·论著· 
 N末端B型利钠肽原联合冠状动脉钙化总积分对老年稳定性冠心病患者预后风险评估的价值研究 
 卞娜娜,胡立群*,李红旗 
   
  基金项目:安徽省科技厅公益联动项目(1604f0804009)
 230001安徽省合肥市,安徽医科大学附属省立医院老年心内科
*通信作者:胡立群,主任医师,硕士生导师;E-mail:hlqae3005@126.com  
  【摘要】 目的 探讨N末端B型利钠肽原(NTproBNP)联合冠状动脉钙化总积分(TCS)对老年稳定性冠心病(SCAD)患者预后风险评估的价值。 方法 选取2013年3月—2016年1月在安徽医科大学附属省立医院老年心内科住院治疗的老年SCAD患者264例,根据随访期(2~34个月)内是否发生主要不良心血管事件(MACE)分为非MACE组(n=151)和MACE组(n=113)。采用德国Roche Elecsys 2010全自动免疫分析仪及Roche试剂盒检测血浆NTproBNP水平;采用美国通用电器公司(GE)的64排128层螺旋CT对患者进行冠状动脉CT平扫,采集数据后将扫描得到的图像传到工作站,利用自带的Smart score软件计算TCS。运用统计学分析将两种指标联合建立综合预测模型实现对老年SCAD患者发生MACE的评估。 结果 两组性别、年龄、BMI、吸烟史、高血压病史、糖尿病病史、血脂异常史间差异均无统计学意义(P>0.05)。MACE组NTproBNP、TCS均高于非MACE组,差异有统计学意义(P<0.05)。构建Logistic回归模型:Logit(P)=-2.602+0.001 NTproBNP+0.010TCS,得到新联合指标Logit(P)。新联合指标预测老年SCAD患者发生MACE的受试者工作特征(ROC)曲线下面积(AUC)为0.891〔95%CI(0.847,0.926),P<0.01〕,灵敏度和特异度分别为0.788、0.848;NTproBNP预测老年SCAD患者发生MACE的AUC为0.770〔95%CI(0.715,0.820),P<0.01〕,灵敏度和特异度分别为0.549、0.808;TCS预测老年SCAD患者发生MACE的AUC为0.833〔95%CI(0.782,0.876),P<0.01〕,灵敏度和特异度分别为0.779、0.755。新联合指标与NTproBNP、TCS预测老年SCAD患者发生MACE的AUC比较,差异均有统计学意义(Z值分别为4.83、2.63,P<0.01);NTproBNP与TCS预测老年SCAD患者发生MACE的AUC比较,差异无统计学意义(Z=1.56,P=0.12)。 结论 NTproBNP联合TCS对老年SCAD患者预后风险评估的价值高于任一单个指标,为老年SCAD患者不良预后早期预测提供更可靠的方法。
  【关键词】  老年人;稳定性冠心病;N末端B型利钠肽原;冠状动脉钙化总积分;主要不良心血管事件 
  【中图分类号】R 541.4 【文献标识码】A DOI:10.3969/j.issn.1007-9572.2017.01.013
  卞娜娜,胡立群,李红旗.N末端B型利钠肽原联合冠状动脉钙化总积分对老年稳定性冠心病患者预后风险评估的价值研究[J].中国全科医学,2017,20(1):62-66.[www.chinagp.net] 
  BIAN N N,HU L Q,LI H Q.Value of N-terminal pro-B-type natriuretic peptide combined with total coronary calcification score in evaluating the risk of prognosis among elderly patients with stable coronary artery disease[J].Chinese General Practice,2017,20(1):62-66. 
 
 Value of N-terminal Pro-B-type Natriuretic Peptide Combined with Total Coronary Calcification Score in Evaluating the Risk of Prognosis among Elderly Patients with Stable Coronary Artery Disease BIAN Na-na,HU Li-qun*,LI Hong-qi 
 Department of Geriatric Cardiology,Provincial Hospital Affiliated to Anhui Medical University,Hefei 230001,China 
 *Corresponding author:HU Li-qun,Chief physician,Master supervisor;E-mail:hlqae3005@126.com 
 
  【Abstract】 Objective  To investigate the value of N-terminal pro-B-type natriuretic peptide(NTproBNP) combined with total coronary calcification score(TCS) in evaluating the risk of prognosis among elderly patients with stable coronary artery disease(SCAD).
