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冠脉搭桥术患者载脂蛋白E£4基因与术后认知功能障碍的关系

时间:2010-08-24 11:35:22  来源:  作者:

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Relationship between the apolipoprotein E ε4 allele and cognitive dysfunction after coronary artery bypass grafting operation

杨旭东 吴新民 王东信 朱姜华 李军 单国瑾 马琼 苏玉

YANG Xu-dong,WU Xin-min,WANG Dong-xin,et al. Department of Anesthesiology,First Hospital,Peking University,Beijing 100034,China

 

Abstract

  Objective:To investigate the relationship of apolipoprotein Eε4 allele to early cognitive dysfunction after cardiac surgery and to identify the predictors of cognitive decline after cardiac operation.

  Methods:Two hundred and thirty patients aged over 18 yr undergoing coronary artery bypass grafting(CABG)were studied. They were capable of completing the preoperative cognitive function tests in terms of the education they had received. Patients with neurological or mental disease and those with serious hepato-renal or cardiac dysfunction were excluded. Cognitive function was evaluated using a battery of nine neuro-psychological tests before operation,at one week and 3 months after operation. Cognitive decline was defined as≥2O% decrement in 2O% or more of the completed tests. The changes in the Z-based scores were used to evaluate the severity of cognitive decline. Logistic regression and multiple linear regression were used to determine the relationship of ApoE genotype to cognitive decline and identify the predictors of postoperative cognitive decfine (POCD) after cardiac operation.

  Results:The incidence of cognitive decline was as high as 51.9% and 21.0% at 1 week and 3 months after operation respectively. The ε4 allele was present in 7.4%,ε3 allele in 86.1% and ε2 allele in 6.5% of the 230 patients. The cognitive decline was not significantly associated with the presence or absence of the ε4 allele. The ε4 allele was associated with poor baseline performance. Age,the use of cardiopulmonary bypass(CPB),duration of endotracheal intubation were predictors of cognitive impairment after cardiac operation. There was positive correlation between the neuro-psychological test scores at 1 week and 3 months after operation.

  Conclusion:The results suggest that age,the use of CPB and duration of endotracheal intubation are the predictors of POCD. The ε4 allele is not associated with POCD after cardiac operation. The cognitive dysfunction at 3 months after operation is positively correlated with the level of cognitive decline at 1 week after operation.

  Key words:Coronary artery bypass;Apolipoproteins E;Cognition disorders;Postoperative complications

 

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  术后认知功能障碍(POCD)是冠脉搭桥术(CABG)患者术后常见的并发症。CABG手术患者POCD的机制尚不清楚,一般认为是年龄、应用体外循环、术中微栓栓塞等围术期多种因素所致,但目前主要可能的致病因素尚不能完全解释术后认知功能的改变[1]。载脂蛋白Eε4(ApoEε4)基因被认为是早老性痴呆(AD)的标志基因[2];流行病学调查显示携带ApoEε4基因的健康老人更容易发生增龄性认知下降[3];ε4等位基因与许多心脑血管疾病的发病和预后有着密切的关系[4,5]。因此,有理由推测ApoEε4基因同样为CABG手术患者POCD的危险因素。Tardi[6]刮初步研究发现携带ApoEε4基因和CABG手术患者POCD明显成正相关。我国关于术后认知功能的大样本临床调查及国人ApoEε4基因在CABG手术患者POCD中的作用尚无定论,本研究拟评价ApoEε4基因与CABG患者POCD的关系。

 

资料与方法

  病例选择 择期行CABG手术的患者230例。年龄≥18岁;受教育程度能够完成术前认知功能测试;无既往脑血管疾病后遗症及神经、精神病史;术前生化指标无明显肾功能不全(血肌酐>177/Lmol/L)或活动性肝脏疾病;术前无严重心功能不全,左室射血分数>30%。

