譚文鵬 李文杰 何曉青
[摘要] 目的 觀察并探討替格瑞洛治療非ST段抬高型急性冠脈綜合征(NSTE-ACS)患者,血清內(nèi)皮細(xì)胞微粒(EMPs)和可溶性細(xì)胞間黏附分子-1(sICAM-1)的水平變化及預(yù)后。 方法 選取2019年1—6月廣州醫(yī)科大學(xué)附屬第三醫(yī)院收治的NSTE-ACS患者146例,根據(jù)隨機(jī)數(shù)字表法分為兩組,每組73例,氯吡格雷組給予氯吡格雷治療,替格瑞洛組給予替格瑞洛治療。觀察兩組經(jīng)皮冠狀動(dòng)脈介入術(shù)(PCI)前、術(shù)后24 h、術(shù)后7 d和術(shù)后30 d的EMPs和sICAM-1的水平變化。隨訪比較兩組術(shù)后6個(gè)月主要不良心臟事件(MACE)和不良反應(yīng)的差異。 結(jié)果 兩組患者EMPs和sICAM-1水平在術(shù)后24 h較PCI前均明顯上升,在術(shù)后7 d較術(shù)后24 h均顯著下降,在術(shù)后30 d較術(shù)后7 d均顯著下降,差異有統(tǒng)計(jì)學(xué)意義(P < 0.05)。替格瑞洛組EMPs和sICAM-1水平在術(shù)后7 d均低于氯吡格雷組、在術(shù)后30 d均低于氯吡格雷組,差異有統(tǒng)計(jì)學(xué)意義(P < 0.05)。與氯吡格雷組比較,替格瑞洛組總體MACE事件降低,差異有統(tǒng)計(jì)學(xué)意義(P < 0.05);兩組出血事件發(fā)生率比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P > 0.05)。 結(jié)論 替格瑞洛治療NSTE-ACS患者,能夠更加迅速改善血管內(nèi)皮功能并降低炎癥反應(yīng),從而穩(wěn)定動(dòng)脈粥樣硬化斑塊,不增加出血風(fēng)險(xiǎn)。
[關(guān)鍵詞] 替格瑞洛;非ST段抬高型急性冠脈綜合征;內(nèi)皮細(xì)胞微粒;可溶性細(xì)胞間黏附分子-1
[中圖分類號(hào)] R54? ? ? ? ? [文獻(xiàn)標(biāo)識(shí)碼] A? ? ? ? ? [文章編號(hào)] 1673-7210(2020)10(c)-0142-04
Effects of Ticagrelor on EMPs and sICAM-1 in patients with acute coronary syndrome and its prognosis
TAN Wenpeng? ?LI Wenjie? ?HE Xiaoqing
Department of Cardiology, the Third Affiliated Hospital of Guangzhou Medical University, Guangdong Province, Guangzhou? ?510150, China
[Abstract] Objective To observe the changes of serum endothelial microparticles (EMPs) and soluble intercellular adhesion molecule-1 (sICAM-1) levels and prognosis of Ticagrelor in treatment of patients with Non-ST-Elevation acute coronary syndrome (NSTE-ACS). Methods A total of 146 patients with NSTE-ACS admitted to the Third Affiliated Hospital of Guangzhou Medical University from January to June 2019, according to the random number table method, patients were divided into two groups, with 73 patients in each group. Clopidogrel group was treated with Clopidogrel, Ticagrelor group was treated with Ticagrelor. The levels of EMPs and sICAM-1 in the two groups were observed before percutaneous coronary intervention (PCI) as well as 24 h, 7 d and 30 d after PCI. The major adverse cardiac events (MACE) and adverse reactions were compared between the two groups within six months after PCI. Results The levels of EMPs and sICAM-1 of the two groups increased significantly at 24 h after PCI, decreased significantly at seven days after PCI compared with 24 h after PCI, and decreased significantly at 30 d after PCI compared with seven days after PCI, the differences were statistically significant (P < 0.05). The levels of EMPs and sICAM-1 in Ticagrelor group were lower than those in Clopidogrel group seven days after PCI, and were lower than those in Clopidogrel group 30 d after PCI, and the differences were statistically significant (P < 0.05). The total MACE events in Ticagrelor group were lower than that in Clopidogrel group, the differences were statistically significant (P < 0.05), and there was no statistical difference in the incidence of bleeding events between the two groups (P > 0.05). Conclusion Ticagrelor can improve endothelial function and reduce inflammatory reaction more rapidly in the treatment of NSTE-ACS patients, andstabilize atherosclerotic plaques, protect myocardium and does not increase bleeding risk.
