CopeptinNTproBNP与心力衰竭的相关性研究

中文摘要：本研究目的旨在研究心力衰竭患者血清氨基末端一脑钠肽前体（NT-proBNP）与和肽素（Copeptin）的相关性，分别观察心衰患者血清NT-proBNP、Copeptin水平与心衰严重程度（纽约心功能分级NYHA）的关系；探讨血清NT-proBNP、Copeptin水平对心力衰竭患者诊断及预后的价值。
方法：选取2011年9月至2013年6月两年间天津市人民医院心内科因冠心病、高血压病合并心功能不全（NYHA II-IV级）而住院的心力衰竭（诊断标准参照Framingham心力衰竭诊断标准）患者，共230例（男112例，女118例）为心衰组。选取我院同期心功能正常的健康体检者51例（男24例，女27例），与心衰组无显著的性别及年龄差异为对照组。收集心衰组和对照组年龄、性别、体重、身高、血压、既往史、个人史、家族史等基本信息和临床及实验室检查结果，超声心动图检测左室射血分数(LVEF)、左室舒张末期内径（LVEDD）、室间隔厚度(IVST)、左室后壁厚度(LVPWT)等指标，计算左室质量指数(LVMI)。酶联免疫法（ELISA）测定血清NT-proBNP、Copeptin水平。将心衰组与对照组进行临床基本资料及NT-proBNP、Copeptin水平的比较；将心功能（NYHAII级、NYHAIII级、NYHAIV级）不同的各组间进行临床基本资料及NT-proBNP、Copeptin、LVEF水平的比较；将NT-proBNP、Copeptin分别与临床基本资料及NYHA分级进行相关性分析，并进一步行逐步回归分析；NT-proBNP、Copeptin水平对心衰诊断价值用受试工作者特征(ROC)曲线表示，利用ROC曲线下面积及该面积的95%可信区间求出诊断界值及其敏感性和特异性，以P<0.05判断为有显著性差异。
结果：1. 心衰组与对照组的临床基本资料比较。心衰组 NT-proBNP、 Copeptin水平升高, FBG、WBC 、TG 、Cr、BUN水平升高，RBC、HGB 、Ccr水平降低，与对照组患者比较，差异有统计学意义(P < 0.05或P < 0.01)。两组年龄、性别、体质指数、TC、LDLc组间差异无统计学意义（P＞0.05）。
2．将心衰患者血清NT-proBNP、Copeptin浓度水平按心功能的严重程度分级与对照组进行比较，结果显示随着心功能严重程度的逐渐加重，NT-proBNP、Copeptin逐渐升高，且差异有统计学意义（P<0.001）。
3．将血清NT-proBNP水平与临床基本资料及NYHA心功能分级进行简单线性相关分析，结果显示血清NT-proBNP水平与Copeptin呈显著正相关(r=0.662，P ＜0.001)；NT-proBNP水平与NYHA心功能分级呈正相关，(r=0.601，P ＜0.001)；NT-proBNP与年龄、WBC 、FBG、BUN、Cr、LVMI呈正相关(P<0.05)，与Ccr、RBC、HBG、LDLc、LVEF呈负相关(P<0.001)。
4． 将血清Copeptin水平与临床基本资料及NYHA心功能分级进行简单线性相关分析，结果显示血清Copeptin水平与NT-proBNP呈显著正相关(r=0.662，P ＜0.001)；Copeptin水平与NYHA心功能分级呈正相关，(r=0.345，P ＜0.001)；Copeptin与WBC 、FBG、TG、BUN、Cr、LVMI、LVDd、TNT、Hs-CRP呈正相关(P<0.05)，与RBC、HBG、LVEF呈负相关(P<0.001)。
5． 以NT-proBNP为因变量时的逐步回归分析显示Copeptin与LVEF 为NT-proBNP 的独立影响因素；以Copeptin为因变量时的逐步回归分析显示LVMI、NT-proBNP为Copeptin的独立影响因素。
6． 分别以NT-proBNP及Copeptin为检验变量，以左室功能不全为状态变量进行ROC曲线分析。以NT-proBNP为检验变量时ROC曲线下面积AUC=0.918，有显著的诊断价值（P<0.001），正确诊断指数Youden指数最大为0.704，此时NT-proBNP取值为≥374.92 fmol/ml，诊断敏感度为70.4%，诊断特异度为100%； 以Copeptin为检验变量时AUC=0.787,有显著的诊断价值（P<0.001）,Youden指数最大为0.476，此时Copeptin取值为≥15.367pmol/l，诊断敏感度为57.4%，诊断特异度为90.2%。本研究结果显示NT-proBNP及Copeptin对心力衰竭均有诊断价值，但NT-proBNP 优于Copeptin。
结论：1本研究通过对心衰组及对照组血清NT-ProBNP及Copeptin水平的测定，显示NT-ProBNP及Copeptin水平与心功能严重程度密切相关，与对照组比较心衰患者血清NT-proBNP及Copeptin水平显著升高，且随着心功能恶化程度逐级显著升高，差异有统计学意义(P<0.0l)。提示copeptin、 NT-proBNP的持续过度表达均参与了疾病的病理、生理机制，并可能影响心力衰竭的进展可作为诊断心衰，预测病情变化趋势及心衰危险分层的敏感指标。此外Copeptin、NT-proBNP水平随着心功能恶化程度逐级显著升高提示对发现早期心衰和无症状心衰有帮助有利于提高心衰诊断的准确性。
2 心衰患者血清NT-proBNP与Copeptin呈显著正相关(r=0.662，P ＜0.001)；NT-proBNP、Copeptin水平与NYHA心功能分级呈正相关(r=0.601、r=0.345，P ＜0.001)，通过ROC曲线分析，本研究结果显示NT-proBNP及Copeptin对心力衰竭均有诊断价值，但NT-proBNP 优于Copeptin。提示copeptin 水平与NT-proBNP 相似，均随着心衰病变程度的不同而变化，同样能够较好地反映心脏工作状态。故联合检测患者 copeptin、NT-proBNP 水平不仅可作为辅助临床评价心衰程度的良好生化指标还有利于更准确的对心衰患者进行治疗和风险监测，同时还可为高危患者的筛查提供一种简便而经济的方法。因本研究未进行心衰患者预后的随访，两者对再入院率、病死率的预测价值未能在本研究中进行进一步的比较。

关键词：慢性心力衰竭 ，和肽素 ， 氨基末端一脑钠肽前体
Abstract
Objective: The purpose of this study was to study heart failure patients serum amino terminal pro brain natriuretic peptide (NT-proBNP) and peptide (Copeptin) correlation, Copeptin level in patients with heart failure were observed and serum NT-proBNP, severity of heart failure (New York Heart Association functional class NYHA) relations; to investigate the value of serum NT-proBNP, Copeptin levels on the diagnosis and treatment of patients with heart failure.