 Methods A total of 264 elderly patients with SCAD,who were under treatment in Department of Geriatric Cardiology,Provincial Hospital Affiliated to Anhui Medical University from March 2013 to January 2016 were selected in the study.According to whether there were major adverse cardiovascular events(MACE) during the follow-up periold(2-34 months) or not,the subjects were classified into non-MACE group(n=151) and MACE group(n=113).The German full-automatic immunoassay analyzer(Roche Elecsys 2010) and Roche kit were applied to detect the plasma levels of NTproBNP;CT scan of coronary artery of the patients was performed by 64-row with 128-slice computed tomography of American General Electric Company(GE),after data collection,send the scanned image to the workstation and calculate TCS by built-in Smart score.With statistical analysis,the two indicators were combined to build integrated prediction model to achieve the evaluation of MACE among elderly patients with SCAD.
 Results There were no significant differences in gender,age,BMI,smoking history,history of hypertension,history of diabetes mellitus and dyslipidemia between the two groups(P>0.05).NTproBNP and TCS in MACE group were significantly higher than those in non-MACE group(P<0.05).Logistic regression model was constructed:Logit(P)=-2.602+0.001 NTproBNP+0.010TCS,and the new combined index Logit(P) was obtained.The area under the curve(AUC) of receiver operating characteristic(ROC) of MACE occurring in elderly patients with SCAD predicted by new combined indicators was 0.891 〔95%CI(0.847,0.926),P<0.01〕,and the sensitivity and specificity were 0.788 and 0.848 respectively;the AUC of ROC of MACE occurring in elderly patients with SCAD predicted by NTproBNP was 0.770 〔95%CI(0.715,0.820),P<0.01〕,and the sensitivity and specificity were 0.549 and 0.808 respectively;the AUC of ROC of MACE occurring in elderly patients with SCAD predicted by TCS was 0.833 〔95%CI(0.782,0.876),P<0.01〕,and the sensitivity and specificity were 0.779 and 0.755 respectively.The AUC of MACE occurring in patients predicted by new combined indictors,NTproBNP and TCS were significantly different(Z=4.83 and 2.63 respectively,P<0.01);the AUC of MACE occurring in patients predicted by NTproBNP and TCS were not significantly different(Z=1.56,P=0.12).
 Conclusion The value of NTproBNP combined with TCS in evaluating the risk of prognosis among elderly patients with SCAD is better than that of any single indicator,and provides a more reliable method of early prediction of the poor prognosis among elderly patients with SCAD.