[Key words] Ticagrelor; Non-ST-Elevation acute coronary syndrome; Endothelial microparticles; Soluble intercellular adhesion molecule-1
急性冠脈綜合征(acute coronary syndrome,ACS)是指冠狀動(dòng)脈的不穩(wěn)定斑塊破裂、血栓形成導(dǎo)致心肌缺血或梗死[1]。經(jīng)皮冠狀動(dòng)脈介入術(shù)(percutaneous coronary intervention,PCI)是治療ACS的主要手段之一[2]。PCI圍術(shù)期的抗血小板治療是決定臨床治療效果的重要因素。PCI圍術(shù)期必須使用兩聯(lián)抗血小板藥物:阿司匹林和P2Y12受體拮抗劑[3]。氯吡格雷是傳統(tǒng)的P2Y12受體拮抗劑已應(yīng)用多年,而近年來(lái)替格瑞洛作為新型的P2Y12受體拮抗劑,應(yīng)用逐漸廣泛,但是臨床療效仍有一定爭(zhēng)議,長(zhǎng)期安全性有待進(jìn)一步考察[4-5]。替格瑞在抗血小板作用以外,還具有保護(hù)內(nèi)皮功能、拮抗炎癥反應(yīng)、改善冠脈微循環(huán)等作用[6]。血清內(nèi)皮細(xì)胞微粒(endothelial microparticles,EMPs)是評(píng)價(jià)內(nèi)皮功能狀態(tài)的有效指標(biāo),可溶性細(xì)胞間黏附分子-1(soluble intercellular adhesion molecule-1,sICAM-1)可用于反映內(nèi)皮損傷和炎癥反應(yīng)程度[7]。本研究觀察替格瑞洛治療非ST段抬高型急性冠脈綜合征(non-ST-elevation ACS,NSTE-ACS)患者過(guò)程中,血清EMPs和sICAM-1的水平變化,及其對(duì)預(yù)后的影響。
1 資料與方法
1.1 一般資料
選取2019年1—6月廣州醫(yī)科大學(xué)附屬第三醫(yī)院收治的NSTE-ACS患者146例,所有病例均符合中華醫(yī)學(xué)會(huì)心血管病學(xué)分會(huì)非ST段抬高型急性冠狀動(dòng)脈綜合征診斷標(biāo)準(zhǔn)[8]。NSTE-ACS的診斷符合以下條件:缺血性胸痛;心電圖ST段下移或者T波改變。排除標(biāo)準(zhǔn):合并嚴(yán)重感染、血液病、風(fēng)濕結(jié)締組織疾病或腫瘤;嚴(yán)重肝腎功能不全;既往有心肌梗死病史或有PCI史;射血分?jǐn)?shù)(EF)<30%;有嚴(yán)重替格瑞洛不良反應(yīng)及氯吡格雷抵抗者;存在抗凝、抗血小板禁忌;其他嚴(yán)重的疾病預(yù)期生存期不確定的。所有患者按照隨機(jī)數(shù)字表法分為兩組,替格瑞洛組73例和氯吡格雷組73例。本研究符合醫(yī)院醫(yī)學(xué)倫理學(xué)相關(guān)要求,所有患者對(duì)治療方案均知情同意,自愿參與本研究,并簽訂知情同意書(shū)。
1.2 方法
所有患者在入院48 h內(nèi)經(jīng)橈動(dòng)脈行冠脈造影檢查和PCI術(shù)。替格瑞洛組給予替格瑞洛(商品名:倍林達(dá);生產(chǎn)廠家:阿斯利康制藥有限公司;批準(zhǔn)文號(hào):國(guó)藥準(zhǔn)字J20181077;產(chǎn)品批號(hào):YAAZ)術(shù)前負(fù)荷劑量180 mg,術(shù)后維持劑量每次90 mg,2次/d;氯吡格雷組給予氯吡格雷[商品名:波立維;生產(chǎn)廠家:賽諾菲(杭州)制藥有限公司;批準(zhǔn)文號(hào):國(guó)藥準(zhǔn)字J20181129;產(chǎn)品批號(hào):8A787]術(shù)前負(fù)荷劑量300 mg,術(shù)后維持劑量每次75 mg,1次/d。均予阿司匹林、他汀、血管緊張素轉(zhuǎn)換酶抑制劑/血管緊張素Ⅱ受體阻劑、β受體阻滯劑或CCB類藥物等常規(guī)治療。
1.3 EMPs和sICAM-1測(cè)定
