【作者】 王强；

【导师】 王璟；

【作者基本信息】 南京大学 ， 内科学， 2014， 硕士

【摘要】 研究背景传统观念上的冠状动脉粥样硬化斑块的发病机制是“由内向外”炎症-损伤-反应学说,即血管内皮损伤为始动环节。然而近年来研究人员研究发现心外膜脂肪与临近的冠状动脉存在密切的解剖与功能联系,可释放大量脂肪因子,即通过滋养血管或直接渗透的“由外向内”途径影响冠脉粥样硬化的病理生理过程。脂肪数量的改变、脂肪因子表达模式的变化可导致冠状动脉功能和结构的改变,所以正成为现今研究冠心病的热点。并且有研究表明心外膜脂肪体积(epicardial adipose tissue, EFV)是影响冠心病发生及狭窄程度的独立危险因素。脂联素(Adiponectin, APN)是最广为研究人员所知的对心血管及代谢系统有保护作用的脂肪细胞因子,且只能由脂肪组织分泌。学者发现与非冠心病相比,冠心病患者的心外膜脂肪及血浆中炎症因子的表达水平是升高的,并且心外膜脂肪中的炎症细胞因子表达高于皮下脂肪组织；而APN与上述炎症因子的表达水平相反,同时低血浆中的APN可作为冠心病发生的独立危险因素。近年来发现的一种新的脂肪细胞因子C1q/肿瘤坏死因子相关蛋白9(C1q/TNF-related protein-9, CTRP9),其与APN同属CTRP家族成员,与APN的结构域有高度相似性,并且两者有共同的作用受体。有研究表明CTRP9可降低血糖,改善胰岛素抵抗,同时可抑制心肌梗死后心肌细胞凋亡,改善心功能等,然而其与EFV的关系以及对冠心病的发生、冠脉狭窄程度及冠脉粥样硬化斑块稳定性的影响尚不清楚。研究目的1.探讨血浆CTRP9及心外膜脂肪体积与冠心病发生的关系；2.血浆CTRP9及心外膜脂肪体积对冠脉狭窄程度的影响；3.血浆CTRP9及心外膜脂肪体积与粥样斑块稳定性的相关性。研究方法收集2013年2月至2013年10月于我院心内科住院,同时行经皮冠脉血管造影及64排双源CT (Dual-source computed tomography, DSCT)的患者88例,其中冠脉造影阴性21例,为非冠心病组；冠脉造影阳性者67例,为冠心病组,通过Gensini积分评价冠脉动脉狭窄程度。根据DSCT结果,通过西门子公司软件计算EFV,根据动脉粥样斑块的①正性重构②低密度斑块③点状钙化三种性质判断斑块的稳定性,并将冠心病组分为易损斑块组33例及非易损斑块组34例。收集患者空腹静脉血液样本检测血生化以及采用ELISA法检测血浆中细胞因子。利用SPSS 16.0软件对相关数据进行统计学分析。研究结果1.冠心病组吸烟人数及糖尿病患者较非冠心病组多；与非冠心病组相比,冠心病组LDL-C、EFV水平较高[(2.480±0.781)与(1.982±0.614),(106.024±40.842)与(83.727±19.692)cm3],P<0.05差异有统计学意义；Logistic回归分析提示糖尿病、LDL-C及EFV为冠心病发生的独立危险因素。2.①与非冠心病组相比,冠心病组血浆TNF-α、IL-6水平均升高[(9.305±4.081)与(7.444±3.130) pg/ml,(4.362±1.350)与(3.673±0.827) pg/ml];而血浆中APN及CTRP9降低[(9.262±1.075)与(9.810±0.707) ng/ml,(78.919±35.572)与(101.031±31.876) pg/ml],P<0.05差异有统计学意义；②血浆CTRP9与APN(r值为0.484)正相关,而与EFV、TNF-a、IL-6(r值分别为-0.355、-0.259、-0.236)负相关,P<0.05差异有统计学意义；③Logistic回归分析示糖尿病、LDL-C及血浆CTRP9为冠心病发生的独立危险因素。3.①在冠心病患者中,Gensini积分与EFV (r=0.257, P=0.036)正相关,而与CTRP9(r值=-0.406,P=0.001)负相关,在排除BMI影响后,Gensini积分仍与EFV正相关(r=0.245,P=0.048),而与CTRP9 (r=-0.402,P=0.001)负相关；②在冠心病患者中,EFV及低血浆CTRP9可分别作为冠脉狭窄程度的独立危险因素。4.①在冠心病患者中,与非易损斑块组相比,易损斑块组中血浆MMP9、 PAPP-A、EFV水平升高[(2.271±0.564)与(1.964±0.554) ng/ml,(105.182±41.618)与(69.794±44.062)ng/ml,(130.297±40.297)与(82.465±24.504)cm3],血浆CTRP9及APN有所降低[(67.672±32.873)与(89.834±35.123) pg/ml,(8.723±0.955)与(9.785±0.925) ng/ml],P<0.05差异有统计学意义；②在冠心病患者中,血浆CTRP9与APN(r=0.469,P<0.001)正相关,而与EFV、MMP9、PAPP-A(r值分别为-0.273、-0.248、-0.294,P<0.05)负相关。研究结论1.心外膜脂肪体积增加对冠心病发生、冠脉狭窄程度及斑块易损性具有促进作用；2.血浆CTRP9对冠心病发生、冠脉狭窄程度及斑块易损性具有保护作用；更多还原

