【作者】 韩轶鹏；

【导师】 王大明； 姜宏志； 沙成； 袁庆国； 杨玉明；

【作者基本信息】 中国协和医科大学 ， 外科学， 2010， 博士

【摘要】 目的：研究缺血性脑血管病患者血清炎性标志物水平与颈动脉斑块稳定性之间的相关性,评估各血清炎性标志物对易损性颈动脉斑块的识别能力,为早期识别易损性颈动脉斑块探索新的途径。方法：研究对象为65例经相关影像学检查证明存在颈动脉斑块的缺血性脑血管病患者,其中TIA 17例,脑梗塞44例,治疗其他疾病或健康体检时偶然发现颈动脉狭窄4例。所有研究对象均排除可能影响血清炎性标志物表达的疾病或状态。所有研究对象均行全脑血管造影及颈动脉斑块高分辨率MRI检查。根据斑块的MRI影像学特征如纤维帽厚度、是否存在较大脂质核及是否存在斑块内出血分为稳定斑块组(21例)和不稳定斑块组(44例)。不稳定斑块组根据纤维帽是否破裂又分为未破裂斑块组(29例)和破裂斑块组(15例)。抽取研究对象静脉血,用乙二胺四乙酸(EDTA)抗凝管搜集,离心后提取血清,零下80℃冷冻储存。应用酶联免疫吸附法(ELISA)测定血清sCD40L、MCP-1、MMP-2、MMP-9、MPO、PAPP-A的水平。结果：不稳定斑块组、不稳定未破裂斑块组和破裂斑块组患者血清sCD40L浓度水平均显著高于稳定斑块组(P值分别为0.011、0.001和0.000)。不稳定未破裂斑块组与破裂斑块组之间sCD40L浓度水平差异无显著性(P=0.085)。sCD40L浓度水平与斑块易损程度呈正相关关系(r=0.556,P=0.000)。不稳定斑块组、不稳定未破裂斑块组和破裂斑块组患者血清MMP-9浓度水平均显著高于稳定斑块组(P值分别为0.045、0.032和0.003)。不稳定未破裂斑块组与破裂斑块组之间MMP-9浓度水平差异无显著性(P=0.192)。血清MMP-9浓度水平与颈动脉斑块易损程度呈正相关关系(r=0.424,P=0.000)。不稳定斑块组和破裂斑块组患者血清PAPP-A浓度水平均显著高于稳定斑块组(P值分别为0.008和0.000),破裂斑块组患者血清PAPP-A浓度水平显著高于不稳定未破裂斑块组(P=0.000)。而稳定斑块组与不稳定未破裂斑块组差异无显著性(P=0.745)。血清PAPP-A浓度水平与斑块易损程度呈正相关关系(r=0.424,P=0.000)。Logistic多元回归分析结果显示血清标志物浓度sCD40L≥673.22pg/ml(OR值为22.47,95%CI为2.11-239.81, P=0.010)、MMP-9≥84.09ng/ml (OR值为10.01,95%CI为1.74-57.78, P=0.010)、PAPP-A≥0. lOlng/ml (OR值为14.29,95%CI为2.69～75.90,P=0.002)与颈动脉斑块的易损性相关。稳定斑块组与不稳定斑块组之间、稳定斑块组与不稳定未破裂斑块组之间、稳定斑块组与破裂斑块组之间、不稳定未破裂斑块组与破裂斑块组之间血清MCP-1、MMP-2和MPO的浓度水平均无显著性差异。结论：存在颈动脉粥样硬化斑块的缺血性脑血管病患者血清中sCD40L、MMP-9、PAPP-A水平与颈动脉斑块的不稳定可能相关,较高的血清sCD40L、MMP-9、PAPP-A水平可能提示斑块易损或破裂。因此,sCD40L、MMP-9、PAPP-A可以作为评价颈动脉斑块稳定程度的标志物,以大样本的血清免疫学实验结果作为标准,通过测定其血清浓度来判断颈动脉斑块是否易损或破裂在一定程度上是可行的,这可能成为早期识别颈动脉易损斑块的新方法。更多还原