于PCI術(shù)前、術(shù)后24 h、術(shù)后7 d、術(shù)后30 d晨起采取空腹肘靜脈血5 mL。3000 r/min離心,離心半徑15 cm,10 min后取血清,-80℃低溫冰箱保存。采用酶聯(lián)免疫吸附法檢測(cè)EMPs和sICAM-1血清表達(dá)水平,試劑盒由上海酶聯(lián)生物科技有限公司提供(產(chǎn)品批號(hào):20181006),操作步驟嚴(yán)格按照試劑盒說(shuō)明書(shū)。
1.4 主要終點(diǎn)觀察
對(duì)兩組患者進(jìn)行6個(gè)月跟蹤隨訪觀察。①主要不良心臟事件(MACE):包括心源性死亡、急性心肌梗死、靶血管再次血運(yùn)重建、支架內(nèi)血栓形成、及腦卒中;②藥物不良反應(yīng):出血事件。
1.5 統(tǒng)計(jì)學(xué)方法
采用SPSS 22.0統(tǒng)計(jì)軟件對(duì)數(shù)據(jù)進(jìn)行分析。計(jì)量資料采用均數(shù)±標(biāo)準(zhǔn)差(x±s)表示,組間比較采用t檢驗(yàn)和重復(fù)測(cè)量方差分析,計(jì)數(shù)資料采用例數(shù)和百分率表示,組間比較采用χ2檢驗(yàn)。以P < 0.05為差異有統(tǒng)計(jì)學(xué)意義。
2 結(jié)果
2.1 兩組一般臨床資料比較
兩組在年齡、性別、體重指數(shù)、心血管危險(xiǎn)因素、PCI前及后TIMI血流3級(jí)比例方面比較,差異均無(wú)統(tǒng)計(jì)學(xué)意義(均P > 0.05)。見(jiàn)表1。
2.2 兩組EMPs和sICAM-1水平比較
整體分析:兩組EMPs、sICAM-1組間、時(shí)間點(diǎn)比較差異有統(tǒng)計(jì)學(xué)意義(P > 0.05),EMPs交互作用差異有統(tǒng)計(jì)學(xué)意義(P < 0.05)。兩組EMPs和sICAM-1水平在PCI術(shù)前、術(shù)后24 h比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P > 0.05)。兩組EMPs和sICAM-1水平在術(shù)后24 h較PCI前均明顯上升,在術(shù)后7 d較術(shù)后24 h均顯著下降,在術(shù)后30 d較術(shù)后7d均顯著下降,差異有統(tǒng)計(jì)學(xué)意義(P < 0.05)。替格瑞洛組EMPs和sICAM-1水平在術(shù)后7 d均低于氯吡格雷組、在術(shù)后30 d均低于氯吡格雷組,差異有統(tǒng)計(jì)學(xué)意義(P < 0.05)。見(jiàn)表2。
2.3 兩組主要終點(diǎn)事件比較
氯吡格雷組有8例MACE事件,其中2例急性心肌梗死、2例支架內(nèi)血栓、2例腦卒中、2例心源性死亡;替格瑞洛組有1例急性心肌梗死、無(wú)其他事件。兩組總體MACE事件發(fā)生人數(shù)比較,差異有統(tǒng)計(jì)學(xué)意義(χ2 = 4.263,P = 0.039)。氯吡格雷組有8例輕微出血,替格瑞洛組有5例輕微出血,兩組均無(wú)大出血事件,出血事件發(fā)生人數(shù)比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2 = 0.760,P = 0.383)。
3 討論
介入手術(shù)是治療ACS的重要手段,術(shù)后必須使用足夠療程的抗血小板藥物。氯吡格雷是臨床常用的傳統(tǒng)抗血小板藥物,顯著改善ACS患者的臨床療效和預(yù)后。近年來(lái)出現(xiàn)的新型抗血小板藥物替格瑞洛,在國(guó)內(nèi)外指南中,被優(yōu)先推薦用于NSTE-ACS的治療[8]。研究證實(shí),與氯吡格雷比較,替格瑞洛能顯著改善ACS患者心血管事件復(fù)合終點(diǎn)[4-5,9]。但是替格瑞洛的臨床療效仍有一定爭(zhēng)議,強(qiáng)效的抗血小板作用也帶來(lái)出血風(fēng)險(xiǎn)升高。本研究觀察ACS患者在PCI后隨訪6個(gè)月,替格瑞洛組患者M(jìn)ACE事件較氯吡格雷組明顯減少,但是兩組的出血事件差異無(wú)統(tǒng)計(jì)學(xué)意義,提示替格瑞洛治療可以使NSTE-ACS患者有更好的獲益,并且無(wú)明顯增加出血風(fēng)險(xiǎn),安全性良好。但本研究樣本量不多,為單中心研究,有待于進(jìn)一步增加樣本量的多中心研究繼續(xù)觀察。