Method: From 2011 September to 2013 June two years the Department of Cardiology of Tianjin People’s Hospital from coronary heart disease, hypertension and heart failure (NYHA II-IV) and hospitalized heart failure (diagnostic criteria of diagnosis of heart failure in patients with reference to Framingham standard), a total of 230 cases (male 112 cases, female 118 cases) for heart failure group. Select 51 patients in our hospital during the same period of cardiac function in normal healthy subjects (male 24 cases, female 27 cases), and heart failure group had no significant differences in age and sex as control group. Collection of heart failure group and control group in age, gender, weight, height, blood pressure, past medical history, personal history, family history and other basic information and clinical and laboratory examination, ultrasonic Heartbeat map detection of left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT) and other indicators, to calculate the left ventricular mass index (LVMI). Enzyme linked immunosorbent assay (ELISA) for determination of serum NT-proBNP, Copeptin levels. Comparison of the heart failure group and control group of basic clinical data and NT-proBNP, Copeptin levels; heart function (NYHAII, NYHAIII, NYHAIV) compared the clinical data and NT-proBNP, Copeptin, LVEF levels in different groups of NT-proBNP, Copeptin respectively; and the basic clinical data and NYHA grading were compared further, and stepwise regression analysis; NT-proBNP, Copeptin level of heart failure diagnostic value by worker characteristics (ROC) curve, the area under ROC curve and the area of the 95% confidence interval is calculated and the sensitivity and specificity of diagnosis value, with a significant difference for P<0.05 judgment.
Result: 1. Clinical comparison of basic data of heart failure group and control group. Elevated heart failure group NT-proBNP, Copeptin levels, increased FBG, WBC, TG, Cr, BUN, RBC, HGB, Ccr levels decreased, and were compared with a control group, the difference was statistically significant (P < 0.05 or P < 0.01). The two groups had no statistically significant age, sex, body mass index, TC, LDLc between group differences (P > 0.05).
2. The heart failure patients serum NT-proBNP, Copeptin levels in cardiac function grading the severity compared with control group, the results showed that with the increasing severity of cardiac function, NT-proBNP, Copeptin increased gradually, and the difference was statistically significant (P<0.001).
3. The cardiac function and the serum NT-proBNP level of basic clinical data and NYHA classification of simple linear correlation analysis, the results showed that the serum NT-proBNP level was positively correlated with Copeptin (r=0.662, P < 0.001); the level of NT-proBNP was positively correlated with NYHA classification of cardiac function, (r=0.601, P < 0.001); NT-proBNP was positively correlated with age, WBC, FBG, BUN, Cr, LVMI (P<0.05), and negatively correlated with Ccr, RBC, HBG, LDLc, LVEF (P<0.001).