【Abstract】 Objective:To study the relationship between serum levels of inflammatory markers and stability of carotid plaques in patients with ischemic cerebrovascular diseases and evaluate the ability of each serum marker in identifying vulnerable carotid plaques. To explore a new approach for identifying vulnerable carotid plaques early.Methods:The study included 65 consecutive patients with ischemic cerebrovascular diseases and with carotid plaques confirmed by imaging examinations. Of these patients,17 were diagnosed as transient ischemic attack,44 cerebral infarction and 4 were detected with carotid stenosis incidentally. Patients were excluded if they have any other disease or disease state influencing the expression of serum inflammatory markers.All the patients were examined by digital subtraction cerebral angiography and high resolution magnetic resonance imaging. Patients were classified as stable plaques group (n=21) or unstable plaques group (n=44) according to the characteristic findings of plaques in MRI such as the thickness of fibrous cap, the existence of a large lipid core and intra-plaque hemorrhage. The patients of unstable plaques group were further classified as unrupture plaques group (n=29) and rupture plaques group (n=15) according to the integrity of fibrous cap.Peripheral blood samples of the study patients were collected in tubes containing ethylenediamine tetraacetic acid (EDTA). After centrifugation the serum was siphoned into freezing vials and stored at-80℃. Serum levels of sCD40L, MCP-1, MMP-2, MMP-9, MPO and PAPP-A were determined by enzyme-linked immunosorbent assay (ELISA).Results:Serum levels of sCD40L in patients of unstable plaques group, unrupture plaques group and rupture plaques group were all significantly enhanced compared to individuals of stable plaques group, P value being 0.011,0.001 and 0.000 respectively. There was no significant difference in serum levels of sCD40L between unrupture plaques group and rupture plaques group, P value being 0.085.Serum levels of MMP-9 in patients of unstable plaques group, unrupture plaques group and rupture plaques group were all significantly enhanced compared to individuals of stable plaques group, P value being 0.045,0.032 and 0.003 respectively. There was no significant difference in serum levels of MMP-9 between unrupture plaques group and rupture plaques group, P value being 0.192.Serum levels of PAPP-A in patients of unstable plaques group and rupture plaques group were all significantly enhanced compared to individuals of stable plaques group, P value being 0.008 and 0.000 respectively. Serum levels of PAPP-A in patients of rupture plaques group were significantly enhanced compared to individuals of unrupture plaques group, P value being 0.000. There was no significant difference in serum levels of PAPP-A between unrupture plaques group and stable plaques group, P value being 0.745.Spearman rank correlation indicated that the serum levels of sCD40L, MMP-9 and PAPP-A were positively correlated with the degrees of vulnerability of plaques, r value being 0.556,0.424 and 0.424 respectively, P value being 0.000,0.000 and 0.000 respectively.Logistic regression indicated that the serum levels of sCD40L≥673.22 pg/ml (OR=22.47,95%CI 2.11-239.81), MMP-9≥84.09 ng/ml (OR=10.01,95%CI 1.74-57.78) and PAPP-A≥0.101 ng/ml (OR=14.29,95%CI 2.69-75.90) were all significantly correlated with the vulnerability of carotid plaques, P value being 0.010, 0.010 and 0.002 respectively.There was no significant difference in the serum levels of MCP-1, MMP-2 and MPO between any two groups.Conclusions:There appear to be a relationship between the serum levels of sCD40L, MMP-9 and PAPP-A and the instability of carotid plaques in patients with cerebrovascular diseases and with carotid plaques. High serum levels of the above-mentioned markers may indicate that the plaques were vulnerable or ruptured. Therefore, sCD40L, MMP-9 and PAPP-A can be used as the markers of stability of carotid plaques. It is feasible in some extent to judge whether the plaques are vulnerable or ruptured by the serum levels of the mentioned markers if we take the results from large-sample trials as standards. And it maybe a new approach to identify vulnerable plaques early.更多还原