué)分析,兩組間計(jì)量資料比較采用t檢驗(yàn),計(jì)數(shù)資料采用Fisher exact檢驗(yàn)。Spearman檢驗(yàn)分析變量之間的相關(guān)性,多因素Logistic回歸分析局部IL-6水平與慢血流的發(fā)生是否獨(dú)立相關(guān)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
一般臨床資料:兩組患者一般臨床資料見表1。復(fù)流組與慢血流組在年齡、性別、冠心病危險(xiǎn)因素(如體重指數(shù)、吸煙、高血壓、冠心病家族史及高血脂)、CK-MB峰值水平,系統(tǒng)IL-6水平及服用藥物情況方面差異均無統(tǒng)計(jì)學(xué)意義。與復(fù)流組相比,慢血流組合并糖尿病的發(fā)生率明顯升高,兩組比較差異有統(tǒng)計(jì)學(xué)意義(P=0.044)。
冠狀動(dòng)脈造影資料:兩組患者冠狀動(dòng)脈造影的相關(guān)資料詳見表2。45例(80.4%)患者PCI術(shù)后冠狀動(dòng)脈血流達(dá)TIMI3級(jí),其中復(fù)流組35例,慢血流組10例,兩組比較差異有統(tǒng)計(jì)學(xué)意義(P<0.001)。33例(58.9%)患者M(jìn)BG 3級(jí),其中復(fù)流組32例,慢血流組1例,兩組比較差異有統(tǒng)計(jì)學(xué)意義(P<0.001)。與復(fù)流組相比,慢血流組血栓負(fù)荷評(píng)分較低(P=0.043),局部IL-6水平較高(P<0.001),病變長度較長(P=0.014),cTFC較高(P<0.001),差異有統(tǒng)計(jì)學(xué)意義。
表1 兩組患者一般臨床和流行病學(xué)資料比較(±s)
表1 兩組患者一般臨床和流行病學(xué)資料比較(±s)
注:1 mmHg=0.133 kPa
復(fù)流組 (n=35) 慢血流組 (n=21) P 值年齡 (歲) 61.9±10.1 65.8±10.3 0.155男性[例(%)]22(62.9) 12(57.1) 0.532體重指數(shù) (kg/m2) 24.6±2.1 25.1±2.2 0.368吸煙[例 (%)]19(54.3) 13(61.9) 0.577高血壓[例(%)]23( 65.7) 14( 66.7) 0.942糖尿病[例(%)]12(34.3) 13(61.9) 0.044心率 (次/分) 73.8±10.6 76.2±12.1 0.423收縮壓 (mmHg) 140.3±18.7 125.3±25.3 0.274舒張壓 (mmHg) 83.8±8.6 81.3±7.9 0.435白細(xì)胞計(jì)數(shù) (×109/L) 8.2±3.0 8.8±2.1 0.455肌酸激酶MB同工酶峰值 (ng/mL) 229.9±81.5 237.9±80.9 0.722空腹血糖 (mmol/L) 8.4±2.7 8.8±2.7 0.527尿酸 (mol/L) 276.5±65.4 284.6±59.7 0.467總膽固醇 (mmol/L) 5.41±1.23 5.49±1.16 0.818高密度脂蛋白膽固醇 (mmol/L) 1.19±0.23 1.13±0.24 0.352低密度脂蛋白膽固醇 (mmol/L) 3.06±0.82 3.24±0.79 0.443甘油三酯 (mmol/L) 1.41±0.68 1.53±0.71 0.291高敏C反應(yīng)蛋白 (mg/L) 73.9±11.9 77.2±15.6 0.350系統(tǒng)白細(xì)胞介素- 6 (pg/ml) 4.51±1.27 4.83±1.17 0.345阿司匹林[例(%)]34(97.1) 20(95.2) 0.710氯吡格雷[例 (%)]33( 94.3) 20(95.2) 0.878他汀類藥物[例 (%)]21(60.0) 10(47.6) 0.367血管緊張素轉(zhuǎn)化酶抑制劑[例 (%)]27(77.1) 15(71.4) 0.633鈣拮抗劑[例 (%)]32(91.4) 20(95.2) 0.592 β受體阻滯劑[例 (%)]27(77.1) 14(66.7) 0.391硝酸酯類藥物[例 (%)]31(88.6) 19(90.5) 0.824
表2 兩組患者介入手術(shù)一般資料比較(±s)
表2 兩組患者介入手術(shù)一般資料比較(±s)
注:“-”無 TIMI:心肌梗死溶栓治療臨床試驗(yàn) MBG: 心肌呈色分級(jí)IL- 6:白細(xì)胞介素-6