4. The cardiac function and the serum Copeptin level of basic clinical data and NYHA classification of simple linear correlation analysis, the results showed that the serum Copeptin level was positively correlated with NT-proBNP (r=0.662, P < 0.001); the level of Copeptin was positively correlated with NYHA classification of cardiac function, (r=0.345, P < 0.001); Copeptin was positively correlated with WBC, FBG, TG, BUN, Cr, LVMI, LVDd, TNT, Hs-CRP (P<0.05), and negatively correlated with RBC, HBG, LVEF (P<0.001).
5. The dependent variable of the stepwise regression analysis showed that Copeptin and LVEF are independent prognostic factors of NT-proBNP with NT-proBNP as the dependent variable; stepwise regression analysis showed that LVMI, NT-proBNP is the independent risk factors of Copeptin based on Copeptin.
6. With NT-proBNP and Copeptin respectively for inspection by variables, left ventricular dysfunction as state variables by ROC curve analysis. Taking NT-proBNP as the test variable area under the ROC curve of AUC=0.918[95%CI0.883-0.953], there are significant diagnostic value (P<0.001), the correct diagnosis of Youden index of a maximum of 0.704, when the NT-proBNP value is greater than or equal to 374.92 fmol/ml, the diagnostic sensitivity was 70.4%, specificity was 100%; with Copeptin as test variables AUC=0.787[95%CI0.726-0.848], have significant diagnostic value (P<0.001), the maximum Youden index was 0.476, the Copeptin value is greater than or equal to 15.367pmol/l, the diagnostic sensitivity was 57.4%, specificity was 90.2%. The results showed that, the value of NT-proBNP and Copeptin in heart failure has diagnosis, but NT-proBNP is better than Copeptin.
Conclusion: 1.  through the study on the determination of heart failure group and the control group of serum NT-ProBNP and Copeptin levels, showed closely related to NT-ProBNP and Copeptin levels and severity of cardiac function in patients with heart failure, compared with the control group, serum NT-proBNP and Copeptin levels significantly increased, and with the heart function deteriorated gradually increased, the difference was statistically significant (P<0.0l). Copeptin, the duration of NT-proBNP over expression were involved in the pathological, physiological mechanism of disease, and may affect the progression of heart failure can be used as a sensitive index of diagnosis of heart failure, prognosis and change trend of heart failure risk stratification. In addition to Copeptin, NT-proBNP levels with the deterioration of cardiac function gradually increased significantly prompts for early detection of heart failure and asymptomatic heart failure have help is beneficial to improve the accuracy of diagnosis of heart failure.
2. heart failure patients with NT-proBNP had significant positive correlation with Copeptin (r=0.662, P < 0.001); NT-proBNP and Copeptin levels and NYHA classification of cardiac function was positively (r=0.601, r=0.345, P < 0.001), through ROC analysis, the results of this study show the value of NT-proBNP and Copeptin in heart failure has diagnosis, but NT-proBNP is better than Copeptin. Results suggest that the level of copeptin and NT-proBNP were similar, which changes with the different degree of heart failure disease, also can reflect the heart condition. The combined detection of copeptin, NT-proBNP levels in patients with not only can be used as a good biochemical indexes used to evaluate the severity of heart failure and to more accurate treatment and risk monitoring of patients with heart failure, also can provide a convenient and economic method for screening high-risk patients. Because this study did not test the outcomes in patients with heart failure of follow-up, the predictive value is not the rate, fatality on readmission were further compared in this study.

