冠状动脉粥样硬化性心脏病患者血浆RIPK1,RIPK3及MLKL水平变化及其临床预测价值

Changes in plasma levels of RIPK1,RIPK3,and MLKL in patients with coronary atherosclerotic heart disease and its clinical predictive value

目的:冠状动脉粥样硬化性心脏病(coronary atherosclerotic heart disease,CHD)为冠状动脉发生粥样硬化引起管腔狭窄甚至闭塞,导致心肌缺血、缺氧或坏死而引起的心脏病,其发病率长期居高不下,CHD的防治具有重要意义。本研究旨在探讨CHD患者血浆程序性坏死标志蛋白受体相互作用蛋白激酶1(receptor-interacting protein kinase 1,RIPK1)、受体相互作用蛋白激酶3(receptor-interacting protein kinase 3,RIPK3)及混合系列蛋白激酶结构域蛋白(mixed-lineage kinase domain-like protein,MLKL)水平变化及其临床预测价值。方法:纳入2015年9月至2017年5月经冠状动脉造影确诊的CHD住院患者190例以及健康受试者70例。根据CHD类型分为稳定型心绞痛组(SAP,n=46)、不稳定型心绞痛组(UAP,n=56)、非ST段抬高型心肌梗死组(NSTEMI,n=42)和ST段抬高型心肌梗死组(STEMI,n=46)。根据冠状动脉造影结果将CHD患者分为单支病变组、双支病变组及多支病变组,同时采用Gensini评分评估冠状动脉狭窄程度。采用酶联免疫吸附试验(ELISA)检测患者血浆RIPK1,RIPK3,MLKL水平。结果:CHD患者血浆RIPK1,RIPK3,MLKL水平显著高于对照组(P<0.05),且UAP组血浆RIPK1,RIPK3,MLKL水平显著高于SAP组(P<0.05),NSTEMI组及STEMI组显著高于UAP组(P<0.05)。而NSTEMI组与STEMI组血浆RIPK1,RIPK3及MLKL水平差异无统计学意义(P>0.05)。血浆RIPK1,RIPK3,MLKL水平随着冠状动脉病变支数的增加而升高(P<0.05),并且与Gensini评分呈正相关。多因素logistic回归显示:RIPK1,RIPK3,MLKL是冠状动脉严重狭窄的独立危险因素。出院后平均随访24个月,根据是否发生主要不良心血管事件(major adverse cardiovascular events,MACE),将患者分为发生MACE组及未发生MACE组。与未发生MACE组相比较,发生MACE组血浆RIPK1,RIPK3及MLKL水平显著升高(P<0.05)。受试者操作特征(receiver operator characteristic,ROC)曲线分析显示:血浆RIPK1曲线下面积为0.72(P<0.001),RIPK3曲线下面积为0.83(P<0.001),MLKL曲线下面积为0.75(P<0.001)。结论:血浆程序性坏死标志蛋白质RIPK1,RIPK3及MLKL水平与CHD密切相关,且对CHD患者预后的评估具有一定的预测价值。

Objective:Coronary atherosclerotic heart disease(CHD)is caused by coronary atherosclerosis,which leads to stenosis and even occlusion of the lumen,resulting in myocardial ischemia,and necrosis subsequently.Its prevalence has been high for a long time.The prevention and treatment of CHD are important.The study aimed to investigate the role of plasma levels of receptor-interacting protein kinase 1(RIPK1),receptorinteracting protein kinase 3(RIPK3),and mixed-lineage kinase domain-like protein(MLKL)in patients with CHD and its clinical predictive value.Methods:A total of 190 patients with CHD who were diagnosed by coronary angiography and 70 healthy subjects in cardiovascular department from September 2015 to May 2017 were enrolled in this study.Patients with CHD were assigned into 4 groups:Patients with stable angina pectoris(SAP,n=46),patients with unstable angina pectoris(UAP,n=56),patients with non-ST-segment elevation myocardial infarction(NSTEMI,n=42),and patients with ST-segment elevation myocardial infarction(STEMI,n=46).Patients with CHD were assigned into a single-vessel lesion group,a double-vessel lesion group,and a multi-vessel lesion group according to the results of coronary angiography,and the severity of coronary artery stenosis was determined by Gensini score.Plasma levels of RIPK1,RIPK3,and MLKL were measured by enzyme-linked immunosorbent assay(ELISA).Results:The plasma levels of RIPK1,RIPK3,and MLKL in patients with CHD were significantly higher than those in the controls(P<0.05).The plasma levels of RIPK1,RIPK3,and MLKL in the UAP group were significantly higher than those in the SAP group(P<0.05).The plasma levels of RIPK1,RIPK3,and MLKL in NSTEMI and STEMI group were significantly higher than those in the UAP group(P<0.05).There was no significant difference between the NSTEMI group and STEMI group(P>0.05).The plasma levels of RIPK1,RIPK3 and MLKL were significantly increased with numbers of coronary artery lesions(P<0.05),which were positively correlated with Gensini scores.The multivariate logistic regression analysis showed that plasma levels of RIPK1,RIPK3,and MLKL were independent risk factors for severe coronary artery stenosis.The average period of follow-up was 24 months after hospital discharge.The patients were divided into2 groups according to whether they had major adverse cardiovascular events(MACE).Compared with patient without MACE,patient with MACE had higher levels of RIPK1,RIPK3,and MLKL(P<0.05).Receiver operator characteristic(ROC)curve analysis showed that the area under curve of RIPK1 was 0.72(P<0.001),the area under curve of RIPK3 was 0.83(P<0.001),and the area under curve of MLKL was 0.75(P<0.001).Conclusion:Plasma levels of RIPK1,RIPK3,and MLKL are closely related to CHD,and they have predictive value for the prognosis evaluation for patients with CHD.