CN109283341A - 一组预测心肌梗死患者的pci术后预后的生物标志物 - Google Patents
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Abstract
本发明涉及一组预测心肌梗死患者的PCI术后预后的生物标志物，所述的分子标志物组包括：颉氨酸，亮氨酸，异亮氨酸；更进一步的，所述的分子标志物组还包括：NT‑pro BNP(脑钠肽前体N端)。
Description
技术领域
本发明属于医药生物领域，具体而言，涉及一组预测心肌梗死患者的PCI术后预后的生物标志物。
背景技术
经皮冠状动脉介入治疗(PCI)是挽救ST段抬高型心肌梗死(STEMI)【1】患者的存活心肌、限制心肌梗死面积和保留的心室收缩功能的首选治疗方法。STEMI患者可能在PCI后出现心肌缺血和缺血再灌注损伤等，导致心内破裂，恶性心律失常和心力衰竭(HF)等院内心血管不良事件(AEs)【2】。据报道，接受直接PCI的STEMI患者的30天死亡率和住院急性心力衰竭(AHF)的发生率分别为7.9％和28％，【3,4】。早期有效的介入策略可以降低心血管AE的可能性并改善短期和长期预后【5】。
PCI术后STEMI患者目前最佳的二级预防疗法主要集中在抗血小板药物，他汀类药物，β-受体阻滞剂，血管紧张素转换酶抑制剂和醛固酮拮抗剂【6】等药物上。目前对于预防和治疗AE的研究表明，控制导致AE的分子途径，尤其是导致AE的不良分子生物学过程能够改善这一问题，而代谢组学的研究提供了解决这个问题的一种方法。
在STEMI患者接受直接PCI治疗后，为了应对长期缺血和缺血再灌注损伤，心脏经历了显着的代谢变化，称为“代谢重塑”。有证据表明心脏代谢重塑对HF的发生和发展至关重要【7 8】。氨基酸虽然是细胞生长和存活的重要营养成分，但也可作为细胞内和信号分子的生物合成底物【9】。一些研究表明，心肌梗塞和缺血再灌注损伤导致氨基酸分解代谢紊乱。氨基酸分解代谢的缺陷使心脏对缺血再灌注损伤敏感，导致不利的心肌重塑和MI后HF【13】。
为了更好的评价PCI患者的预后，需要评估接受PCI并且患有院内心血管AE的STEMI患者血样中循环氨基酸代谢物的异常，并将其与未患AE的年龄和性别匹配的对照进行比较，从而找到和PCI术后AE直接关联的不良代谢物。
发明内容
本发明首先涉及一组分子标志物在制备预测或辅助预测ST段抬高型心肌梗死(STEMI)患者经皮冠状动脉介入治疗(PCI)后院内心血管不良事件发生的产品中的应用，
所述的分子标志物组包括：颉氨酸，亮氨酸，异亮氨酸；
更进一步的，所述的分子标志物组还包括：NT-pro BNP(脑钠肽前体N端)。
本发明还涉及检测所述分子标志物的产品在制备预测或辅助预测ST段抬高型心肌梗死(STEMI)患者经皮冠状动脉介入治疗(PCI)后院内心血管不良事件发生的产品中的应用，
所述的分子标志物组包括：颉氨酸，亮氨酸，异亮氨酸；
更进一步的，所述的分子标志物组还包括：NT-pro BNP(脑钠肽前体N端)。
所述的院内心血管不良事件包括，心肌缺血和缺血再灌注损伤、心内破裂，恶性心律失常和心力衰竭(HF)，以及由上述不良事件导致的死亡。
本发明还涉及一种检测试剂盒，所述的检测试剂盒中包括检测所述分子标志物组的检测试剂，
所述的分子标志物组包括：颉氨酸，亮氨酸，异亮氨酸；
进一步的，所述的分子标志物组还包括：NT-pro BNP(脑钠肽前体N端)；
所述的检测试剂包括但不限于：
(1)特异性结合所述分子标志物的抗体，所述的抗体包括但不限于多克隆抗体、单克隆抗体、单链抗体、功能性抗体片段、抗体Fab区，纳米抗体、嵌合抗体、多特异性抗体等；
(2)特异性结合所述分子标志物的配体蛋白或多肽；
(3)特异性识别所述分子标志物的非蛋白类化合物；
优选的，所述的检测试剂盒是，
(1)酶联免疫法检测试剂盒；
(2)胶体金试纸检测试剂盒；
(3)化学发光检测试剂盒；
(4)流式细胞仪检测试剂盒。
附图说明
图1、在AE组和No AE组中使用随机森林生存分析确定六种代谢组学因子的权重。
图2、与因子2中最低三分位数的受试者相比，最高三分位数的患者AE发生率增加9.45倍。
图3、不同预设参数的受试者ROC曲线的AUC下的面积。
图4、入组患者情况说明图。
具体实施方式
入组患者和临床考察指标
研究人群包括974名>18岁的患者，在2014年1月至2017年1月期间在吉林大学第一医院入院，在胸痛发作后12小时内确诊为首次STEMI并接受直接PCI治疗(ChiCTR简介-EPC-16008199)。STEMI诊断为：胸痛发作≥20分钟且ST段抬高≥0.1mv、至少两个连续心电图导联或新左束支传导阻滞、血清心脏生物标志物水平至少比正常的上限提高两倍的患者。如果患者入院时超过Killip I级，在过去12个月内接受住院患者入院时诊断为HF、肾功能不全(血清肌酐>250μmol/L)、肝功能不全(血清丙氨酸氨基转移酶>135U/l)，在过去12个月内诊断为肝硬化和严重脂肪肝，已知恶性肿瘤，或在前3个月内服用过氨基酸补充剂，则排除患者。最终研究人群由834名患者组成。在通过急诊医疗服务转诊到直接PCI之前，每名患者服用300毫克阿司匹林和300毫克氯吡格雷(或180毫克替卡格雷)。在直接PCI后，根据现代指南对患者进行医学治疗。该研究符合赫尔辛基宣言，并经吉林大学第一医院医学伦理委员会批准，所有患者都签署了书面知情同意书。