 以上研究均表明在心力衰竭患者中血浆 Copeptin水平在判断心力衰竭程度与其预后中的价值。本文研究结果显示血清NT-proBNP 、Copeptin水平均高于正常对照组,且随NYHA分级的增加而显著升高，且两者具有相关性(相关系数=0.662)。提示二者在心衰过程中可能具有相互促进作用。但通过ROC曲线分析，以NT-proBNP为检验变量时ROC曲线下面积AUC=0.918[95%CI0.883-0.953]，有显著的诊断价值（P<0.001），诊断敏感度为70.4%，诊断特异度为100%。以Copeptin为检验变量时AUC=0.787[95%CI0.726-0.848],有显著的诊断价值（P<0.001），诊断敏感度为57.4%，诊断特异度为90.2%。本研究结果显示对CHF的诊断价值NT-proBNP 优于Copeptin，这说明NT—porBNP是心衰诊断中的一项非常有价值的检查。但是目前尚无统一标准的NYHAⅡ一Ⅳ级的NT—porBNP浓度的参考水平，尤其国内只有一些小样本的参考值。我们在本研究中分别以NT-proBNP及Copeptin为检验变量，以左室功能不全为状态变量进行ROC分析。以NT-proBNP为检验变量时正确诊断指数Youden指数最大为0.704，此时NT-proBNP取值为≥374.92 fmol/ml，以Copeptin为检验变量时，Youden指数最大为0.476，此时Copeptin取值为≥15.367pmol/l。 随着Copeptin、NT—porBNP检查的临床普及，有待于更多的大规模的多中心临床研究指导今后在临床上的普遍应用。因本研究未进行心衰患者预后的随访，两者对再入院率、病死率的预测价值未能进一步的比较。
4 .5 Copeptin与心力衰竭相关性研究的临床意义
Copeptin与心力衰竭的关系研究可能对心力衰竭的发病机制、判断预后以及相关药物的开发有着较好的前景：(1)Copeptin通过多种途径参与心力衰竭的发病，使人们对心力衰竭的发病机制有了更深入的认识；(2)血液中Copeptin的水平随着心力衰竭的进展逐步升高。其升高程度与心力衰竭的严重程度成正相关，可能成为临床监测心力衰竭患者心功能严重程度和判断预后的客观依据之一；(3)在动物实验和心力衰竭的病人中得到Copeptin升高的证据，促使人们去寻找抑制AVP作用的药物。用以阻断AVP在慢性心力衰竭中的有害作用。
综上所述，血浆Copeptin 含量与BNP 、NT-proBNP 相似，均随着心衰病变程度的不同而变化，同样能够较好地反映心脏工作状态。故联合检测患者Copeptin、NT-proBNP 水平不仅可作为辅助临床评价心衰程度的良好生化指标还有利于更准确的对心衰患者进行治疗和风险监测，同时还可为高危患者的筛查提供一种简便而经济的方法。美国国家临床生化学会将Copeptin列为最有潜 质的心脏标记物之一[77]。在不久的将来，Copeptin作为一项重要的客观指标可能会用于心力衰竭的初步筛查和诊断，其临床应用价值相当可观。
4.7本研究的潜在影响因素与不足之处
本研究有如下几个不足之处：首先，受时间及精力等客观条件限制，本研究是单中心、小样本观察性临床研究，可能得到的研究结果及临床观察结果带有一定的偏倚尚不能完全准确代表一般人口统计学以及心力衰竭患者的临床特征，但在实施过程中严格按照心力衰竭诊断标准选取病例，因此我们期待开展有关Copeptin、NT-proBNP 在心力衰竭对比性的、多中心、大样本、随机临床试验。其次，本研究受时间的限制，未进行心衰患者预后的随访，Copeptin、NT-proBNP对再入院率、病死率的预测价值未能在研究中进一步的比较。再次，受患者依从性等方面的限制，本研究仅仅在患者入院初期进行了一次采血标本检测，无法了解随着疾病的进展时指标的变化情况，这方面的工作有待今后的研究继续进行。

结论
1本研究通过对心衰患者及对照组血清NT-ProBNP及Copeptin水平的测定，显示NT-ProBNP及Copeptin水平与心功能NYHA分级严重程度密切相关(P<0.0l)，与对照组比较心衰患者血NT-proBNP及Copeptin水平显著升高，差异有统计学意义(P<0.0l)。提示copeptin、 NT-proBNP的持续过度表达均参与了疾病的病理、生理机制，并可能影响心力衰竭的进展可作为诊断心衰，预测病情变化趋势及心衰危险分层的敏感指标 。此外Copeptin、NT-proBNP水平随着心功能恶化程度逐级显著升高提示对发现早期心衰和无症状心衰有帮助有利于提高心衰诊断的准确性。
2 心衰患者血清NT-proBNP与Copeptin水平呈显著正相关(P<0.0l)，通过ROC曲线分析，本研究结果显示对CHF的诊断价值NT-proBNP 优于Copeptin，因本研究未进行心衰患者预后的随访，两者对再入院率、病死率的预测价值未能在本研究中进行进一步的比较。
3 NT-proBNP与年龄、WBC 、FBG、BUN、Cr、LVMI呈正相关(P<0.05)，与Ccr、RBC、HBG、LDLc、LVEF呈负相关(P<0.001)。逐步回归分析显示Copeptin与LVEF为NT-proBNP 的独立影响因素。Copeptin与WBC 、FBG、TG、BUN、Cr、LVMI、LVDd、TNT、Hs-CRP呈正相关(P<0.05)，与RBC、HBG、LVEF呈负相关(P<0.001)。逐步回归分析显示LVMI、NT-proBNP为Copeptin的独立影响因素。

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