  【Key words】  Aged;Stable coronary artery disease;N-terminal pro-B-type natriuretic peptide;Total coronary calcification score;Major adverse cardiovascular events    
  
  
目前冠心病是威胁人类健康和生命的最常见慢性病之一,其中我国老年人群中最常见的心血管疾病是稳定性冠心病(stable coronary artery disease,SCAD),现指南定义SCAD不仅包括冠状动脉狭窄,还包括冠状动脉痉挛及无症状心肌缺血等,由于其临床特征多样且不典型,致死风险较大,常规诊断方法如血清学指标、心电图、冠状动脉造影检查等结果多为阴性,易造成老年SCAD患者对自身病情认识不足,缺乏有效长期管理疾病的方法,从而导致严重的主要不良心血管事件(major adverse cardiovascular events,MACE)发生 [1]。N末端B型利钠肽原(N-terminal pro-B-type natriuretic peptide,NTproBNP)主要存在于心室肌分泌颗粒中,NTproBNP水平随着心室壁张力升高而变化,是临床上目前公认最有价值的诊断心功能不全和判断预后的工具 [2]。近年来已有研究证实NTproBNP水平升高也可增加SCAD患者发生MACE风险 [3]。另外钙化积分作为冠状动脉钙化检测和定量分析的一项无创检查手段正被广泛使用,有研究表明传统的冠心病危险因素评估可以被冠状动脉钙化总积分(total coronary calcification score,TCS)评估冠心病风险所替代 [4]。目前也尚无指南可清晰提供关于SCAD患者危险评估模型 [5],故本研究通过临床随访分析,旨在探讨NTproBNP联合TCS对老年SCAD患者发生MACE风险的预测价值,为老年SCAD患者的早期诊断及预后找到更具价值的预测模型。
 1 对象与方法 
1.1 研究对象 选取2013年3月—2016年1月在安徽医科大学附属省立医院老年心内科住院治疗的老年SCAD患者264例。SCAD诊断标准:(1)有明确心肌梗死病史,且>3个月;(2)冠状动脉CT血管成像或冠状动脉造影存在1支以上冠状动脉血管狭窄程度>50%;(3)无创心电图运动负荷试验证实存在心肌缺血证据,满足以上条件中≥1项且心绞痛症状60 d内稳定 [6]。纳入标准:(1)均由本科2名以上高年资医生诊断确定,无重复且无亲缘关系;(2)年龄>60岁。排除标准:(1)存在急性冠状动脉综合征、心脏瓣膜疾病、心肌炎或先天性心脏疾病患者;(2)近3个月伴严重感染、手术、创伤患者;(3)严重肝肾功能不全、甲状腺功能异常患者;(4)贫血、恶性肿瘤、结缔组织异常患者。根据随访期内是否发生MACE分为非MACE组(n=151)和MACE组(n=113),其中MACE组中发生心源性再入院61例,非致死性急性心肌梗死(AMI) 34例,死亡18例。本研究经安徽医科大学附属省立医院伦理委员会批准,患者及其家属均签署知情同意书。
1.2 方法
1.2.1 资料收集 记录患者性别、年龄、体质量、身高,询问有无吸烟史(吸烟的定义为1支/d,连续吸烟6个月以上)、高血压病史、糖尿病病史、血脂异常史等,并计算BMI。
1.2.2 NTproBNP水平检测 患者均于入院后第2天清晨空腹10 h以上采集肘静脉血5 ml,置于乙二胺四乙酸(EDTA)抗凝管中,立即于常温下以离心半径6 cm、3 000 r/min离心5 min后取上清液用于快速检测,采用德国Roche Elecsys 2010全自动免疫分析仪及Roche试剂盒检测血浆NTproBNP水平,操作过程遵照仪器规程及试剂盒说明书进行。
1.2.3 TCS计算 采用美国通用电器公司(GE)的64排128层螺旋CT对患者进行冠状动脉CT平扫,扫描范围从气管隆突至心尖部水平,嘱患者吸气后屏气一次性完成扫描,扫描时间为5~6 s,采集数据后将扫描得到的图像传到工作站,利用自带的Smart score软件计算TCS,设定斑块钙化CT阈值>130 HU,其中相应的高密度血管钙化区域会被自动识别,将其选中后软件可相应计算出各冠状动脉钙化积分,并相加可得到TCS,记录结果。
1.2.4 出院随访 对入选的264例患者住院期间密切关注病情发展变化,出院后利用门诊回访、病历复查及电话方式,共随访2~34个月,主要记录随访期间患者有无新发的MACE,即有无心源性再入院、非致死性AMI、冠状动脉血运重建及死亡等。随访期间患者是否经历MACE需由2名主治及以上级别医生达成统一意见确定。若第1次随访未成功的患者,在1周内重复3次随访;如果仍未成功或者患者不能提供有效信息,则记录为失访,在本研究中无失访患者。
1.3 统计学方法 采用SPSS 22.0统计软件进行统计学分析。符合正态分布的计量资料以(x   ±s)表示,组间比较采用t检验;不符合正态分布的计量资料以中位数(四分位数间距)〔M(QR)〕表示,组间比较采用Mann-Whitney U检验;计数资料采用χ2检验;采用建立的Logistic回归模型得到新联合指标Logit(P),再依据受试者工作特征(ROC)曲线计算新联合指标及NTproBNP、TCS的曲线下面积(AUC)、灵敏度、特异度;不同指标AUC比较采用MedCalc软件中的Z检验。以P<0.05为差异有统计学意义。
 2 结果 
2.1 两组一般资料比较 两组性别、年龄、BMI、吸烟史、高血压病史、糖尿病病史、血脂异常史间差异均无统计学意义(P>0.05,见表1)。
2.2 两组NTproBNP、TCS比较 两组NTproBNP、TCS间差异均有统计学意义(P<0.05,见表2)。
2.3 建立Logistic回归模型 以随访34个月内是否发生MACE为因变量(赋值:未发生=0,发生=1),以NTproBNP、TCS为自变量,进行多元Logistic回归分析,构建Logistic回归模型:Logit(P)=-2.602+0.001NTproBNP+0.010TCS,对该模型进行似然比检验,结果显示有统计学意义(χ2=134.53,P<0.01,见表3)。 
