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1、介入治疗对急性冠脉综合征患者炎症反应及血小板活性的影响    摘要 目的:观察急性冠脉综合征患者冠脉介入治疗术前、术后炎症介质IL-6、hsCRP水平及血小板活性指标CD62p、CD63的改变。方法:58例急性冠脉综合征患者在冠脉介入术前30 min,术后2、24、72、96 h分别检测炎症介质IL-6、hs-CRP和血小板功能活性指标CD62p、CD63水平。hs-CRP测定采用乳胶增强免疫散射比浊法,IL-6测定采用双抗体夹心酶联免疫吸附法(ELISA),流式细胞仪测定CD62p、CD63水平。选择53例冠状动脉造影结果正常者作对照,观察冠脉介入前后

2、指标的变化并与对照组比较。结果:与对照组比,急性冠脉综合征组IL-6、hs-CRP、CD62p、CD63明显增高(P<0.05);急性冠脉综合征患者介入术后2、24、72 h IL-6、hs-CRP、CD62p、CD63水平与术前相比明显增高(P<0.05),在术后24 h达峰值,术后72 h降低,术后96 h恢复到术前水平(P>0.05)。结论:血小板活化和炎症反应在急性冠脉综合征发生和发展过程中起重要作用,冠脉介入治疗激活急性冠脉综合征患者血小板活性因子及炎症反应因子。 关键词 急性冠状动脉综合征; 冠脉介入治疗; 炎症反应; 血小板活化 Effect of percut

3、aneous coronary intervention on inflammatory reactions and platelet activation in patients with acute coronary syndrome Abstract Objective: To observe the changes of serum level of inflammatory mediators IL-6, hsCRP and platelet activity index CD62p, CD63 before and after percutaneous coronary inter

4、vention(PCI) in patients with acute coronary syndrome(ACS). Methods: The blood was collected respectively at 30 min before PCI and 2, 24, 72, 96 h after PCI in 58 patients with ACS and control group. The serum levels of the CD62p, CD63 were assayed by flow cytometry, the hs-CRP was measured by immun

5、e scatter turbidimetry and IL-6 was analyzed by enzyme linked immunosorbent assay(ELISA). Results: The IL-6, hs-CRP, CD62p, CD63 levels in the patients with ACS increased significantly compared with control group(P<0.05), and those indices at 2, 24 and 72 h group increased significantly compared

6、with pre-PCI group(P<0.05). Those indices peaked at 24 h after PCI, declined at 72 h after PCI, and recovered to pre-PCI level at 96 h(P>0.05). Conclusion: Platelet activation and inflammatory reactions play an important role in the occurrence and development of ACS. PCI may activate platelet

7、activation and inflammatory reactions factors in patients with ACS. Key words acute coronary syndrome; percutaneous coronary intervention; inflammatory reactions; platelet activation 急性冠脉综合征(acute coronary syndrome, ACS)主要病理改变是冠状动脉粥样硬化斑块的破裂,诱发血栓形成。经皮冠状动脉介入治疗(percutaneous coronary intervention, PCI)包

8、括经皮腔内冠状动脉成形术和经皮冠状动脉支架置入术,是ACS重建冠状动脉血运的有效方法。PCI可诱导和加重冠状动脉局部炎症反应1,对血管内皮的增生与再狭窄(restenosis, RS)起着重要作用,同时引起斑块破裂与内皮损伤,易引起急性血栓形成2。本研究通过检测ACS患者行冠脉介入术前、术后的炎症介质如白细胞介素-6(interleukin-6,IL-6)、血清高敏C反应蛋白(hypersensitive C reactive protein, hs-CRP)和血小板功能活化指标CD62p、CD63水平,探讨冠脉介入治疗与炎症反应、血小板活化的关系。 1 对象与方法 1.1 研究对象 选择我院

