骨保护素和相关炎性因子的血清含量与冠心病及其病变程度的关系

Relationship between serum levels of osteoproteins,inflammatory cytokines and coronary heart disease and disease severity

目的探讨骨保护素(OPG)、可溶性核转录因子-κB受体活化因子配体(sRANKL)和相关炎性因子血清含量与冠心病(CHD)及病变严重程度的关系。方法选择2017年4月至2018年12月因胸痛入住天津市胸科医院心内科并接受冠状动脉造影(CAG)的患者,根据CAG结果将患者分为CHD组和非CHD组。收集所有入选者的性别、年龄、高血压史、吸烟史、糖尿病等一般资料以及总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白AI(apoAI)、载脂蛋白B(apoB)、脂蛋白(a)〔Lp(a)〕、肌酸激酶同工酶(CK-MB)等生化指标;采用酶联免疫吸附试验(ELISA)检测血清OPG、sRANKL、基质金属蛋白酶9(MMP-9)、单核细胞趋化因子-1(MCP-1)、胰岛素样生长因子-1(IGF-1)、白细胞介素-6(IL-6)水平。根据CAG结果将CHD患者分为单支、双支、三支冠状动脉(冠脉)病变组,观察CHD患者血清OPG、sRANKL及相关炎性因子的含量与冠脉病变严重程度的关系。采用多因素Logistic回归法分析CHD的危险因素;绘制受试者工作特征曲线(ROC),分析主要危险因素对CHD的预测价值。结果研究期间共472例患者纳入最终分析,其中CHD组264例,非CHD组208例,CHD患者中单支病变79例,双支病变75例,三支病变110例。①与非CHD组比较,CHD组男性患者更多,年龄更大,高血压史、糖尿病患者比例更高,且血Lp(a)、CK-MB水平显著升高,血HDL-C、apoAI水平显著降低;而两组血TC、LDL-C、apoB水平比较差异无统计学意义。CHD组患者血清OPG、MMP-9、MCP-1、IGF-1、IL-6水平明显高于非CHD组〔OPG(μg/L):1.79±0.50比1.50±0.30,MMP-9(μg/L):57.91(33.50,130.46)比38.33(29.43,109.78),MCP-1(μg/L):298.30(207.96,537.16)比252.73(165.22,476.01),IGF-1(μg/L):734.03±486.11比217.75±126.45,IL-6(ng/L):64.76±40.25比48.60±15.80,均P<0.05〕,血清sRANKL水平明显低于非CHD组(ng/L:344.31±122.14比378.74±109.27,P<0.05)。②血清OPG水平随冠脉病变支数增加呈轻微上升趋势,sRANKL水平呈轻微下降趋势〔单支、双支、三支冠脉病变组OPG(μg/L)分别为1.74±0.49、1.76±0.50、1.85±0.52,sRANKL(ng/L)分别为354.96±116.64、340.05±124.24、339.57±125.03〕,差异均无统计学意义(均P>0.05);IGF-1、IL-6水平随冠脉病变支数增加而升高〔单支、双支、三支冠脉病变组IGF-1(μg/L)分别为372.13±258.42、676.06±350.29、1033.47±468.06,IL-6(ng/L)分别为48.87±16.72、65.36±18.84、75.76±22.72〕,不同病变组间比较差异均有统计学意义(均P<0.01)。相关性分析显示,IGF-1水平与冠脉病变支数呈显著正相关(r=0.612,P<0.01),而IL-6与病变支数无明显相关性(r=0.185,P>0.05)。③多因素Logistic回归分析显示,血清OPG、IGF-1水平升高是CHD发病的危险因素〔OPG:优势比(OR)=1.995,95%可信区间(95%CI)=1.936~2.067,P=0.012;IGF-1:OR=1.009,95%CI=1.004~1.015,P=0.001〕。④ROC曲线分析显示,OPG和IGF-1预测CHD的ROC曲线下面积(AUC)分别为0.716、0.867。当OPG的最佳截断值为1.13μg/L时,敏感度为81.7%,特异度为58.1%;当IGF-1的最佳截断值为401.20μg/L时,敏感度为69.7%,特异度为95.7%。结论血清OPG和相关炎性因子MMP-9、MCP-1、IGF-1、IL-6水平升高以及sRANKL水平降低与CHD有关;IGF-1水平与冠脉病变严重程度呈正相关;血清OPG和IGF-1是CHD发生的危险因素,对CHD的发生具有良好的预测价值。

