【作者】 刘其伟；

【导师】 崔连群；

【作者基本信息】 山东大学 ， 内科学， 2011， 硕士

【摘要】 目的冠心病是严重威胁人类健康的疾病,而急性冠脉综合征(Acute Coronary Syndrome, ACS)则是冠心病的冠状动脉粥样硬化病变进行到末期,导致冠状动脉内不稳定斑块出现溃疡、破裂及糜烂,并发血栓形成、血管痉挛收缩、微血管栓塞等情况导致冠状动脉血流急剧减少所致。ACS是冠心病的急性发病的临床类型,发作时往往心绞痛症状严重,甚至可发生猝死,风险极大。多能蛋白聚糖是一种细胞外基质(extracellular matrix, ECM)蛋白,主要由动脉平滑肌细胞合成。它可以参与动脉粥样硬化、动脉瘤等多种血管病变的病变发展过程,是存在于血管损害过程中的主要ECM蛋白。含1型凝血酶敏感蛋白基序的解聚素样金属蛋白酶(a disintegrin and metalloprotease with thrombosponding type 1 motifs ADAMTS-1)是一种新发现的ECM蛋白水解酶,有可能通过裂解ECM蛋白中的多能蛋白聚糖等成分来加速动脉粥样硬化的形成进程,促进ACS的发生发展。本研究拟通过应用双抗体夹心酶联免疫吸附(ELISA)法测定各类冠心病患者及健康人血清中ADAMTS-1的水平,探讨ADAMTS-1水平测定在预测ACS发生中的价值。方法于2009年12月-2010年11月山东省立医院心内科经治冠心病患者中选择冠心病病例组。入选标准为通过行冠状动脉CT检查或冠状动脉造影确定有至少一支冠状动脉直径狭窄程度大于等于50%者。其后再根据各患者的具体临床症状及相关检查等,按Braunwald心绞痛分型及WHO公布的急性心肌梗死诊断标准分为稳定型心绞痛(SAP)组、不稳定型心绞痛(UAP)组和急性心肌梗死(AMI)组。对照组从同期于我院进行健康体检人员中选择年龄、性别与病例组匹配且无冠心病病史及症状、表现者组成。排除标准为：合并脑卒中、严重的肝肾功能不全者；合并脑血管疾病及周围血管疾病者；合并恶性肿瘤患者和免疫系统疾病患者；合并感染性疾病或有严重外伤的患者；存在瓣膜病、心肌病、严重心功能不全者。最终所有入选者分组情况为：急性心肌梗死(AMI)组40例,不稳定心绞痛(UAP)组50例；稳定性心绞痛(SAP)组40例；对照组32例。其中UAP组和AMI组合并为ACS组；SAP组和对照组合并为非ACS组。收集统计各组患者的性别、年龄、身高、体重、血压、病史、个人烟酒史、心电图等基础资料,和血常规、血生化、血脂、凝血指标、超敏C反应蛋白High Sensitivity C-Reactive Protein,HS-CRP)等血液检查项目及心脏彩超、冠状动脉CT检查、冠状动脉造影等检查结果。采集各患者肘静脉血,离心取上清液。应用ELISA法测定其中ADAMTS-1的水平。结果ADAMTS-1水平在冠心病组(100.71±37.06 ng/ml)显著高于对照组(47.04±11.79 ng/ml),差异具有统计学意义(P<0.05)。ADAMTS-1在SAP组69.33±15.87 ng/ml,UAP组93.43±21.36 ng/ml, AMI组141.18±31.01 ng/ml,显示ADAMTS-1水平有随冠心病临床症状的加重而增高的趋势(P<0.05)。经双元相关分析,在所有入选者中,ADAMTS-1与HS-CRP、肥胖、高血压病史、高密度脂蛋白-胆固醇、血尿酸、复杂狭窄病变数有显著相关性(P<0.05)；在冠心病组中,ADAMTS-1与HS-CRP、纤维蛋白原、高密度脂蛋白-胆固醇、复杂狭窄病变数有显著相关性(P<0.05)；在ACS组中,ADAMTS-1与HS-CRP、纤维蛋白原有显著相关性(P<0.05)。经多元logistic回归分析后结果显示,在所有入选者中(n=162)及在冠心病组(n=130)中,ADAMATS-1均与ACS独立相关。经ROC曲线分析,HS-CRP曲线下面积为92.9%(95%CI：88.6%,97.1%),ADAMTS-1曲线下面积为94.0%(95%CI：90.7%,97.3%)。提示ADAMTS-1在预测ACS的发生方面不劣于甚至略优于HS-CRP.结论一、外周血ADAMTS-1水平在冠心病患者中明显升高。二、外周血ADAMTS-1水平能够反应动脉粥样硬化斑块的稳定性,并可能参与粥样硬化斑块的去稳定性过程。三、外周血ADAMTS-1水平可作为预测ACS发生的良好指标。更多还原