復(fù)流組 (n=35) 慢血流組 (n=21) P 值發(fā)病到球囊擴(kuò)張時(shí)間 (h) 5.30±1.73 6.71±1.45 0.074病變血管數(shù)目 (支) 2.29±0.86 2.19±0.98 0.705罪犯血管[ 例 (%) ]0.964前降支 14 (40.0) 9 (42.9) -回旋支 4 (11.4) 2 (9.5) -右冠狀動(dòng)脈 17 (48.6) 10 (47.6) -術(shù)前 TIMI 0血流[ 例 (%) ]35 (100) 21 (100) 1靶病變部位[ 例 (%) ]0.494近段 16 (45.7) 9 (42.9) -中段 17 (48.6) 12 (57.1) -遠(yuǎn)段 2 (5.7) 0 (0) -病變長度 (mm) 26.7±12.3 36.1±15.1 0.014血栓負(fù)荷評(píng)分≥4[ 例 (%) ]21 ( 60.0) 18 (85.7) 0.043抽吸導(dǎo)管的應(yīng)用[ 例 (%) ]34 (97.1) 17 (81.0) 1局部IL- 6 (pg/ml) 10.22±2.19 13.77±3.03 <0.001直接置入支架[ 例 (%) ]34 (97.1) 17 (81.0) 1支架數(shù)目 1.43±0.50 1.71±0.56 0.054術(shù)后TIMI 血流3級(jí)[ 例 (%) ]35 (100) 10 (47.6) <0.001校正的TIMI計(jì)幀數(shù)[幀數(shù)]26.62±4.71 48.59±6.95 <0.001 MBG 3 級(jí) [ 例 (%) ]32 (91.4) 1 (4.8) <0.001
慢血流的獨(dú)立預(yù)測因子:無論臨床或?qū)嶒?yàn)室變量之間均無明顯相關(guān)性。PCI術(shù)前局部IL-6水平與cTFC呈負(fù)相關(guān)性(R=0.477,P=0.0002)。對(duì)影響事件發(fā)生的變量包括年齡、糖尿病、收縮壓、甘油三酯、發(fā)病到球囊擴(kuò)張時(shí)間、病變長度、血栓負(fù)荷評(píng)分、局部IL-6水平進(jìn)行回歸分析(表3)。單因素分析結(jié)果提示糖尿病、發(fā)病到球囊擴(kuò)張時(shí)間、病變長度、血栓負(fù)荷評(píng)分、局部IL-6是慢血流發(fā)生的危險(xiǎn)因素(P<0.05)。多因素Logistic回歸分析表明糖尿?。∣R=0.124,95%CI:0.019~0.804,P=0.029)、 血 栓 負(fù) 荷 評(píng) 分 (OR=0.080,95%CI:0.007~0.909,P=0.042)、局部 IL-6 水平 (OR=0.623,95%CI:0.441~0.881,P=0.007)是慢血流發(fā)生的獨(dú)立危險(xiǎn)因素。
表3 慢血流的獨(dú)立預(yù)測因子
ROC曲線結(jié)果顯示局部IL-6水平(曲線下面積:0.824,OR:1.704,95% CI:1.274~2.281,P<0.001;理想閾值11.3 pg/ml)對(duì)慢血流發(fā)生具有較好的預(yù)測價(jià)值,敏感性為73%,特異性為71%。
本研究證實(shí)IL-6作為一種炎癥反應(yīng)標(biāo)志物,促進(jìn)了慢血流的發(fā)生,這為我們防治慢血流的發(fā)生提供了一個(gè)新的靶點(diǎn)。
IL-6是多效能因子,主要表現(xiàn)為促進(jìn)炎癥反應(yīng)的作用。IL-6的促炎作用在慢血流的發(fā)生中發(fā)揮了重要作用。我們發(fā)現(xiàn)慢血流組梗死相關(guān)動(dòng)脈病變局部IL-6水平顯著高于復(fù)流組,這與近期其他關(guān)于炎癥反應(yīng)與慢血流關(guān)系的研究報(bào)道相一致。與正常血流組相比,慢血流組炎癥標(biāo)志物包括CRP、IL-6、細(xì)胞間粘附分子-1、血管粘附因子-1、E-選擇素等表達(dá)水平明顯升高[14,15]。另外本研究發(fā)現(xiàn)與外周動(dòng)脈的系統(tǒng)IL-6水平相比,兩組病變局部IL-6水平均較高。在體實(shí)驗(yàn)研究證實(shí)易損斑塊可以合成并釋放IL-6[16,17],IL-6水平的高低反應(yīng)了斑塊內(nèi)炎癥反應(yīng)的強(qiáng)度。因此,我們推測動(dòng)脈粥樣硬化斑塊是局部IL-6的重要來源,局部IL-6可能通過促進(jìn)慢血流的發(fā)生而對(duì)STEMI患者產(chǎn)生不利影響。為了排除手術(shù)操作本身對(duì)IL-6水平的影響,本研究尚需免疫細(xì)胞化學(xué)證據(jù)進(jìn)一步證實(shí)IL-6的來源。
局部IL-6促進(jìn)慢血流發(fā)生的可能機(jī)制如下:①中性粒細(xì)胞浸潤與慢血流的發(fā)生密切相關(guān)[18],炎癥因子IL-6可以募集中性粒細(xì)胞促進(jìn)微血管阻塞[19,20]。②本研究發(fā)現(xiàn)糖尿病患者IL-6水平顯著高于非糖尿病患者。有研究報(bào)道表明炎癥標(biāo)志物在糖尿病患者高血糖狀態(tài)時(shí)明顯升高,降紙患者對(duì)氯吡格雷、阿司匹林的反應(yīng)性[21],而且慢性炎癥還能夠降低阿司匹林的抗血小板聚集作用[22]。由此,我們推測較高水平的IL-6可能通過增強(qiáng)STEMI患者血小板反應(yīng)性,降低抗血小板藥物的作用而促進(jìn)慢血流的發(fā)生。
