【作者】 高磊；

【导师】 陈文强；

【作者基本信息】 山东大学 ， 内科学（心血管病）（专业学位）， 2021， 硕士

【摘要】 背景及目的:冠状动脉粥样硬化性心脏病,又被称之为冠心病,近些年来在全球各地发病率逐步上升。随着人群中超重、肥胖比例上升,在我国,冠心病造成的心因性死亡也逐年升高。从临床上针对冠心病的诊断情况来看,其“金标准”对应为经皮冠状动脉造影检测,尚没有较为明显的具有特异性的血清标记物。因此,找到一种具有特异性的血清标记物有利于冠心病的早期诊疗。研究显示,一个与心脏发育密切相关,并且影响动脉粥样硬化的信号通路即Wnt/β-catenin信号通道,这在冠心病的发生期间具备关键的影响,参与了冠心病的发病机制。Dickkopfs家族分泌蛋白,包含DKK1-4,这些物质能够在一定程度上抑制 Wnt/β-catenin信号通道,研究表明体外抑制DKK2表达可以激活Wnt信号通路,增强心脏成纤维细胞的存活。DKK2可能在冠心病中发挥重要作用,而DKK2与冠脉狭窄程度相关性尚未有探讨。方法:本研究选取2019年10月—2020年10月在因冠心病在山东大学齐鲁医院住院治疗,并初次行冠状动脉造影检查的患者,根据CAG结果分为缺血伴非阻塞性冠状动脉疾病(Ischaemia with non-obstructive coronary arteries,INOCA)组和阻塞性冠状动脉缺血疾病(Ischemia with obstructive coronary artery,IOCA)组。其中INOCA组39例,IOCA组145例。分别测定两组患者外周血白细胞、血清NT-pro BNP、空腹血糖、血脂水平与肝功能等,同时包括纤维蛋白原、肾功能与D-二聚体、同型半胱氨酸、脂蛋白磷脂酶A2,心脏多普勒超声检测评估患者的左心室射血分数(Leftventricularfraction,LVEF),ELISA测定患者血清中的DKK2水平;参考SYNTAX的评分情况,基于此判定冠脉病变情况:低危组(SYNTAX积分≤22分)和中危组(22<SYNTAX积分≤32分)、高危组(SYNTAX积分>32分)。统计分析两组患者血清DKK2的水平及其与SYNTAX评分进行相关性,评价DKK2对于冠心病诊断的临床应用价值。结果:1.一般基线资料比较:INOCA组与IOCA组的低危组、中危组、高危组之间年龄、性别和身高、体重、BMI、舒张压、收缩压、高血压史、低密度脂蛋白胆固醇、游离脂肪酸、外周血白细胞、总胆固醇、血清载脂蛋白B与甘油三酯等,同时包括同型半胱氨酸、空腹血糖、游离脂肪酸、肌酐、D-二聚体、尿素氮都不存在显著的统计学差异;各组从高密度脂蛋白胆固醇、血清载脂蛋白A1、脂蛋白a、胱抑素C、NT-proBNP与纤维蛋白原、LVEF等方面来看,其中的差异存在显著的统计学意义(P<0.05)。2.IOCA组患者血清DKK2水平与SYNTAX积分呈现负相关(r=-0.543,P<0.001),IOCA组患者血清DKK2水平与高密度脂蛋白胆固醇呈正相关(r=0.542,P<0.001)。3.INOCA组与阻塞性缺血性冠心病的低危组、中危组、高危组各组血清DKK2水平分别为:INOCA组(5.8±2.92)、低危组(4.29±1.60)、中危组(3.47±1.10)、高危组(2.39±0.89),各组间的血清DKK2水平差异具有统计学意义(P<0.001)。4.通过ROC曲线评估DKK2水平对IOCA患者的预测价值,DKK2水平对IOCA 患者预测的曲线下面积是 0.812[95%CI:0.725-0.899,P<0.001],当DKK2水平切值取4.324ng/ml时,其诊断价值最高,灵敏度76.7%,特异度 70.4%。5.多因素二分类Logistic回归分析显示:DKK2浓度、血清载脂蛋白A1、HDL-C、脂蛋白a、年龄、胱抑素C与高血压病史等情况来看,其中的差异存在显著的统计学意义(P<0.05)。脂蛋白a、胱抑素C、年龄、高血压病史与IOCA呈正相关;从DKK2浓度、HDL-C和血清载脂蛋白A1的情况来看,这些指标与IOCA之间呈现出负相关关系。6.多因素二分类Logistic回归分析显示:DKK2浓度与冠状动脉狭窄程度相关,DKK2浓度越低,冠状动脉狭窄程度越重,在调整其他变量情况下,DKK2每增加1ng/ml,冠状动脉狭窄程度越重的可能性是EXP(-0.136)=0.873倍。结论:与缺血伴非阻塞性冠状动脉疾病患者相比较,阻塞性冠状动脉缺血疾病患者血清DKK2水平更低;针对阻塞性冠状动脉缺血疾病患者进行分析,体内的血清DKK2浓度和冠状动脉病变情况存在相关关系,即与SYNTAX评分呈现出负相关关系,研究结果显示,DKK2本身的浓度越低,冠脉病变情况越严重;DKK2是冠心病发生的独立危险因素,血清中的DKK2浓度有助于辅助评估冠状动脉狭窄程度。更多还原