替格瑞洛除了抗血小板作用起效快、作用強(qiáng)以外,還可以提高腺苷水平,產(chǎn)生臨床多效性[6]。腺苷具有改善內(nèi)皮功能、拮抗炎癥因子、清除氧自由基、擴(kuò)張冠狀動(dòng)脈、改善冠脈微循環(huán)等作用。EMPs是內(nèi)皮細(xì)胞在激活或凋亡時(shí)脫落到外周血的小囊泡狀物質(zhì),作為內(nèi)皮細(xì)胞的產(chǎn)物,能夠準(zhǔn)確反映出內(nèi)皮細(xì)胞的功能。對(duì)于各種內(nèi)皮細(xì)胞功能異常的疾病,如冠心病、糖尿病、心力衰竭等患者,血漿EMPs水平會(huì)明顯升高[10-12]。研究發(fā)現(xiàn),EMPs反映冠脈斑塊炎性程度和內(nèi)皮功能,促進(jìn)斑塊形成和斑塊的不穩(wěn)定,還可以通過(guò)促進(jìn)血小板的聚集導(dǎo)致血栓形成,是心血管風(fēng)險(xiǎn)的獨(dú)立預(yù)測(cè)因子[13]。介入手術(shù)中的缺血再灌注也可以誘導(dǎo)內(nèi)皮細(xì)胞釋放內(nèi)皮微粒,并通過(guò)促進(jìn)細(xì)胞凋亡和氧化應(yīng)激的作用損害心肌[14-15]。EMPs可能成為冠心病新的標(biāo)志物和治療靶點(diǎn)[16]。ICAM-1是免疫蛋白超家族黏附分子之一,在炎癥因子刺激后的內(nèi)皮細(xì)胞、單核細(xì)胞、淋巴細(xì)胞表面高度表達(dá),反映炎癥反應(yīng)的水平[17]。sICAM-1是細(xì)胞表面脫落下來(lái)的ICAM-1的細(xì)胞外成分,sICAM-1的水平可以用來(lái)反映ICAM-1的表達(dá)程度。ICAM-1參與炎癥細(xì)胞與內(nèi)皮細(xì)胞黏附,促使巨噬細(xì)胞吞噬氧化脂質(zhì)后轉(zhuǎn)化為泡沫細(xì)胞,在動(dòng)脈粥樣硬化形成中起重要作用[18]。ACS患者ICAM-1水平明顯高于穩(wěn)定性心絞痛患者,能反映動(dòng)脈粥樣硬化斑塊的不穩(wěn)定性[19]。心肌梗死后sICAM-1水平升高,與炎癥反應(yīng)密切相關(guān),可用于預(yù)測(cè)血管成形術(shù)后冠狀動(dòng)脈再狹窄和心肌梗死后心力衰竭的危險(xiǎn)性[20-21]。本研究顯示,在PCI治療后7 d、30 d替格瑞洛組EMPs和ICAM-1水平均明顯低于氯吡格雷組。提示替格瑞洛對(duì)改善NSTE-ACS患者內(nèi)皮功能和炎癥反應(yīng)的效果優(yōu)于氯吡格雷。其主要作用機(jī)制可能與提高腺苷水平有關(guān)。
綜上所述,替格瑞洛在NSTE-ACS患者治療中能夠更好地改善血管內(nèi)皮功能并降低炎癥反應(yīng),從而穩(wěn)定動(dòng)脈粥樣硬化斑塊、減少心血管事件,不增加出血風(fēng)險(xiǎn)。
[參考文獻(xiàn)]
[1]? Hedayati T,Yadav N,Khanagavi J. Non-ST-Segment Acute Coronary Syndromes [J]. Cardiol Clin,2018,36(1):37-52.
[2]? Morici N,Savonitto S,F(xiàn)erri LA,et al. Outcomes of Elderly Patients with ST-Elevation or Non-ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention [J]. Am J Med,2019,132(2):209-216.
[3]? Gorog DA,Geisler T. Platelet Inhibition in Acute Coronary Syndrome and Percutaneous Coronary Intervention:Insights from the Past and Present [J]. Thromb Haemost,2020.
[4]? Brener SJ,Alapati V,Benson MM,et al. Ticagrelor vs Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention:Insights From a Single Institution Registry [J]. J Invasive Cardiol,2019,31(8):235-238.