2.4 新联合指标及NTproBNP、TCS对老年SCAD患者发生MACE的预测作用 新联合指标预测老年SCAD患者发生MACE的AUC为0.891〔95%CI(0.847,0.926),P<0.01〕,灵敏度和特异度分别为0.788、0.848;NTproBNP预测老年SCAD患者发生MACE的AUC为0.770〔95%CI(0.715,0.820),P<0.01〕,灵敏度和特异度分别为0.549、0.808;TCS预测老年SCAD患者发生MACE的AUC为0.833〔95%CI(0.782,0.876),P<0.01〕,灵敏度和特异度分别为0.779、0.755。新联合指标与NTproBNP、TCS预测老年SCAD患者发生MACE的AUC比较,差异均有统计学意义(Z值分别为4.83、2.63,P<0.01);NTproBNP与TCS预测老年SCAD患者发生MACE的AUC比较,差异无统计学意义(Z=1.56,P=0.12,见图1)。
 
 
 
 
 3 讨论 
目前NTproBNP是指南上推荐应用于诊断心力衰竭和判断预后的有用工具 [2],同样有研究表明其也是SCAD及急性冠状动脉综合征患者强大的预后独立预测指标 [7]。NTproBNP要比传统的冠心病危险因素价值更高 [8],老年SCAD患者MACE发生率与NTproBNP水平增加有着密不可分的关系,研究报道当心脏心室腔内压力或心室壁张力增加,会使B型利钠肽(BNP)前体从心室肌细胞中大量释放入血,其在内切酶作用下迅速分解为有生物活性的BNP及无生物活性的NTproBNP,其中NTproBNP化学稳定性好、t1/2长、个体差异性小,还能代表BNP新合成的量,且不受重组人BNP(rhBNP)影响,所以NTproBNP的临床价值更大而被广泛应用 [9]。本研究通过对选取的老年SCAD患者随访2~34个月,结果显示不同预后患者性别、年龄、BMI、吸烟史、高血压病史、糖尿病病史、血脂异常史间无差异,而MACE组NTproBNP水平高于非MACE组,NTproBNP水平是老年SCAD患者重要的预后独立预测指标,这与以往研究结果相符 [10]。本研究通过ROC曲线进一步分析结果显示,NTproBNP预测老年SCAD患者发生MACE的AUC为0.770,说明NTproBNP对老年SCAD患者预后有一定的预测价值,但其灵敏度、特异度欠佳。
冠状动脉粥样硬化是一种长期缓慢进展演变的疾病,动脉最早可在10岁左右就出现脂质条纹,目前临床上通过CT或多层螺旋CT(MSCT)对冠状动脉钙化程度进行量化,用自动钙化积分分析软件对超过钙化阈值的斑块面积进行识别,并相加得到TCS [11]。COLLETTI等 [12]采用心脏MRI发现室壁节段性异常运动和冠状动脉钙化程度有明显相关性。在COLLETTI等 [12]的研究中一半以上心室壁运动异常的患者有冠状动脉钙化的临床证据,这表明SCAD患者中冠状动脉钙化会造成不同程度冠状动脉狭窄,影响心肌缺血灌注,最终引起心脏结构功能性障碍,进而诱发随访过程中终点事件发生。在老年SCAD患者中,冠状动脉狭窄与其钙化程度有关,TCS可将冠状动脉粥样硬化斑块面积量化,还可大致评估心肌缺血灌注情况,使老年SCAD患者无创筛查上了一个台阶 [13]。目前TCS已被广泛用于冠心病患者无创筛查及危险评估中,当然指南中也提出对于存在弥漫性冠状动脉钙化的患者,TCS诊断价值欠佳 [1]。本研究结果显示,MACE组TCS高于非MACE组,TCS是老年SCAD患者重要的预后独立预测指标,TCS预测SCAD患者发生MACE的AUC为0.833,同样提示TCS对老年SCAD患者预后有一定的预测价值,但其灵敏度、特异度亦欠佳。
NTproBNP与TCS在预测老年SCAD患者预后中均展示了良好前景,且这两个指标都是独立单一变量,对老年SCAD患者发生MACE的预测灵敏度和特异度欠佳,因此在本研究中将实验室指标与影像学指标整合在一起,通过Logistic回归构建新的综合预测模型,得到的方程中自变量OR均>1,b均>0,代表NTproBNP和TCS对SCAD预后的评估起到重要作用,通过ROC曲线对该模型进行效能评估,结果显示新联合指标的AUC大于任何单一指标的AUC,灵敏度和特异度都较单一指标更佳,这说明联合实验室指标与影像学指标的新联合指标要比其中任何单一指标对老年SCAD患者预后的评估价值都大,入院时就可以及时准确地评估SCAD患者预后,以指导临床早期治疗干预,这也大大合理有效地控制了MACE的发生,取得更好的临床疗效。
综上所述,对于老年SCAD患者远期预后的预测,联合了实验室指标与影像学指标,发现新预测模型可以增加老年SCAD患者发生MACE的预测价值,两者结合可更进一步提升诊断的灵敏度和特异度。该模型无创快捷,易实施操作,一旦患者两项指标都升高或者达到高值,就需要提高意识,督促患者改变其生活方式,以期来干预MACE的发生。当然本研究随访时间较短、样本量不足也会使试验结果造成一定局限性,仍需进行更多大样本及具有较长随访期的试验来验证上述结论。
 
作者贡献:卞娜娜负责试验设计与实施、数据收集与统计分析、撰写论文并对文章负责;卞娜娜、李红旗负责试验实施评估并进行论文修订;胡立群负责质量控制及审校。
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 参考文献 
   [1] Task Force Members,MONTALESCOT G,SECHTEM U,et al.2013 ESC guidelines on the management of stable coronary artery disease:the Task Force on the management of stable coronary artery disease of the European Society of Cardiology[J].Eur Heart J,2013,34(38):2949-3003.
