Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (2): 302-307.doi: 10.12307/2022.049
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Liu Xiaopeng1, Zhang Sisen1, 2, 3
Received:
2021-02-04
Revised:
2021-02-20
Accepted:
2021-03-24
Online:
2022-01-18
Published:
2021-10-28
Contact:
Zhang Sisen, MD, Chief physician, Professor, The Fifth Clinical School of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China; Department of Emergencym, People’s Hospital of Henan University of Chinese Medicine/People’s Hospital of Zhengzhou, Zhengzhou 450000, Henan Province, China; The Second Clinical School of Southern Medical University, Guangzhou 510280, Guangdong Province, China
About author:
Liu Xiaopeng, Master candidate, The Fifth Clinical School of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
Supported by:
CLC Number:
Liu Xiaopeng, Zhang Sisen. Predictive value of blood biomarkers for brain injury after cardiac arrest[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(2): 302-307.
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2.1 神经元特异性烯醇化酶 (neuronspecific enolase,NSE) 到目前为止,NSE无疑是心搏骤停术后最广泛使用和最有用的预后预测生物标志物。NSE是一种78 kD的二聚糖酵解酶,主要存在于神经元和神经内分泌细胞中,生物学半衰期为 24 h。然而,NSE也有一些脑外来源,可以在红细胞和血小板中发现,也可以在神经内分泌和胰腺肿瘤中发现;它也是小细胞肺癌的生物标志物[8]。 心脏骤停后目标温度管理(targetted temperature management,TTM) 试验比较了33 ℃和36 ℃两种目标温度管理水平,作为证实NSE作为心搏骤停术后预后预测因子的基础[9]。有趣的是,根据临床试验终点,NSE被证明不受目标温度管理水平的影响,这一发现也得到了其他人的证实[10]。此外,当数值较高,并在24,48和72 h进行系列测量时,NSE提高了结果预测能力,NSE在两个时间点之间升高4-7.9 μg/L与不良预后相关[9,11-12]。前者48 h的临界值为33 μg/L,敏感度为0.65,特异度为0.91,太低不能作为停止生命支持治疗的临床推荐标准。NSE测定结果预测的最佳时间点为48 h或72 h(AUC值分别为0.83和0.86)。对于可靠的结果预测而言,24 h时间点似乎还为时过早(AUC值为0.77)。根据连续时间测量的NSE散点图和ROC曲线显示[13],48-72 h NSE的准确度高于24 h,这是因为在神经预后差的患者中,48-72 h的中位数NSE值高于24 h,而在神经预后好的患者中,中位数NSE值保持稳定或下降,这表明个体NSE随时间的变化趋势可能具有额外的预后价值。在另一项研究中表明,与结果的关联因采血时间不同而不同[14]:第1天测得的NSE水平与其他天数和最高NSE水平之间的相关性明显较弱;从数值上看,第4天的NSE水平与预后的相关性最强,其次是第3天的值。结果表明,NSE水平是预测在33 ℃下接受靶向温度管理的心脏骤停幸存者的 30 d神经预后和长期死亡率的有用工具。NSE与预后的最高相关性出现在心脏骤停后的第4天和第3天。