  神经、精神功能测试 使用中文版韦氏成人智力量表(WAIS)和韦氏记忆量表(WMS)对患者进行术前1 d和术后l周、术后3月的神经、精神功能测试。测试包括7个题目,总共9项目:(1)数字广度测试(顺向、逆向);(2)累加测试;(3)联想学习测试;(4)视觉再生能力;(5)数字符号测试;(6)连线试验;(7)钉板测验(利手、非利手)。以患者术后在9个测试项目中有多于20%的项目认知结果比术前下降20%以上为POCD的诊断标准。用取z值的方法 将患者每一项测试的结果进行标准化转换,得到标准化值(z值)。z值=(该项目成绩一该项目均数)/该项目标准差,所有9个测试项目术前z值的均数作为该患者术前的基础认知水平。同理,计算得到术后1周和术后3月标准化的认知水平。

  麻醉与监测方法 所有患者术中常规监测:桡动脉压、中心静脉测压、肺动脉压、五导联心电图、脉搏氧饱和度、鼻咽部体温、呼气末二氧化碳分压、尿量。静脉注射芬太尼(1O~15 ttg/kg)、咪唑安定(0.1~0.2 mg/kg)、依托咪酯(0.2~0.4 ms/ks)、罗库溴铵(0.6 ms/kg)麻醉诱导,间断静脉注射芬太尼并复合1%异氟烷吸入维持麻醉;静脉注射哌库溴铵或维库溴铵维持肌松。非体外循环的手术在心脏固定器的辅助下完成。体外循环的手术使用滚压式灌注泵(Stocket,德国),中空纤维膜肺(Med0s,德国),40.姗动脉滤器(Baxter,美国)。体外循环温度控制在25~37℃,灌注压维持在5O~90 n1n1 Hg(1 kPa:7.5 IllIllHg),灌注流量控制在2~2.4 L/In-2/min-1。采用。稳态,维持动脉血气pH值在7.35~7.45、动脉血二氧化碳分压35~45 nll/l Hg。复温的速度维持在大约每3分钟1℃。

  基因型的检测及分组 采用聚合酶链反应.限制性片段长度多态性(PCR.RFLP)技术检测患者的ApoE基因型[8]。全麻诱导后采静脉血2ml,EDTA抗凝,NaI盐析法提取DNA,PCR扩增目的基因序列。引物1:5 ACAGAATI'CGCCCCGGCCTGGTACAC.3 ;引物2:5. TAAGCTYGGCACGGCTGTCCAAGGGA.3。PCR总反应体系3Oμl,其中包括DNA模板0.5μg(5μ1),dNTP 2μl(2.5 mmol/L),两引物各0.5μl,二甲基亚砜3μl,10×缓冲液3μl(含25 mmol/L氯化镁),Taq酶0.05μl。PCR反应过程:95℃ 预变性5min,然后按95℃ 1 min,55℃ 2min,70℃ 2min的循环程序进行3O个循环,7O℃ 7 min延伸扩增产物。取PCR产物26μl加HhaI内切酶5U,37℃孵育3 h,置于-20℃终止酶切。12%的聚丙烯酰胺凝胶中电泳,以酶切产物与分子标准品(pBR 322/Msp I)在1×TBE缓冲液中恒流22 mA电泳1.5 h,以0.2%AgNO3快速银染后鉴定基因型,ε4等位基因携带者含有72bp条带。根据是否携带ApoEε4等位基因将患者分为ApoEε4基因携带组和ApoEε4基因非携带组。

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  统计学处理 采用SPSS 10.0进行分析,计量资料以均数±标准差(x±s)表示,组间比较采用成组t检验。计数资料比较采用卡方检验或Fisher精确检验。用Lgistic回归和多元线形回归分析发生POCD和影响POCD程度的危险因素。P<0.05为差异有统计学意义。

 

结 果

  1.ApoE基因结果230例患者的ApoE基因型的分布如下:ε2/2,3例(1.3%);ε2/3,23例(10%);ε3/3,172例(74.8%);ε3/4,29例(12.6%);ε2/4,1例(0.4%);ε4/4,2例(0.9%)。总计携带有ε4基因的为32例(13.9%);不携带有ε4基因的198例(86.1%)。ε4基因的基因频率为:7.4% [0.9%(ε4/4)+1/2×0.5% (ε2/4)+1/2×12.6% (ε3/4)=7.4%];ε3、ε2等位基因的基因频率分别为86.1%和6.5%。