【Abstract】 Objective Coronary atherosclerotic heart disease (CAD) is now thought to be a great threat to human health all over the world. The end phase of CAD would be acute coronary syndrome (ACS). Rupture of plaques with superimposed thrombosis is now considered to be the main cause of ACS. It would usually cause serious angina symptoms when ACS was triggered, even cause death. Therefore, ACS is such kind of a disease of great risk.Versican is a kind of extracellular matrix (ECM) protein. It is mainly produced by the arterial smooth muscle cells. As the major ECM protein during the process of vessel injury, versican get involved in many vascular disease, such as atherosclerosis, aneurysms, etc. A disintegrin and metalloprotease with thrombosponding type 1 motifs (ADAMTS-1) is a member of the ADAMTS family, which is recently discovered to be a new kind of metalloproteinase. It is assumed to have played an important part in accelerating the process of atherosclerosis, therefore promoted the onset of ACS, by cleaving the versicans and many other proteoglycans in vessel ECM. In this current study, we set up to explore the circulating level of ADAMTS-1 in the CAD patients. Thus we can discuss the value of ADAMTS-1 testing in predicting the occurrence of ACS.Methods Selected from the patients of Shandong Provincial Hospital during December 2009 to November 2010, a total number of 130 patients and 32 healthy subjects were enrolled in this study. They were separated into 4 groups of 40 patients in acute myocardial infarction (AMI) group, 50 patients in unstable angina pectoris (UAP) group,40 patients in stable angina pectoris (SAP) group and 32 patients in control group. Gather all patients’basic information such as age, gender, weight, height, medical history, routine blood test result and body examine result, etc. Blood were drawn from all patients’median cubital veins to measure their ADAMTS-1 level by using Enzyme Linked Immunosorbent Assay (ELISA) kit.Result Patients with CAD had a higher level of ADAMTS-1 in contrast to those without CAD. Serum ADAMTS-1 in patients with and without CAD were (100.71±37.06 ng/ml) and (47.04±11.79 ng/ml). The difference was significant (P<0.05). In addition, we found a stepwise increase in ADAMTS-1 level in patients with SAP, UAP and AMI. Serum ADAMTS-1 level in patients with SAP, UAP and AMI were 69.33±15.87 ng/ml,93.43±21.36 ng/ml and 141.18±31.01 ng/ml. The difference was also significant (P<0.05).By bivariate analysis, ADAMTS-1 was found correlated with HSCRP, HDL-C, UA. In patients with CAD, the correlation between ADAMTS-1 and HS-CRP remained significant. Moreover, an statistically significant association between ADAMTS-1 and the number of complex stenoses was also observed. Ordinal regression revealed that ADAMTS-1 increase with the increase of the clinical severity of CAD. Among 162 studies subjects, higher ADAMTS-1 levels was found to be the independent factor associated with ACS. Even among the 130 patients with CAD, such association remained to be significant. Furthermore, a ROC curve analysis showed a good discriminatory power of serum ADAMTS-1 in predicting the onset of ACS.Conclusion1. Patients with CAD had a higher level of ADAMTS-1.2. Serum ADAMTS-1 level may serve as a novel biomarker of atherosclerosis plaque vulnerability. It may also involved in the process of plaque destabilization.3. Serum ADAMTS-1 level can be used as a significant biomarker to predict the occurrence of ACS.更多还原