9、心内科2006年2月2008年9月收治的ACS患者58例,ACS诊断标准按美国心脏病学会(ACC)及美国心脏病协会(AHA)制定的标准3。ACS患者中男35例,女23例,平均年龄(67.9±5.3)岁,包括急性心肌梗死21例,不稳定型心绞痛37例。以上病例均排除心肌炎,心肌病,感染性心内膜炎,风湿性心脏病,结缔组织病,严重肝肾功能不全,近期服用糖皮质激素,近期有急、慢性感染和手术、外伤史者。全部患者经冠状动脉造影显示至少1支冠脉管径狭窄70%,且均行冠脉介入治疗。ACS患者冠状动脉造影共检出106支病变血管,其中单支病变25例,双支病变20例,多支病变13例。选择对照组53例,均为因

10、临床有心绞痛类似症状而进行冠状动脉造影检查结果正常者,其中男32例,女21例,年龄(62.6±4.9)岁,与ACS组相比在性别、年龄构成上差异无显著性。 1.2 研究方法 所有ACS患者冠脉介入治疗术前常规给予硝酸酯类药物、 -受体阻滞剂、钙通道阻滞剂、血管紧张素转换酶抑制剂类药物进行抗心绞痛治疗,均成功行PCI术,术后残余狭窄<10%,造影TIMI血流达级,同时术前服用300 mg拜阿司匹林及300 mg氯吡格雷,术后所有患者皮下注射低分子肝素5 000 U,2 次d-1,共5 d,继续每日服用拜阿司匹林300 mg,氯吡格雷75 mg。对照组于冠状动脉造影术前均服用300

11、mg拜阿司匹林及300 mg氯吡格雷。对照组于术前30 min以及ACS组于术前30 min,术后2、24、72、96 h分别检测炎症介质IL-6、hs-CRP和血小板功能活化指标CD62p、CD63水平。 1.3 观察指标检测 1.4 统计学处理 采用SPSS 13.0统计软件包对数据进行处理,计量资料用±s表示,两组之间比较采用t检验,3组以上比较采用方差分析,P<0.05为差异有统计学意义。 2 结果 2.1 ACS患者治疗结果 ACS患者均冠脉介入治疗成功,术后临床症状缓解,未见并发症。 2.2 炎症反应介质和血小板活化指标测定结果 ACS组患者IL-6、hsCRP、C

12、D62p、CD63水平术前明显高于对照组(均P<0.05),术后2、24 h明显高于术前,在术后24 h达峰值,术后72 h降低但仍高于术前,有显著性差异(P<0.05);术后96 h恢复到术前水平,无显著性差异(P>0.05)。见表1。 3 讨论 动脉粥样硬化斑块不稳定并继发血栓形成是ACS的主要病理学基础4,炎症在不稳定斑块的发生、演变及破裂过程中起着至关重要的作用,炎症介质CRP在炎症和组织损伤后明显升高,急性反应中CRP明显升高,是反映机体炎症反应的敏感指标;IL-6是血管壁和平滑肌细胞产生的前炎症介质,是冠状动脉粥样硬化斑块炎症反应的标记。研究显示hs-CRP已被认

13、为是急性冠脉事件发生的强有力的、独立的预测指标5。Ziakas等6研究表明,在预测UAP和非ST段抬高型心肌梗死患者未来心血管病死亡危险中,CRP和IL-6独立于其他临床因子。Gallagher等7发现,不稳定型冠心病血液IL-6水平是增加病死率的独立预测指标。同时,粥样斑块病变部位血栓的形成是导致ACS发生的直接原因,血栓的形成与血小板激活有关,血小板活化的最主要表现是黏附和聚集,在这个过程中,血小板膜表面的黏附分子起着关键作用。CD62p、CD63是血小板黏附、聚集和释放功能的分子基础,当血小板与内皮下组织接触后,在黏附开始阶段是血流中血小板停滞,在黏附过程中,最早起作用的是作为血小板外层