Objective To explore the relationship between serum levels of osteoprotein(OPG),soluble nuclear factor-κB receptor activator ligand(sRANKL),inflammatory factors and coronary heart disease(CHD)and its severity.Methods The patients who underwent coronary angiography(CAG)due to chest pain admitted to department of cardiology of Tianjin Chest Hospital from April 2017 to December 2018 were enrolled,and they were divided into CHD group and non-CHD group according to the CAG results.The gender,age,history of hypertension,smoking history,diabetes,the levels of cholesterol(TC),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),apolipoprotein AI(apoAI),apolipoprotein B(apoB),lipoprotein(a)[Lp(a)],MB isoenzyme of creatine kinase(CK-MB)and other clinical data of patients were collected.The serum levels of OPG,sRANKL,matrix metalloproteinase-9(MMP-9),monocyte chemotactic protein-1(MCP-1),insulin-like growth factor-1(IGF-1)and interleukin-6(IL-6)were determined by enzyme-linked immunosorbent assay(ELISA).According to the results of CAG,the patients with CHD were divided into single-,double-,triple-branch coronary artery lesion groups,and the relationship between the levels of serum OPG,sRANKL,inflammatory factors and the degree of coronary artery lesions was observed.Multivariate Logistic regression was used to analyze the risk factors of CHD,and receiver operating characteristic(ROC)curve was plotted to analyze the predictive value of main risk factors for CHD.Results A total of 472 patients were enrolled in the final analysis during the study period,including 264 patients in the CHD group,208 patients in the non-CHD group,79 patients in the CHD group with single-branch disease,75 patients with double-branch disease,and 110 patients with three-branch disease.①Compared with the non-CHD group,the CHD group had more older male patients,as well as higher proportion of hypertension and diabetes,the levels of serum Lp(a)and CK-MB were significantly increased,and the levels of serum HDL-C and apoAI were significantly lowered.There was no statistically significant difference in serum TC,LDL-C,or apoB between the two groups.The levels of serum OPG,MMP-9,MCP-1,IGF-1 and IL-6 in the CHD group were significantly higher than those in the non-CHD group[OPG(μg/L):1.79±0.50 vs.1.50±0.30,MMP-9(μg/L):57.91(33.50,130.46)vs.38.33(29.43,109.78),MCP-1(μg/L):298.30(207.96,537.16)vs.252.73(165.22,476.01),IGF-1(μg/L):734.03±486.11 vs.217.75±126.45,IL-6(ng/L):64.76±40.25 vs.48.60±15.80,all P<0.05],and the levels of serum sRANKL was significantly lower than that in the non-CHD group(ng/L:344.31±122.14 vs.378.74±109.27,P<0.05).②The serum OPG level showed a slight upward tendency with the increase in the number of coronary artery lesions,and the sRANKL level showed a slight downward tendency[OPG(μg/L)in the single-,double-,triple-branch coronary artery lesion groups was 1.74±0.49,1.76±0.50,1.85±0.52,and sRANKL(ng/L)was 354.96±116.64,340.05±124.24,339.57±125.03,respectively)without statistically significant differences(all P>0.05).The levels of IGF-1 and IL-6 were increased with the number of coronary artery lesions[IGF-1(μg/L)in the single-,double-and triple-branch coronary artery lesions groups was 372.13±258.42,676.06±350.29,1 033.47±468.06,and IL-6(ng/L)was 48.87±16.72,65.36±18.84,75.76±22.72,respectively],and the differences among different lesion groups were statistically significant(all P<0.01).Correlation analysis showed that IGF-1 level was significantly positively correlated with the number of coronary artery lesions(r=0.612,P<0.01),while IL-6 was not correlated with the number of coronary artery lesions(r=0.185,P>0.05).③Multivariate Logistic regression analysis showed that elevated serum OPG and IGF-1 levels were risk factors for CHD[OPG:odds ratio(OR)=1.995,95%confidence interval(95%CI)=1.936-2.067,P=0.012;IGF-1:OR=1.009,95%CI=1.004-1.015,P=0.001].④ROC curve analysis showed that the area under ROC curve(AUC)of OPG and IGF-1 was 0.716 and 0.867,respectively.When the cut-off value of OPG was 1.13μg/L,the sensitivity was 81.7%,the specificity was 58.1%;when the cut-off value of sRANKL was 401.20μg/L,the sensitivity was 69.7%,the specificity was 95.7%.Conclusions CHD was associated with increased in OPG,related inflammatory cytokines including MMP-9,MCP-1,IGF-1 and IL-6,and decreased in sRANKL.The level of IGF-1 was positively correlated with the severity of CHD.The serum levels of OPG and IGF-1 were risk factors for CHD,which had good predictive value for CHD.