到目前为止,还没有NSE的正式建议截止值,而是一个范围或一个数量级的高值,远远高于33 μg/L;没有明确的预后不良分界值,但在48 h和72 h高于45 μg/L的值与不良预后相关,假阳性率低于5%。显然,当预期的特异性为100%时,必须考虑更高的值。因此,这种绝对的特异性导致敏感度下降,从而限制了如此高的临界值的有用性。根据大量研究结果,NSE是预测心搏骤停术后不良预后的最佳生物标志物,因此,NSE已被纳入欧洲复苏理事会的心搏骤停术后预测算法准则[15]。 尽管NSE是一个强有力的结果预测者,但它也有一些潜在的缺陷。NSE的测定受溶血的影响,由于溶血导致NSE值假升高,可见溶血的样本必须丢弃。另一方面,在随后的样本中没有检测到溶血,可能不能完全排除源于红细胞的“大脑外”NSE的存在。由于游离血红蛋白的半衰期比NSE低得多,溶血可能不再被检测到,但红细胞NSE可能仍然存在。其他可能影响计量的因素是冷冻样品的储存和不同制造商用于计量的化验方法[16],这可能会导致测量值最多相差30%[17]。 2.2 S100B蛋白 S100B蛋白是S100蛋白家族和钙蛋白超家族的一部分,也被称为细胞内钙结合蛋白。特征包括低分子量(21 kD)和二聚体结构(ββ或αβ链)。S100B蛋白的β亚基主要由星形胶质细胞合成,也会由许旺细胞合成[18];相反,α亚单位是无处不在的。S100B蛋白最重要的定位是胞浆室。一些研究已经确定了S100B蛋白的细胞内功能(细胞生长、细胞骨架维持、能量代谢、信号转导)和细胞外功能(激活不同的神经元和神经胶质膜受体,如RAGE受体和碱性成纤维细胞生长因子受体1),与蛋白质之间的相互作用有关[19]。由于大脑损伤,S100B从受损的胶质细胞迅速释放到血流中,这说明在创伤后1 h就可以检测到这种蛋白。 S100B蛋白通常被描述为心搏骤停术后一个合适的预后预测指标,一些报告提到其与神经学结果有很好的相关性。有研究表明血清中的S100B蛋白水平在心搏骤停后明显升高,从自主循环恢复(return of spontaneous circulation,ROSC)后即刻到自主循环恢复后72 h,S100B蛋白的高值预示着神经预后不良结局[20-21]。使用S100B的一个潜在优势是半衰期短,而且在血清中出现的时间较早,但这也可能是一个缺点。由于S100B的分子质量比NSE低,半衰期短,预计S100B在缺氧缺血性脑损伤后血流中的峰值更早。DEYE等[22]描述了S100B在心搏骤停后的预后价值,主要研究结果包括在入院时,预后不良患者的血清所有标志物水平均显著高于预后良好患者;入院时S100B的总体预后准确率最高(AUC值为0.83),入院至24 h内S100B水平升高与不良神经结局显著相关,这种在24 h前的早期升高可能是有意义的预测,但尚未在研究中得到适当的解决,需要在未来的更早和更连续的采血试验中进行探索。尽管S100B在结果预测方面有一定的价值,但它的表现明显低于NSE,从而限制了人们对其在这种情况下的常规使用。 2.3 胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP) 胶质纤维酸性蛋白是胶质细胞(特别是星形胶质细胞)胞浆中中间丝的主要成分。胶质纤维酸性蛋白被认为是高度大脑特异性的,作为一种结构蛋白,它在生理条件下不会从细胞中释放出来,健康人的血液中也不会显示出可检测到的胶质纤维酸性蛋白水平。然而,导致星形胶质细胞坏死的事件会导致胶质纤维酸性蛋白释放到血浆中。综上所述,在心肺复苏幸存者中研究胶质纤维酸性蛋白似乎是值得的。 一项基于新开发的胶质纤维酸性蛋白免疫分析原型的回溯性研究和发表的对125例心搏骤停后患者的前瞻性评估显示,神经功能预后较差的患者胶质纤维酸性蛋白水平较高[23-24]。另有一项前瞻性多中心研究显示胶质纤维酸性蛋白是复苏患者神经功能不良的独立预测因子,有很高的阳性预测值[25],这意味着在血清值升高(即假阳性发现)的情况下,获得良好预后的机会非常低。LARSSON等[24]的研究结果与此相似,他们还发现在存活的心搏骤停患者中,预后不良组的胶质纤维酸性蛋白水平显著升高,血清胶质纤维酸性蛋白在125例患者队列中预测不良神经结局的特异性为100%,但不如NSE或S-100B敏感。关于研究血清胶质纤维酸性蛋白的文献很少。然而,关于这一主题的少数文献表明[23-24,26],胶质纤维酸性蛋白水平在心搏骤停后24-48 h升高,显示出损伤后12 h不同结果组之间的水平差异,这与心搏骤停后脑损伤标志物时间分布的假设模型一致[27],将胶质纤维酸性蛋白归类为心搏骤停后12 h左右水平升高,24 h达到峰值。 