多種因素參與慢血流的發(fā)生,因此任何單一藥物的治療效果可能不佳。但是,本研究證實(shí)病變局部高水平的IL-6與慢血流的發(fā)生密切相關(guān),為選擇性抗炎治療從而減少慢血流的發(fā)生提供了一個(gè)新的治療思路。
本研究表明以局部IL-6水平升高為代表的炎癥反應(yīng)與STEMI患者PCI術(shù)后慢血流的發(fā)生密切相關(guān)。
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Association Between Local Interleukin-6 Levels and Slow Flow in Patients With Acute Myocardial Infarction Undergone PCI
DONG Mei, REN Fa-xin, MU Nan, ZHANG Chuan-huan, LI Jian-ping, TAO Zhi-gang, YANG Jun.
Department of Cardiology, Yuhuangding Hospital, Yantai (264000), Shandong, China
YANG Jun, Email: yangjqh@126.com
Objective: We aimed to investigate the association between local interleukin-6 (IL-6) levels at the infarct-related artery and the risk of slow fl ow after PCI in ST segment elevation myocardial infarction (STEMI) patients treated by successful primary PCI.
Methods: 56 eligible STEMI patients (34 male/22 female, mean age: 63.5±10.3 years), undergoing successfully primary PCI, were included in the current study. Blood samples were obtained from the extraction catheter placed distal to the lesion before PCI. Plasma IL-6 levels were determined by immunoassay method.
Results: Slow flow was observed in 21 patients (37.5%). Using multiple logistic regression analysis, local IL-6 levels (OR=0.623, 95%CI 0.441-0.881, P=0.007) were found to be a signif i cant risk factor of slow fl ow together with diabetes mellitus (OR=0.124, 95%CI 0.019-0.804, P=0.029) and thrombus score (OR=0.080, 95%CI 0.007-0.909,P=0.042). Receiver operating characteristic (ROC) curve analysis revealed that local IL-6 (ROC area 0.824, OR=1.704,95%CI 1.274-2.281, P=0.001 and optimal threshold≥11.3 pg/ml) had a predictive value of slow fl ow with sensitivity of 73% and specif i city of 71%.
Conclusion: Our study indicated that inf l ammatory response as presented by local IL-6 levels was associated with slow fl ow in patients with STEMI after successfully primary PCI.
Interleukin-6; Slow fl ow; Inf l ammation reaction; Acute myocardial infarction
煙臺(tái)市科技發(fā)展計(jì)劃(批準(zhǔn)編號(hào):2013WS221)
264000 山東省煙臺(tái)市,煙臺(tái)毓璜頂醫(yī)院 心內(nèi)科 (董梅、任法新、張傳煥、李建平、陶志剛、楊軍),婦科 (牟楠)
董梅 主治醫(yī)師 博士 主要從事心肌缺血再灌注損傷及心肌微循環(huán)研究 Email:dongmei0212@126.com 通訊作者:楊軍Email:yangjqh@126.com.
R54
A
1000-3614( 2014 ) 03-0185-04
10.3969/ j. issn. 1000-3614. 2014.03.007
2013-11-13)
(編輯:汪碧蓉)