14、表面上的重要成分膜糖蛋白,这些变化是血小板聚集性增高的早期指征和结构基础。近来研究认为,CD62p、CD63为活化血小板膜糖蛋白,是反映血小板活化的特征性标记物8-9。CD62p是目前最具有特征性的血小板活化分子标记物,CD63被认为是一种较CD62p更为敏感的血小板活化标记物,因此检测这些指标可了解血小板活化程度。 本研究观察到ACS患者术前循环血中IL-6、hs-CRP、CD62p、CD63水平显著高于对照组,表明ACS患者粥样斑块不稳定,炎症介质水平和血小板活化程度明显增高,提示炎症、血小板活化参与ACS的病理过程。 目前PCI已广泛应用于临床,但手术后血管闭塞和RS两个主要问题会影响其

15、疗效10。冠脉介入治疗造成动脉内皮的损伤和粥样斑块的破裂,两者都激活了血小板活化因子及炎症反应因子,增加了急性血栓形成的风险以及RS发生率11。血小板是经皮介入反应的关键性介质,介入致动脉内膜创伤、内皮下胶原和血小板黏附蛋白的暴露,触发血小板血栓形成来填封损伤的部位,这种血栓可扩展导致血管的阻塞12。Miyamoto等13对189例冠心病患者进行前瞻性队列研究,多元logistic回归分析显示,PCI术后RS的患者术前伴随着较高水平的血小板聚集物。本研究结果发现所有ACS患者CD62p、CD63表达水平PCI术后较手术前显著升高(P<0.05),术后24 h达高峰,术后72 h逐渐下调;

16、术后96 h恢复到术前水平(P>0.05),表明PCI对冠状动脉内皮的损伤更加强了血小板的活化,增加了血栓形成的风险。PCI术后的炎症机制的激活及血管内皮的增生对RS起着重要作用,而且RS与血管损伤后炎症反应程度相关。RS是局部血管损伤后的一种修复反应,血栓、炎症和平滑肌细胞增生迁移是RS的3个重要阶段。内皮损伤是RS的启动因素,可以促进局部血栓形成;内皮细胞损伤、血小板聚集、胶原暴露可以产生趋化因子和黏附分子,促进炎症的发生;炎症细胞、内皮细胞及血小板又可释放大量的细胞因子、生长因子促使血管平滑肌细胞增殖和迁移,直至RS发生。Jeong等14对272例冠心病并行PCI的患者进行前瞻性研

17、究发现,CRP水平是PCI术后RS重要的预测因素。PCI术中机械损伤、低氧及支架对血管壁的持续伸展均可诱导IL-6释放入血15;IL-6在体内促进血小板增多,血液黏度增加而促进凝血及血栓形成,IL-6还可强烈刺激平滑肌细胞自分泌血小板源生长因子(platelet-derived growth factor, PDGF)而促平滑肌细胞增生,因而推测IL-6在血栓、缺血并发症及RS中发挥重要作用。同样本研究结果显示IL-6、hs-CRP水平PCI术后较手术前显著升高,术后24 h达高峰,术后72 h逐渐下降(P<0.05),术后96 h恢复到术前水平(P>0.05),表明冠脉介入治疗激

18、活ACS患者血小板活化因子及炎症反应因子。由于本研究样本量有限,ACS患者冠脉介入治疗术前、术后炎症介质IL-6、hsCRP水平及血小板活化指标CD62p、CD63的改变尚有待大规模临床试验结果来进一步证实。 参考文献 1 WILSON S H, BERGER P B, MATHEW V, et a1.Immediate and late outcomes after direct stent implantation without balloon predilatationJ.J Am Co11 Cardiol, 2000,35(4):937-943. 2 JASTER M, SCHWIM

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20、atients with Unstable Angina and Non- St-Segment Eleration Myocardial Infarction. A report of American collage of cardiology/American heart association task force or practice guidelinesJ. JAM Coll Cardiol, 2000, 36(3): 970-1062. 4 LIBBY P, ROUX P.Pathophysiology of coronary artery diseaseJ. Circulat