2.4 Tau Tau是一种微管相关轴突蛋白,在生理条件下具有稳定功能,该蛋白既参与轴突微管束的组装,又参与轴浆顺行运输[28]。由于tau优先定位于轴突,轴突损伤后可在脑细胞外液、脑脊液和血清中检测到tau。Tau通常由受损神经元分泌到脑脊液。在低氧条件下,它可能会通过继发于破坏的血脑屏障,因此可以在血液中检测到[29]。 一项针对22例患者的研究发现,在心搏骤停后,48 h或96 h的血清tau升高与不良的神经预后有关[30]。在一项大型前瞻性队列研究中,使用轴突损伤标记物tau的超灵敏分析,发现血清tau升高与不良的神经结局和心脏骤停后的短生存期相关[31]。这表明tau不仅可用于鉴别预后不良的患者,还可用于预测心搏骤停后脑损伤的程度,结果表明,血清tau是一个很有前途的生物标志物,可以预测急性脑损伤的严重程度,并有可能用于预测心搏骤停后的不良结局。 在神经结果差的患者中,血清tau水平在心肺复苏后72-96 h达到峰值,而神经结果好的患者则没有相应的升高[32]。在目标温度管理试验中,血清tau对不良神经结局的预测准确率随着时间的推移而增加,在心肺复苏后72 h达到最大(AUC值为0.91),但由于观察期有限[31],目前尚不清楚在随后的过程中是否会有进一步的改善。 2.5 泛素羧基末端水解酶L1(ubiquitin carboxyl-terminal hydrolase L1 ,UCH-L1) UCH-L1是一种发现于神经元胞浆中的中枢神经系统蛋白,参与泛素代谢,它在大脑中含量丰富,但也存在于周围神经系统的神经肌肉接头中。UCH-L1是一种26 kD的神经元脱泛素酶,主要表达于神经元和神经内分泌细胞,对脑损伤后神经轴突的稳定和修复很重要[33-34]。 UCH-L1在成人心搏骤停的情况下是一种新的血清生物标志物,可准确预测心搏骤停后不良的神经结局。颅脑损伤后,血清水平可指示损伤的严重程度,被证明可以可靠地区分预后好与差[35]。在EBNER等[36]的研究中,研究了UCH-L1作为预测靶向温度管理治疗的大量心搏骤停患者的神经学结果的指标,发现目标温度水平不影响UCH-L1,溶血对UCH-L1血清水平无影响,研究结果表明,胶质纤维酸性蛋白和UCH-L1联合检测比单独检测单个生物标志物和NSE更能全面准确地预测心搏骤停后的神经预后。在特异度≥为95%时,GFAP+UCH-L1模型在24 h内的敏感性优于NSE,且随时间的变化很小,这有助于早期预测。在临床床边信息评测中加入GFAP+UCH-L1可提高诊断准确性,溶血不影响预后预测,它们的组合可能对心脏骤停后神经功能的早期预后有一定价值,因为其组合的性能明显优于目前推荐的生物标志物NSE。 2.6 神经丝轻链(neurofilament light,NFL) 神经丝是一组中等大小的结构支架蛋白,构成轴突的细胞骨架。这些IV类纤维是专性杂聚体,由3个亚基组成:轻链(NFL,70 kD)、中链(NFM,150 kD)和重链(NFH 200 kD),仅见于神经元[37]。神经丝轻链亚基主要在中枢神经系统的有髓轴突中表达。导致轴突损伤或变性的病理过程将神经营养因子释放到脑脊液和外周血中,在成人心搏骤停所致缺氧缺血性脑损伤后外周血中均可检测到。心搏骤停缺氧缺血性损伤后神经丝轻链水平的升高可能与多种机制有关,包括直接的轴突或少突胶质细胞病理,神经元损伤后的轴突变性,或两者的结合[38]。这些损伤机制的时间进程可能解释了神经丝轻链的峰值比其他脑损伤生化标志物相对较晚的原因。 KIRSCHEN等[39]的研究表明高的神经丝轻链水平与儿童心搏骤停后的死亡有关,从而使神经丝轻链成为儿童心搏骤停后缺氧缺血性脑损伤的一个有前途的血液生物标志物。同样,在颅脑损伤后的成人患者中,损伤后24 h内的神经丝轻链水平与生存和神经预后相关。 另有研究表明血清神经丝轻链水平是预测心搏骤停术后远期神经功能转归的一种新的良好标记物[40]。在心搏骤停后神经功能不良的成人中,神经丝轻链水平在心搏骤停后 24-48 h内翻了一番,但在心搏骤停后48-72 h内稳定。与其他常规预测方法(包括头部CT、EEG、SSEP和无瞳孔或角膜反射)相比,神经丝轻链水平预测神经功能不良的敏感性更高。血清神经丝轻链水平是心搏骤停神经学转归的早期和高度特异性指标,它的表现优于其他生化、临床、神经成像和电生理方法。 2.7 MiRNAs MicroRNAs(MiRNAs)是一种小RNA分子,长度通常为20-24个核苷酸,由人类基因组中高度保守的DNA区域编码,但不能翻译成蛋白质。在过去的几年中,分子和细胞研究强调了miRNAs作为生物标志物在脑外伤的发生和发展中的重要作用。