【Abstract】 Objective:Coronary atherosclerotic heart disease,also known as coronary heart disease,has gradually increased in recent years around the world.With the increase of overweight and obesity,the psychogenic death caused by coronary heart disease is increasing year by year in China.From the clinical diagnosis of coronary heart disease,its "gold standard" corresponds to percutaneous coronary angiography,and there is no obvious specific serum marker.Therefore,finding a specific serum marker is beneficial to the early diagnosis and treatment of coronary heart disease.Studies have shown that Wnt/β-catenin signal channel,which is closely related to heart development and affects atherosclerosis,plays a key role in the occurrence of coronary heart disease and participates in the pathogenesis of coronary heart disease Dickkopfs secrete egg whites,including DKK1-4,which can inhibit Wnt/β-catenin signal channel to a certain extent.Studies have shown that inhibiting DKK2 expression in vitro can activate WNT signal channel and enhance the survival of cardiac fibroblasts.DKK2 may play an important role in coronary heart disease,but the correlation between DKK2 and the degree of coronary stenosis has not been discussed.Methods:In this study,patients who were hospitalized in Qilu Hospital of Shandong University from October 2019 to October 2020 for coronary heart disease and underwent coronary angiography for the first time were divided into ischemic with non-obstructive coronary artery diseases(IOCA)group and ischemic with obstructive coronary artery diseases(IOCA)group according to CAG results.There are 39 cases in the INOCA group and 145 cases in the IOCA group.The levels of peripheral blood leukocytes,serum NT-pro BNP,fasting blood glucose,blood lipid and liver function,including fibrinogen,renal function,D-dimer,homocysteine and lipoprotein phospholipase A2,were measured respectively in the two groups.Left ventricular fraction fraction(LVEF)was evaluated by cardiac Doppler ultrasound,and DKK2 level in serum was measured by ELISA.According to the score of SYNTAX,the coronary lesions were determined:low risk group(SYNTAX score ≤22),medium risk group(22<SYNTAX score≤32)and high risk group(syntax score>32).The level of serum DKK2 and its correlation with SYNTAX score were statistically analyzed,and the clinical application value of DKK2 in the diagnosis of coronary heart disease was evaluated.Results:1,Comparison of general baseline data:age,sex,height,weight,BMI,diastolic blood pressure,systolic blood pressure,peripheral blood white blood cells,total cholesterol,serum apolipoprotein B and triglyceride,etc.,including homocysteine,fasting blood glucose,free fatty acid and creatinine,D-dimer and BUN,have no significant statistics between INOCA group and IOCA group.There were significant differences in high density lipoprotein cholesterol,serum apolipoprotein A1,lipoprotein A,cystatin C,LUEF,NT-proBNP and fibrinogen among the groups(P<0.05).2.The serum DKK2 level in IOCA group was negatively correlated with SYNTAX score(r=-0.543,P<0.001),while the serum DKK2 level in IOCA group was positively correlated with high density lipoprotein cholesterol(r=0.542,P<0.001).3.The serum DKK2 levels of the INOCA group,the low-risk group,the intermediate-risk group,and the high-risk group were:INOCA group(5.8±2.92),low-risk group(4.29±1.60),intermediate-risk group(3.47±1.10),and high-risk group(2.39±0.89).(P<0.001).4.The predictive value of DKK2 level for IOCApatients was evaluated by ROC curve.the area under the curve of DKK2 level for IOCA patients was 0.812[95%CI:0.725-0.899,P<0.001].when DKK2 level cut-off value was 4.324ng/ml,its diagnostic value was the highest,with sensitivity of 76.7%and specificity of 70.4%.5.Multivariate binary Logistic regression analysis showed that there were significant differences between DKK2 concentration and serum apolipoprotein A1,HDL-C,lipoprotein A,age,cystatin C,hypertension history(P<0.05).There is a positive correlation between lipoprotein a,cystatin c a,age,hypertension history and IOCA,and there is a negative correlation between these indexes and IOCA according to DKK2 concentration,HDL-C and serum apolipoprotein A1.6.Multivariate binary Logistic regression analysis showed that the concentration of DKK2 was related to the degree of coronary artery stenosis,and the lower the concentration of DKK2,the more severe the degree of coronary artery stenosis.When other variables were adjusted,the probability of increasing DKK2 by 1 ng/ml was EXP(-0.136)=0.873 times.Conclusion:Compared with ischemic patients with non-obstructive coronary artery disease,the serum DKK2 level in patients with obstructive coronary artery ischemia disease was lower.According to the analysis of patients with obstructive coronary ischemia,there is a correlation between serum DKK2 concentration and coronary artery disease,and this degree is negatively correlated with SYNTAX score.The results show that the lower the concentration of DKK2 itself,the more serious the coronary artery disease is.DKK2 is an independent risk factor for coronary heart disease,and the concentration of DKK2 in serum is helpful to evaluate the degree of coronary artery stenosis.更多还原