白细胞介素-17对原发性高血压患者左心室舒张功能不全的诊断及预后价值

The diagnostic and prognostic value of interleukin-17 for left ventricular diastolic dysfunction in patients with essential hypertension

目的:探讨血清白细胞介素-17(IL-17)对原发性高血压患者左心室舒张功能不全(LVDD)的诊断及预后评估价值,并从细胞水平初步阐明其潜在机制。方法:前瞻性入选2017年7月至2018年1月在江苏大学附属医院心内科住院行左心导管检查的原发性高血压患者,根据左心室舒张末压(LVEDP)水平,分为高LVEDP组(LVEDP≥16 mmHg)(1 mmHg=0.133 kPa)和正常LVEDP组(LVEDP<16 mmHg)。行左心导管检查时从主动脉窦部采集血样,检测血清IL-17、IL-6、IL-23及IL-1β表达水平,并比较其受试者工作特征(ROC)曲线下面积(AUC)。同时与可溶性细胞粘附分子(sICAM-1)、单核细胞趋化蛋白(MCP-1)和E选择素(E-selectin)进行相关性分析。采用多因素logistic回归分析评估LVDD的预测因素。在体外细胞水平,使用重组人IL-17蛋白刺激内皮细胞,评估内皮细胞迁移、增殖及凋亡情况。结果:本研究共纳入80例高血压患者,高LVEDP组47例,正常LVEDP组33例。与正常LVEDP组比较,高LVEDP组血清IL-17、IL-6及IL-23表达水平明显升高,差异均有统计学意义(P均<0.05)。ROC曲线分析结果显示,血清IL-17在预测LVDD时AUC值最大[0.896,95%可信区间(CI)0.824~0.967,P<0.001],界值为18.5pg/mL。多因素logistic回归分析结果显示,IL-17表达增加是LVDD的独立预测因子(比值比1.27,95%CI 1.09~1.24,P<0.05)。根据血清IL-17界值,将患者分为低表达IL-17(<18.5pg/mL)组(n=35)和高表达IL-17(≥18.5 pg/mL)组(n=45)。低表达IL-17组患者末次随访时LVDD改善的比例更高,主要终点事件发生率更低。血清IL-17水平与sICAM-1、MCP-1、E-选择素表达水平呈正相关(P均<0.05)。在体外细胞水平,IL-17刺激使内皮细胞迁移和增殖减少,凋亡增加。IL-17刺激使内皮细胞的sICAM-1、MCP-1及E-选择素表达增加。结论:血清IL-17水平对原发性高血压患者发生LVDD可能具有重要的诊断和预后判断价值。

Objective To investigate the diagnostic and prognostic value of serum interleukin-17(IL-17)for left ventricular diastolic dysfunction(LVDD)in patients with essential hypertension,and to elucidate the potential mechanism in vitro.Medthods Patients with essential hypertension who underwent left ventricular catheterization for left ventricular end-diastolic pressure(LVEDP)measurement in the Department of Cardiology,Affiliated Hospital of Jiangsu University,were prospectively enrolled from July 2017 to January 2018.According to the level of LVEDP,patients were divided into higher LVEDP(≥16 mmHg)group and normal LVEDP(<16 mmHg)group.Blood samples were collected from the aortic sinus during left cardiac catheterization to detect the serum levels of IL-17,IL-6,IL-23,and IL-1β.The receiver operating characteristic(ROC)curve analyses were conducted,and the the optimal diagnostic cut-off value was derived from the area under the curve(AUC).Multivariate logistic regression analysis was used to evaluate the predictors of LVDD.Moreover,the correlations between serum IL-17 and soluble cell adhesion molecule(sICAM-1),monocyte chemotactic protein(MCP-1)and E-selectin were analyzed with correlation coefficients.In vitro,endothelial cell functions,such as migration,proliferation and apoptosis,were evaluated using recombinant human IL-17 protein to stimulate endothelial cells.Results A total of 80 patients with essential hypertension were enrolled in this study,including 47 patients in the higher LVEDP group and other 33 patients in the normal LVEDP group.The serum levels of IL-17,IL-6 and IL-23 were significantly higher in the higher LVEDP group than those in the normal LVEDP group(all P<0.05).ROC curve analysis revealed that IL-17 showed the highest diagnostic accuracy in predicting LVDD with the highest AUC[0.896,95%confidence interval(CI)0.824-0.967,P<0.001],with the cut-off value of 18.5 pg/mL.On logistic regression analysis,higher serum IL-17 was an independent predictor for the prognosis of LVDD(odd ratio 1.27,95%CI 1.09-1.24,P<0.05).According to the serum IL-17 cut-off value,patients were classified as lower expression of IL-17(<18.5pg/mL)group(n=35)and higher expression of IL-17(≥18.5 pg/mL)group(n=45).Patients with lower expression of IL-17 had a higher percentage of LVDD improvement and a lower incidence of primary endpoint events at the last follow-up than those with higher expression of IL-17.Serum level of IL-17 was positively correlated with sICAM-1(r=0.26,P=0.001),MCP-1(r=0.30,P=0.007)and E-selectin(r=0.24,P=0.031).In vitro,IL-17 stimulation reduced endothelial cell migration and proliferation,and increased apoptosis.Furthermore,IL-17 stimulation increased the expression of sICAM-1,MCP-1 and E-selectin in endothelial cells.Conclusion Serum IL-17 may be an important diagnostic and prognostic value for LVDD in patients with essential hypertension.