  2.术后1周的认知测试结果全部患者术后1周POCD发病率为59.1%,ε4基因携带组POCD的发病率(50%)与ε4基因非携带组POCD的发病率(60.6%)比较差异无统计学意义。ε4携带基因组与ε4基因非携带组的一般情况、围术期主要参数、认知结果z值变化情况比较差异无统计学意义。见表1。Logistic回归分析显示是否携带ε4基因不作为诊断POCD的危险因素。多元线形回归显示高龄(B=0.002,P=0.039)、使用体外循环(B=0.043,P=0.024)、术后拔除气管导管时间延长(B=0.029,P=0.001)为术后1周认知功能下降的相关因素。携带ε4等位基因(B=0.129,P=0.016)为术前总体认知水平的相关因素。

  3.术后3月的认知功能结果 66例患者完成了术后3月的认知功能测试。其中7例携带有ε4等位基因。术后3月的POCD发病率为21.0%。术后3月POCD的发病率与是否携带ε4等位基因无关。在Logistic回归分析中,是否携带ε4等位基因不构成诊断POCD的相关因素,多元线形回归显示术后1周的认知水平(B=-0.06,P=0.03)是术后3月认知功能下降唯一的相关因素。

 

讨 论

  本研究表明国人CABG手术术后1周及3月确有相当一部分患者发生POCD,但与是否携带ApoEε4基因无明显关系,表明尚不能肯定ApoEε4基因为CABG手术患者POCD的遗传危险因素,Steed等[7]的研究结果与本研究一致。尽管大量的研究表明ApoEε4基因携带者更易发生AD或健康老年人的增龄性认知下降,但ApoEε4基因对认知功能的确切影响仍有争议。Murphy等[9]认为AD患者认知功能下降和是否携带ApoE ε4基因不相关。Deary等[10]认为ApoE基因对健康老人认知功能的影响和其在早老性痴呆中的机制不同。Hyman等[11]对1688名大于65岁的健康老人进行了4~7年的认知功能随访,发现ApoE ε4基因携带者并不比其他基因型更多发生认知障碍,相反85%的ε4/4纯合子老人(平均81岁)认知功能在正常范围。

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2. Edawrdson J,Morris C.The genetics of Alzheimer' s disease. BMJ,1998,317:361-362.

3. Fillenbaum GG,Landernmn LR,Blazer DG,et a1. The relationship of ApoE genotype to cognitive functioning in older AfYieRil-American and Caueasian community residents.J Am Geriatr Soc,2001,49:1148-1155.

4. Alberts MJ.ApoE genotype and survival from intracerebral haemorrhage. Lancet,1995,346:575.

5. MeCarron MO,Delong D,Alberts MJ,et a1.ApoE genotype as a risk fact0r for ischemie eerebrovaacular disease:a Beta-analysis.Neurology,1999,53:1308-13l1.

6. Tardif BE.Preliminary report of a genetic basisfor cognitive decline after cardiac operations.Ann Thorae Surg,1997,64:715-720.

7. Steed L,Kong R,Stygall J,et a1.The role of apolipoprotein E in cognitive decline after cardiac operation.Ann Thorae Surg,2001,71:823-826.

8. James E,Murray RK,Senti M,et a1.Restriction isotyping of human Apo E by gene and amplification and cleavage with Hhal I.J Lipid Res,1990,31:545-548.

9. Murphy GM,Taylor J,Kraeme r HC,et a1.No association between apolipoprotein E epsilon 4 allele and rate of decline in Alzheimer’ s disease.Am J Psychiatry,1997,154 :603?608.

10. Deacy IJ,Whitemaa MC,Pattie A,et a1.Cognitive change and the AroE epsilon 4 allele.Nature,2002,29,418:932.

11. Hyman BT,Gomez Isla T,Briggs M,et a1.Apolipoprotein E and cognitive change in an elderly population.An Neurol,1996,40:55-66.

12. Ti LK,Mathew JP,Burkhacd MG. Effect of apoliporotein E genotype on cerebral autoregulation during eardiopulmonary bypass. Stroke,2001,32:l5l4-15l9.

13. Newman MF. Kirchner JL,Phillips Bute B,et a1. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med,2001,344:395-402

 

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