大内皮素与心力衰竭患者预后的关系

Relationship between plasma big endothelin-1 level and prognosis of heart failure

目的探讨大内皮素(big ET-1)对心力衰竭(心衰)的预后价值。方法纳入2015年7月至2017年7月期间因心衰在中国医学科学院阜外医院心衰重症监护病房住院的患者。以基线big ET-1水平三分位数为依据将研究对象分为低big ET-1组、中big ET-1组及高big ET-1组,比较三组患者一般临床资料。设定全因死亡或心脏移植为主要临床终点事件,多因素COX回归分析、Kaplan-Meier生存曲线、限制性立方样条图、time-ROC曲线及多因素COX回归模型风险预测检验用于评估基线big ET-1对心衰的预后价值。结果共纳入704例患者,低big ET-1组(big ET-1≤0.34 pmol/L)、中big ET-1组(big ET-10.34-0.70 pmol/L)及高big ET-1组(big ET-1≥0.70 pmol/L),分别为233例、236例和235例。规律随访期间共有86例(12.2%)患者失访,经中位随访930天,199例(28.2%)患者发生了全因死亡或心脏移植。多因素COX回归分析显示,基线big ET-1是心衰患者发生全因死亡或心脏移植的独立预测因子[每一个单位log,校正后风险比(HR)1.58,95%可信区间(CI)1.35~1.85,P<0.001],以基线big ET-1三分位数分组,结果显示,与低big ET-1组患者相比,中big ET-1组和高big ET-1患者发生全因死亡或心脏移植的风险分别增加近1倍(HR 1.78,95%CI 1.05~3.02,P=0.032)和2倍(HR 3.16,95%CI 1.88~5.32,P<0.001)。Kaplan-Meier生存曲线分析显示各组间的生存率差异具有统计学意义(P<0.001)。限制性立方样条图分析显示全因死亡或心脏移植风险随big ET-1水平增加而增加。Time-ROC曲线分析显示,基线big ET-1对心衰患者3个月、1年及2年发生全因死亡或心脏移植风险均具有较好的预测价值(AUC分别为0.76、0.76及0.76)。多因素Cox回归模型风险预测检验显示,在N末端B型利钠肽原(NT-proBNP)基础上联用big ET-1有助于为心衰预后评估提供额外的预测价值(P<0.001)。亚组分析中,基线big ET-1是缺血性心衰患者发生全因死亡或心脏移植的独立预测因子(每一个单位log,校正后HR 1.99,95%CI 1.32~3.00,P<0.001),亦是非缺血性心衰患者发生全因死亡或心脏移植的独立预测因子(每一个单位Log,校正后HR 1.47,95%CI 1.23~1.76,P<0.001)。此外,基线big ET-1在射血分数降低的心力衰竭(HFrEF)(每一个单位log,校正后HR 1.50,95%CI 1.22~1.84,P<0.001)、射血分数轻度降低的心力衰竭(HFmrEF)(每一个单位log,校正后HR 4.70,95%CI 1.74~12.69,P=0.002)及射血分数保留的心力衰竭(HFpEF)(每一个单位log,校正后HR 2.29,95%CI 1.54~3.42,P<0.001)患者中均可作为全因死亡或心脏移植的独立预测因子。结论基线big ET-1是心衰患者发生全因死亡或心脏移植的独立预测因子。在NT-proBNP基础上,big ET-1有助于为心衰预后评估提供额外的预测价值。

Objective To investigate the prognosis value of big endothelin-1(big ET-1)for heart failure.Methods Patients who were admitted to Heart Failure Care Unit of Fuwai hospital and diagnosed with heart failure from July 2015 to July 2017 were enrolled and divided into three groups according to the tertiles of baseline big ET-1 level.The clinical characteristics of three groups were compared.The primary endpoint was the composite of all-cause death or heart transplantation.Multivariate Cox regression analysis,Kaplan-Meier analyses,restricted cubic spline(RCS),receiver operating characteristic(ROC)curves and risk prediction test with multivariate Cox regression model were used to identify the prognosis value of baseline big ET-1 for heart failure.Results A total of 704 patients were enrolled and divided into low big ET-1 group(big ET-1≤0.34 pmol/L,n=233),medium big ET-1 group(big ET-10.34-0.70 pmol/L,n=236)and high big ET-1 group(big ET-1≥0.70 pmol/L,n=235).During the median follow-up of 930 days,86 patients(12.2%)were lost to follow-up and 199 patients(28.2%)died for all-cause or underwent heart transplantation.Multivariate Cox regression analysis showed that baseline big ET-1 was the independent predictor of all-cause death or heart transplantation for patients with heart failure[per 1 log unit,adjusted hazard ratio(HR)1.58,95%confidence interval(CI)1.35-1.85,P<0.001].Compared with patients in low big ET-1 group,the risk of all-cause death or heart transplantation in medium big ET-1 group was nearly doubled(HR 1.78,95%CI 1.05-3.02,P=0.032)and patients in the high big ET-1 group had a 2-fold increased risk of all-cause death or heart transplantation(HR 3.16,95%CI 1.88-5.32,P<0.001).Kaplan-Meier analyses showed that the survival rates were significantly different among three groups(P<0.001).RCS demonstrated that the risk of all-cause death or heart transplantation increased along with the level of big ET-1.Time-ROC curves revealed that baseline big ET-1 could serve as an excellent predictor of all-cause death or heart transplantation for patients with heart failure within 3 months,1 year and 2 years,with the area under the cureve(AUC)of 0.76,0.76 and 0.76,respectively.Risk prediction test with multivariate Cox regression model showed that baseline big ET-1 could provide additional predictive value for the prognostic assessment of heart failure with the combination of N terminal-pro B type natriuretic peptide(NT-proBNP)(P<0.001).In subgroup analysis,it was showed that big ET-1 was the independent predictor of all-cause death or heart transplantation in patients with ischemic heart failure(per 1 log unit,adjusted HR 1.99,95%CI 1.32-3.00,P<0.001)and non-ischemic heart failure(per 1 log unit,adjusted HR 1.47,95%CI 1.23-1.76,P<0.001).In addition,it turned out that big ET-1 was also the independent risk factor of adverse clinical outcome for patients with heart failure with reduced ejection fraction(HFrEF)(per 1 log unit,adjusted HR 1.50,95%CI 1.22-1.84,P<0.001),heart failure with midly reduced ejection fraction(HFmrEF)(per 1 log unit,adjusted HR 4.70,95%CI 1.74-12.69,P=0.002)and heart failure with preserved ejection fraction(HFpEF)(per 1 log unit,adjusted HR 2.29,95%CI 1.54-3.42,P<0.001).Conclusion Baseline big ET-1 was the independent predictor of all-cause death or heart transplantation for patients with heart failure.It could provide additional predictive value for the prognostic assessment of heart failure with the combination of NT-proBNP.