21、ion, 2005,111(25):3481-3488. 5 LI J J, FANG C H.C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseaseJ. MedHypotheses, 2004,62(4):499-506. 6 ZIAKAS A, GAVRILIDIS S, GIANNOGLOU G, et a1.In-hospital and long-term prognostic value of fibrinogen, CRP, an

22、d IL-6 levels in patients with acute myocardial infarction treated with thrombolysisJ.Angiology, 2006,57(3):283-293. 7 GALLAGHER G, MENZIE S, HUANG Y, et a1.Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocar

23、dial infarction in sheepJ. Basic Res Cardiol, 2007,102(1):63-72. 8 BOOS C J, LIP G Y. Platelet activation and cardiovascular outcomes in acute syndromesJ. J Thromb Haemost, 2006,4(12):2542-2543. 9 YAZICI M, DEMIRCAN S, DURNA K, et al. Relationship between myocardial injury and P-selectin in non-ST e

24、levation acute coronary syndromesJ. Circ J, 2005,69(5):530-535. 10 CARLOS V, GIRALDEZ R R, FERNANDES J L, et al. Platelet and leukocyte adhesion and activation in unstable angina and post-PTCAJ.Inter J Cardiol, 2005,99(3):423-428. 11 SHEN Q S, HU Y S, ZHU R, et al. Efects of fluvastatin on blood lev

25、els of inflammatory cytokines in patients with unstable angina undergoing percutaneous coronary interventionJ. Chin J Cardi, 2005,33(4):320-322. 12 CHATURVEDI S, YADAV J S. The role of antiplatelet therapy in carotid stenting for ischemic stroke preventionJ. Stroke, 2006,37(6):1572-1577. 13 MIYAMOTO

26、 S, KAWANO H, KUDOH T, et a1. Usefulness of preprocedural platelet aggregation to predict restenosis after percutaneous coronary interventionJ.Am J Cardiol, 2005,96(1):71-73. 14 JEONG W K, JEONG M H, KIM K H, et a1.An elevated value of C reactive protein is the only predictive factor of restenosis a

27、fter percutaneous coronary interventionJ. Korean J Intern Med, 2003,18(3):154-160. 15 HOJO Y, IKEDA U, KATSUKI T, et al. Interleukin-6 expression in coronary circulation after coronary angioplasty as a risk factor for restenosisJ. Heart, 2000,84(1):83-876 ZIAKAS A, GAVRILIDIS S, GIANNOGLOU G, et a1.

28、In-hospital and long-term prognostic value of fibrinogen, CRP, and IL-6 levels in patients with acute myocardial infarction treated with thrombolysisJ.Angiology, 2006,57(3):283-293. 7 GALLAGHER G, MENZIE S, HUANG Y, et a1.Regional cardiac dysfunction is associated with specific alterations in inflam

29、matory cytokines and matrix metalloproteinases after acute myocardial infarction in sheepJ. Basic Res Cardiol, 2007,102(1):63-72. 8 BOOS C J, LIP G Y. Platelet activation and cardiovascular outcomes in acute syndromesJ. J Thromb Haemost, 2006,4(12):2542-2543. 9 YAZICI M, DEMIRCAN S, DURNA K, et al.

30、Relationship between myocardial injury and P-selectin in non-ST elevation acute coronary syndromesJ. Circ J, 2005,69(5):530-535. 10 CARLOS V, GIRALDEZ R R, FERNANDES J L, et al. Platelet and leukocyte adhesion and activation in unstable angina and post-PTCAJ.Inter J Cardiol, 2005,99(3):423-428. 11 S

31、HEN Q S, HU Y S, ZHU R, et al. Efects of fluvastatin on blood levels of inflammatory cytokines in patients with unstable angina undergoing percutaneous coronary interventionJ. Chin J Cardi, 2005,33(4):320-322. 12 CHATURVEDI S, YADAV J S. The role of antiplatelet therapy in carotid stenting for ische