MicroRNAs (miRNAs-短单链非编码RNA) 越来越被认为是潜在的疾病标志物。它们可以在不同的体液中找到,要么自由循环,要么与蛋白质结合,要么被包装成微囊[41-42]。值得注意的是,miRNAs可以在病理过程中比蛋白质更早地释放,并且它们的表达水平很容易通过不同的技术如定量PCR、微阵列和高通量测序来检测,具有很高的特异性和敏感性[43]。心脏骤停期间,大脑缺氧,导致缺血性脑损伤,缺血性脑损伤可以改变脑缺血动物模型和脑卒中患者miRNA的表达,提示miRNAs参与了对缺血性脑损伤的早期应激反应[44-45]。 第一项评估miRNAs作为神经预后潜在预后生物标志物的研究发现,预后不良(大脑功能分类[CPC]3-5)的患者过度表达miR-122和miR-2,在这项研究中,miRNAs水平与心肌损伤程度或炎症程度无关,这表明神经元死亡本身就是miR-122和miR-21升高的原因[46]。循环中miR-122、miR-21和NSE水平的升高也与死亡率显著相关。 已经有研究报道了miRNAs的潜力,例如脑丰富的 miR-124-3p,有助于预测院外心搏骤停后的预后[47-48]。另一项研究前瞻性地跟踪了65例接受低温治疗的院外心脏骤停患者,发现与年龄和性别匹配的健康对照组相比,院外心脏骤停患者入院时miR-123的水平升高了10倍;预后不良(CPC值:3-5;P < 0.0001)的患者在24 h(AUC值为0.87;95%CI为0.79-0.96)和48 h(AUC值为0.89;95%CI为0.80-0.97)的miR-124显著升高[48]。在一项多中心、单盲、随机临床试验的子研究中,值得注意的是,神经结果预后不良结果组中的miR-124-3p水平升高(P < 0.001),并且与神经系统不良结果(OR为6.72; 95%CI为4.53-9.97)和低生存率显着相关[47]。在多变量分析中,miR-124-3p水平是神经预后的独立预测因子,MiR-124-3p水平高的患者死亡风险也较高(95%CI为1.37-1.93)。这些发现证实了GILJE等[48]的结果。有趣的是,治疗性低温并不影响miR-124-3p的循环水平,该miRNA的预测效果不受33 ℃或36 ℃的目标温度的影响。 尽管有报道称,心搏骤停后自主循环恢复后的第一个24 h内,脑血屏障被破坏,允许miRNAs从大脑释放到血液中,但仍不清楚循环中的miRNAs水平是否反映了脑损伤的程度。这是miRNAs作为心搏骤停后预后生物标志物价值的先决条件。DEVAUX等[49]的研究报道循环中miR-122-5p水平可改善院外心搏骤停后预后的预测,循环miR-122-5p水平低的患者预后不良的风险较高(OR为0.71;95%CI为0.57-0.88)。STEFANIZZI等[50]的研究旨在探讨循环miRNAs与心搏骤停患者脑损伤的相关性,报道了3种脑丰富的miRNAs-miR9-3p、miR-124-3p和miR-129-5p的循环水平与NSE之间的强相关性,提示这些miRNAs可能反映了脑损伤的程度;此外,这些miRNAs与神经学结果和6个月后的存活率有关。这些观察结果支持大脑丰富的miRNAs有助于预测心搏骤停后结果的价值。它们在心搏骤停后血液中的存在或水平升高,很可能反映了心搏骤停后血脑屏障的破坏和细胞功能障碍或死亡。总而言之,循环中脑部丰富的miRNAs水平反映了心搏骤停患者的脑损伤程度。 理想的损伤生物标志物容易获得,半衰期长,具有组织和疾病特异性,可以常规检测,具有很高的敏感性和特异性。miRNA对于心脏骤停和神经损伤的患者满足这些要求。虽然大多数miRNAs位于细胞内,但循环中的miRNAs可以在细胞外检测到,包括血液、血浆和血清,其表达谱与潜在的病理生理过程相关[51]。miRNAs可以满足理想生物标志物的标准,尤其是疾病过程中的早期释放、循环的稳定性、易于非侵入性的获取和高特异性和敏感性的检测。尽管有证据表明miRNA具有巨大的潜力,但仍需要进一步的临床证据来支持miRNA作为一种预测工具的实际应用。目前miRNA在心脏骤停患者中的效用的证据很少,并且试验设计和方法存在重大差异。使用标准化技术观察心脏骤停中miRNA的表达可能需要更全面和更大规模的研究,以支持或降低其在临床环境中的实用性。目前的miRNA定量方法包括高通量测序、实时PCR等,虽然这些定量方法具有高度的敏感性和特异性,并且不需要针对基于蛋白质的标记物开发单独的抗体或检测剂,但与基于ELISA的蛋白质生物标记物的检测相比,它们也更昂贵、耗时和费力。"
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