 [2] 中华医学会心血管病学分会,中华心血管病杂志编辑委员会.中国心力衰竭诊断和治疗指南2014[J].中华心血管病杂志,2014,42(2):98-121.
Chinese Society of Cardiology,Editorial Board of Chinese Journal of Cardiology.2014 Chinese guidelines for the diagnosis and treatment of heart failure[J].Chinese Journal of Cardiology,2014,42(2):98-121.DOI:10.3760/cma.j.issn.0253-3758.2014.02.004.
 [3] MISHRA R K,BEATTY A L,JAGANATH R,et al.B-type natriuretic peptides for the prediction of cardiovascular events in patients with stable coronary heart disease:the Heart and Soul Study[J].J Am Heart Assoc,2014,3(4):e000907.DOI:10.1161/JAHA.114.000907.
 [4] CHANG S M,NABI F,XU J,et al.The coronary artery calcium score and stress myocardial perfusion imaging provide independent and complementary prediction of cardiac risk[J].J Am Coll Cardiol,2009,54(20):1872-1882.
 [5] 许锋.慢性稳定性冠心病患者的管理[J].中国心血管杂志,2014,19(6):410-412.
XU F.Management of patients with chronic stable coronary artery disease[J].Chinese Journal of Cardiovascular Medicine,2014,19(6):410-412.
 [6] GANDHI S,DORIAN P,GREENLAW N,et al.Characteristics and evidence-based management of stable coronary artery disease patients in Canada compared with the rest of the world:insights from the CLARIFY registry[J].Can J Cardiol,2014,30(1):132-137.
 [7] PALAZZUOLI A,CAPUTO M,FINESCHI M,et al.B-type natriuretic peptide as an independent predictor of coronary disease extension in non-ST elevation coronary syndromes with preserved systolic function[J].Eur J Prev Cardiol,2012,19(3):366-373.
 [8] BIBBINS-DOMINGO K,GUPTA R,NA B,et al.N-terminal fragment of the prohormone brain-type natriuretic peptide(NT-pro-BNP),cardiovascular events,and mortality in patients with stable coronary heart disease[J].JAMA,2007,297(2):169-176.
 [9] RUSKOAHO H.Cardiac hormones as diagnostic tools in heart failure[J].Endocrine Reviews,2003,24(3):341-356.
 [10] SCHNABEL R,RUPPRECHT H J,LACKNER K J.Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease:results from the AtheroGene Study[J].Eur Heart J,2005,26(3):241-249.
 [11] SUN B, LIU J, HUANG D, et al.Analysis of the characteristics of coronary artery lesions in patients with obstructive sleep apnea-hypopnea syndrome and influencing factors[J].Fam Med Community Health,2014,2(4):41-47.
 [12] COLLETTI P M,DUSTIN L D,WONG N D,et al.Does coronary calcium score predict future cardiac function? Association of subclinical atherosclerosiswith left ventricular systolic and diastolic dysfunction at MR imaging in an elderly cohort[J].Radiology,2010,257(1):64-70.
 [13] BONSDORFF M B,GROFFEN D A,VIDAL J S,et al.Coronary artery calcium and physical performance as determinants of mortality in older age:the AGES-Reykjavik Study[J].Int J Cardiol,2013,168(3):2094-2099. 
 
  (收稿日期:2016-08-08;修回日期:2016-11-16)
  (本文编辑:崔沙沙)