32、mic stroke preventionJ. Stroke, 2006,37(6):1572-1577. 13 MIYAMOTO S, KAWANO H, KUDOH T, et a1. Usefulness of preprocedural platelet aggregation to predict restenosis after percutaneous coronary interventionJ.Am J Cardiol, 2005,96(1):71-73. 14 JEONG W K, JEONG M H, KIM K H, et a1.An elevated value of

33、 C reactive protein is the only predictive factor of restenosis after percutaneous coronary interventionJ. Korean J Intern Med, 2003,18(3):154-160. 15 HOJO Y, IKEDA U, KATSUKI T, et al. Interleukin-6 expression in coronary circulation after coronary angioplasty as a risk factor for restenosisJ. Hear

34、t, 2000,84(1):83-876 ZIAKAS A, GAVRILIDIS S, GIANNOGLOU G, et a1.In-hospital and long-term prognostic value of fibrinogen, CRP, and IL-6 levels in patients with acute myocardial infarction treated with thrombolysisJ.Angiology, 2006,57(3):283-293. 7 GALLAGHER G, MENZIE S, HUANG Y, et a1.Regional card

35、iac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheepJ. Basic Res Cardiol, 2007,102(1):63-72. 8 BOOS C J, LIP G Y. Platelet activation and cardiovascular outcomes in acute syndromesJ. J Thromb Haemos

36、t, 2006,4(12):2542-2543. 9 YAZICI M, DEMIRCAN S, DURNA K, et al. Relationship between myocardial injury and P-selectin in non-ST elevation acute coronary syndromesJ. Circ J, 2005,69(5):530-535. 10 CARLOS V, GIRALDEZ R R, FERNANDES J L, et al. Platelet and leukocyte adhesion and activation in unstabl

37、e angina and post-PTCAJ.Inter J Cardiol, 2005,99(3):423-428. 11 SHEN Q S, HU Y S, ZHU R, et al. Efects of fluvastatin on blood levels of inflammatory cytokines in patients with unstable angina undergoing percutaneous coronary interventionJ. Chin J Cardi, 2005,33(4):320-322. 12 CHATURVEDI S, YADAV J

38、S. The role of antiplatelet therapy in carotid stenting for ischemic stroke preventionJ. Stroke, 2006,37(6):1572-1577. 13 MIYAMOTO S, KAWANO H, KUDOH T, et a1. Usefulness of preprocedural platelet aggregation to predict restenosis after percutaneous coronary interventionJ.Am J Cardiol, 2005,96(1):71

39、-73. 14 JEONG W K, JEONG M H, KIM K H, et a1.An elevated value of C reactive protein is the only predictive factor of restenosis after percutaneous coronary interventionJ. Korean J Intern Med, 2003,18(3):154-160. 15 HOJO Y, IKEDA U, KATSUKI T, et al. Interleukin-6 expression in coronary circulation

40、after coronary angioplasty as a risk factor for restenosisJ. Heart, 2000,84(1):83-876 ZIAKAS A, GAVRILIDIS S, GIANNOGLOU G, et a1.In-hospital and long-term prognostic value of fibrinogen, CRP, and IL-6 levels in patients with acute myocardial infarction treated with thrombolysisJ.Angiology, 2006,57(

41、3):283-293. 7 GALLAGHER G, MENZIE S, HUANG Y, et a1.Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheepJ. Basic Res Cardiol, 2007,102(1):63-72. 8 BOOS C J, LIP G Y. Platelet activation

42、 and cardiovascular outcomes in acute syndromesJ. J Thromb Haemost, 2006,4(12):2542-2543. 9 YAZICI M, DEMIRCAN S, DURNA K, et al. Relationship between myocardial injury and P-selectin in non-ST elevation acute coronary syndromesJ. Circ J, 2005,69(5):530-535. 10 CARLOS V, GIRALDEZ R R, FERNANDES J L,