【Abstract】 Background In traditional concept the pathogenesis of coronary atherosclerotic plaque is inflammation-injury-reaction theory from inside to outside, and vascular endothelial injury is the key factors for triggering the atherosclerosis. Study show that epicardial adipose tissue is adjacent to coronary artery, and it may influence on the pathophysiology of coronary atherosclerotic plaque through releasing cytokines by the way of vasa vasorum or direct infiltration from outside to inside. The change of the volume of epicardial adipose tissue and the expression of cytokines may result in structural and functional change, therefore epicardial adipose tissue become a research focus in nowadays. Some researches show that epicardial fat volume (EFV) is an independent risk factor for coronary heart disease (CHD).Adiponectin is the most widely recognized beneficial adipocytokine to cardiovascular and metabolism. It can only release by adipose tissue. Study show that EFV and the expression of plasma inflammatory cytokine are higher in CHD than in non-CHD. Inflammatory factors expressed in epicardial adipose tissue are higher than subcutaneous adipose tissue, while adiponectin (APN) is on the contrary. Plasma APN is an independent risk factor for CHD. AS a new adipocytokine, C1q/TNF-related protein-9 (CTRP9) and APN all belong to the Clq/CTRP protein family. They have comparable structural domain, and they have the same receptor. Some researches demonstrate that CTRP9 can regulate blood sugar level, improve insulin resistance, inhibit myocardial cells apoptosis after myocardial infarction, and improve cardiac function. It is not clear that the relationship between CTRP9 and EFV, and the influence on CHD and the stability of coronary atherosclerosis plaques.Objective1. This article was to elucidate the effect of plasma CTRP9 and EFV on CHD;2. The impacting of plasma CTRP9 and EFV on coronary stenosis was analyzed;3. This paper was also analyzed the effect of plasma CTRP9 and EFV on stability of atherosclerosis plaque.MethodsPatients who were undergoing coronary angiography and dual-source 64 slices CT were collected from February to October in 2013. According to coronary angiography results they were divided into two groups:non-CHD group (21 cases) and CHD group (67cases). The degrees of coronary artery stenosis were evaluated by Gensini score according to coronary angiography results. EFV and stability of plaque were evaluated by software of SIMENS on the basis of the results of DSCT. CHD group were divided into two groups:vulnerable plaque group (33cases) and non-vulnerable plaque group (34cases). The stability of plaque was evaluated by positive remodeling, spotty calcification and low attenuation plaque. Fasting blood sample were collected for biochemical examination and cytokines by ELISA. Data were statistically analyzed by software of SPSS 16.0.Results1. Numbers of smokers and diabetic in CHD are more than non-CHD; Compare with non-CHD group, LDL-C and EFV of CHD group was significantly higher[(2.480±0.781) and (1.982±0.614), (106.024±40.842) and (83.727±19.692) cm3], P<0.05; Diabetic, LDL-C and EFV were independent risk factors for CHD.2.①Compared with non-CHD, in CHD plasma TNF-a and IL-6 were higher [(9.305±4.081)and(7.444±3.130)pg/ml, (4.362±1.350)and(3.673±0.827)pg/ml], however plasma APN and CTRP9 were lower[(9.262±1.075)and(9.810± 0.707)ng/ml,(78.919±35.572)and(101.031±31.876)pg/ml], P<0.05;②Plasma CTRP9 was positively correlated with APN (r=0.484), however it was negatively correlated with EFV, TNF-a and IL-6 (r=-0.355,-0.259,-0.236), P<0.05;③ Diabetic, LDL-C and plasma CTRP9 were independent risk factors for CHD.3. ①In CHD group, Gensini scores were positively related with EFV(r=0.257), while it was negatively related with CTRP9(r=-0.406). After adjusting for BMI, Gensini scores were still positively related with EFV(r=0.245), and it was negatively related with CTRP9(r=-0.402), P<0.05;②EFV and Low level of plasma CTRP9 were independent risk factors for the severity of coronary artery stenosis in CHD4. ①In CHD group, The level of plasma MMP9、PAPP-A and EFV in vulnerable plaque group were higher than Stable plaque group[(2.271±0.564) and (1.964± 0.554) ng/ml, (105.182±41.618) and (69.794±44.062) ng/ml, (130.297± 40.297)and (82.465±24.504) cm3], while CTRP9 and APN were lower[(67.672± 32.873) and (89.834±35.123) pg/ml, (8.723±0.955) and (9.785±0.925)ng/ml], (P< 0.05);②In CHD group, plasma CTRP9 was positively correlated with APN (r=0.469), while it was negatively related with EFV, MMP9, PAPP-A(r=-0.273,-0.248,-0.294),(P<0.05).Conclusion1. EFV could prompt the happen of CHD, the severity of coronary artery stenosis and the vulnerability of plaque;2. Plasma CTRP9 had a protective effect on CHD, the severity of coronary artery stenosis and stability of plaque;更多还原