[5]? Guan W,Lu H,Yang K. Choosing between ticagrelor and clopidogrel following percutaneous coronary intervention:A systematic review and Meta-Analysis (2007-2017)[J]. Medicine (Baltimore),2018,97(43):e12978.
[6]? Ow KW,Wae P,Porter MM,et al. Offset of ticagrelor prior to coronary artery bypass graft surgery for acute coronary syndromes:effects on platelet function and cellular adenosine uptake [J]. Platelets,2020:1-7.
[7]? Gunay M,Mertoglu C. Increase of endocan,a new marker for inflammation and endothelial dysfunction,in acute kidney injury [J]. North Clin Istanb,2019,6(2):124-128.
[8]? 中華醫(yī)學(xué)會(huì)心血管病學(xué)分會(huì),中華心血管病雜志編輯委員會(huì).非ST段抬高型急性冠狀動(dòng)脈綜合征診斷和治療指南(2016)[J].中華心血管病雜志,2017,45(5):359-376.
[9]? Wang D,Yang XH,Zhang JD,et al. Compared efficacy of clopidogrel and ticagrelor in treating acute coronary syndrome:a meta-analysis [J]. BMC Cardiovasc Disord,2018,18(1):217.
[10]? Tun?觭ez A,Altunkeser BB,?魻ztürk B,et al. Comparative effects of atorvastatin 80 mg and rosuvastatin 40 mg on the levels of serum endocan,chemerin,and galectin-3 in patients with acute myocardial infarction [J]. Anatol J Cardiol,2019,22(5):240-249.
[11]? Benameur T,Osman A,Parray A,et al. Molecular Mechanisms Underpinning Microparticle-Mediated Cellular Injury in Cardiovascular Complications Associated with Diabetes [J]. Oxid Med Cell Longev,2019,2019:6475187.
[12]? Kosir G,Jug B,Novakovic M,et al. Endocan Is an Independent Predictor of Heart Failure-Related Mortality and Hospitalizations in Patients with Chronic Stable Heart Failure [J]. Dis Markers,2019,2019:9134096.
[13]? Zarà M,Guidetti GF,Camera M,et al. Biology and Role of Extracellular Vesicles (EVs) in the Pathogenesis of Thrombosis [J]. Int J Mol Sci,2019,20(11):2840.
[14]? Zhang Q,Shang M,Zhang M,et al. Microvesicles derived from hypoxia/reoxygenation-treated human umbilical vein endothelial cells promote apoptosis and oxidative stress in H9c2 cardiomyocytes [J]. BMC Cell Biol,2016,17(1):25.
[15]? Gan L,Xie D,Liu J,et al. Small Extracellular Microvesicles Mediated Pathological Communications between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanisms Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice [J]. Circulation,2020,141(12):968-983.
[16]? Wang B,Li T,Han X,et al. The Level of Circulating Microparticles in Patients with Coronary Heart Disease:a Systematic Review and Meta-Analysis [J]. J Cardiovasc Transl Res,2020,13(5):702-712.
[17]? Anbarasan C,Bavanilatha M,Latchumanadhas K,et al. ICAM-1 molecular mechanism and genome wide SNP's association studies [J]. Indian Heart J,2015,67(3):282-287.
[18]? Tishko VV,Sokolov AA,Belskih AN,et al. Impact of double filtration plasmapheresis on adhesion molecules levels in patients with stable coronary heart disease after coronary stenting [J]. Atheroscler Suppl,2017,30:92-98.
[19]? Ma CY,Xu ZY,Wang SP,et al. Change of Inflammatory Factors in Patients with Acute Coronary Syndrome [J]. Chin Med J(Engl),2018,131(12):1444-1449.
[20]? Hu P,Dai T,Yu W,et al. Intercellular adhesion molecule 1 rs5498 polymorphism is associated with the risk of myocardial infarction [J]. Oncotarget,2017,8(32):52594-52603.
[21]? Doc L,F(xiàn)reitas IA,Meneses GC,et al. Interleukin-6 and adhesion molecules VCAM-1 and ICAM-1 as biomarkers of post-acute myocardial infarction heart failure [J]. Braz J Med Biol Res,2019,52(12):e8658.
(收稿日期:2020-03-11)
[基金項(xiàng)目] 廣東省醫(yī)學(xué)科研基金立項(xiàng)項(xiàng)目(B2019066)。
[作者簡(jiǎn)介] 譚文鵬(1983-),男,博士,廣州醫(yī)科大學(xué)附屬第三醫(yī)院心血管內(nèi)科副主任醫(yī)師;研究方向:冠心病及心力衰竭。