43、 et al. Platelet and leukocyte adhesion and activation in unstable angina and post-PTCAJ.Inter J Cardiol, 2005,99(3):423-428. 11 SHEN Q S, HU Y S, ZHU R, et al. Efects of fluvastatin on blood levels of inflammatory cytokines in patients with unstable angina undergoing percutaneous coronary intervent

44、ionJ. Chin J Cardi, 2005,33(4):320-322. 12 CHATURVEDI S, YADAV J S. The role of antiplatelet therapy in carotid stenting for ischemic stroke preventionJ. Stroke, 2006,37(6):1572-1577. 13 MIYAMOTO S, KAWANO H, KUDOH T, et a1. Usefulness of preprocedural platelet aggregation to predict restenosis afte

45、r percutaneous coronary interventionJ.Am J Cardiol, 2005,96(1):71-73. 14 JEONG W K, JEONG M H, KIM K H, et a1.An elevated value of C reactive protein is the only predictive factor of restenosis after percutaneous coronary interventionJ. Korean J Intern Med, 2003,18(3):154-160. 15 HOJO Y, IKEDA U, KA

46、TSUKI T, et al. Interleukin-6 expression in coronary circulation after coronary angioplasty as a risk factor for restenosisJ. Heart, 2000,84(1):83-876 ZIAKAS A, GAVRILIDIS S, GIANNOGLOU G, et a1.In-hospital and long-term prognostic value of fibrinogen, CRP, and IL-6 levels in patients with acute myo

47、cardial infarction treated with thrombolysisJ.Angiology, 2006,57(3):283-293. 7 GALLAGHER G, MENZIE S, HUANG Y, et a1.Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheepJ. Basic Res Car

48、diol, 2007,102(1):63-72. 8 BOOS C J, LIP G Y. Platelet activation and cardiovascular outcomes in acute syndromesJ. J Thromb Haemost, 2006,4(12):2542-2543. 9 YAZICI M, DEMIRCAN S, DURNA K, et al. Relationship between myocardial injury and P-selectin in non-ST elevation acute coronary syndromesJ. Circ

49、 J, 2005,69(5):530-535. 10 CARLOS V, GIRALDEZ R R, FERNANDES J L, et al. Platelet and leukocyte adhesion and activation in unstable angina and post-PTCAJ.Inter J Cardiol, 2005,99(3):423-428. 11 SHEN Q S, HU Y S, ZHU R, et al. Efects of fluvastatin on blood levels of inflammatory cytokines in patient

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54、inases after acute myocardial infarction in sheepJ. Basic Res Cardiol, 2007,102(1):63-72. 8 BOOS C J, LIP G Y. Platelet activation and cardiovascular outcomes in acute syndromesJ. J Thromb Haemost, 2006,4(12):2542-2543. 9 YAZICI M, DEMIRCAN S, DURNA K, et al. Relationship between myocardial injury a

55、nd P-selectin in non-ST elevation acute coronary syndromesJ. Circ J, 2005,69(5):530-535. 10 CARLOS V, GIRALDEZ R R, FERNANDES J L, et al. Platelet and leukocyte adhesion and activation in unstable angina and post-PTCAJ.Inter J Cardiol, 2005,99(3):423-428. 11 SHEN Q S, HU Y S, ZHU R, et al. Efects of

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57、6):1572-1577. 13 MIYAMOTO S, KAWANO H, KUDOH T, et a1. Usefulness of preprocedural platelet aggregation to predict restenosis after percutaneous coronary interventionJ.Am J Cardiol, 2005,96(1):71-73. 14 JEONG W K, JEONG M H, KIM K H, et a1.An elevated value of C reactive protein is the only predictive factor of restenosis after percutaneous coronary interventionJ. Korean J Intern Med, 2003,18(3):154-160. 15 HOJO Y, IKEDA U, KATSUKI T, et al. Interleukin-6 expression in coronary circulation after coronary angioplast

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