主要临床结果是住院期间PCI后因心血管问题死亡和急性心力衰竭(AHF)的复合变量；次要临床结果包括主要结果的各个组成部分。“心血管死亡”包括心脏泵功能衰竭，心律失常或机械并发症导致的死亡，包括室间隔破裂和游离壁破裂。AHF定义为患有呼吸困难的患者，其体检结果包括外周水肿和肺部啰音，肺充血等放射学证据，并需要静脉注射利尿剂，或持续正压通气。共有96例接受直接PCI治疗的STEMI患者出现了院内心血管问题死亡和急性心力衰竭，将这组患者入组为AE组。我们分析了96个AE受试者的代谢物和96个没有事件的受试者(1：1比例)(平均年龄间隔±3年)。
PCI术后STEMI患者的基线特征在住院期间，96名STEMI患者经历了主要结果：20例心血管死亡和76例AHF。表1中列出了AE组和无AE组患者的基线临床特征。患者在性别，年龄，BMI，血压，心率症状发作至再灌注时间方面的分布相似。
表1、入组患者基本信息
统计分析
使用GRACE评分法计算死亡或复发性心肌梗死风险，GRACE评分是一种广泛使用的预测工具【32】，GRACE风险评分的依据包括年龄，心率，收缩压，肌酐，Killip分类，入院时是否存在心脏骤停，ST段抬高与否以及入院时的心肌酶水平。
使用Mann-Whitney U-连续变量检验和分类变量的卡方检验，比较No AE组和AE组之间的基线特征。使用PCA分析将大量相关代谢物中的不相关因子减少。Varimax rotation【33】用于识别重要因素：仅考虑特征值≥1.0的因子。为评估PCA衍生因素与临床结果的关系，采用单变量和多变量逻辑回归模型，调整传统STEMI危险因素(年龄，BMI，症状发作至再灌注时间，Gensini评分，前壁心肌梗死，高血压病史，病史糖尿病，当前吸烟史)，建立OR曲线并统计95％CI。
为了验证PCA分析结果，我们进行了随机生存林(RSF)分析【34】，这是一种功能强大的机器学习统计算法，是验证小样本结果的适当框架。PCA因子用作协变量，事件作为结果。计算基于RSF变量重要性的PCA因子的排名以验证结果。通过计算C统计量，净重分类指数(NRI)和综合歧视改善(IDI)来评估模型绩效。计算每个参数的95％置信区间(CI)。为了比较传统生物标志物和因子的准确性，产生ROC曲线并计算AUC。统计分析用商业软件(SPSS25.0，IBM，Armonk NY，USA)和R版本3.3.3(R Foundation for Statistical Computing，Vienna，Austria)分别进行。在本研究中，P值<0.05被认为具有统计学意义。
实施例1、液相色谱-串联质谱(LC-MS)分析氨基酸代谢物
入院时从所有STEMI患者收集血液样本。通过在室温下以3000rpm离心10分钟获得血浆，然后储存在-80℃直至分析。我们使用液相色谱-串联质谱(LC-MS)分析氨基酸代谢物。LC-MS级溶剂和同位素标记的分析标准品分别购自Sigma-Aldrich(St.Louis MO，USA)和Cambridge Isotope Laboratories，Inc。(Andover MA，USA)。分析方法如下：
(1)通过用库存的血浆等比稀释使用稳定同位素标记的参考化合物制备标准曲线(D5-谷氨酸，D3-天冬氨酸，[13C4]-天冬酰胺，D3-丝氨酸，D5-谷氨酰胺，D5-组氨酸，D5-苏氨酸，D7-丙氨酸，D7-精氨酸，D7-脯氨酸，D8-缬氨酸，D3-甲硫氨酸，D10-异亮氨酸，D10-亮氨酸，D8-苯丙氨酸，D8-色氨酸，D9-赖氨酸)。
(2)将200μL等分试样添加到含有适当体积的混合内标的800μL预冷的乙腈中进行蛋白质沉淀，将其涡旋混匀并离心。
(3)使用液相色谱-串联质谱系统进行血浆样品的代谢物分布的分析，所述系统由与质谱系统(Q-Enactive MS，Thermo Scientific，Logan UT，USA)偶联的Ultimate3000UHPLC系统组成。使用Waters HESS T3柱(1.8am，100mm×2.1mm)进行色谱分离。流动相A(水)和B(甲醇)均含有0.1％甲酸和5mM乙酸铵，向流动相A中加入0.015％七氟丁酸。线性梯度为：2％B洗脱0.5min，20％B洗脱7分钟，50％B洗脱10分钟，98％B洗脱10.1分钟，98％B洗脱14分钟，2％B洗脱14.1分钟，和2％B洗脱17分钟。流速为0.3毫升/分钟，柱温设定在40℃。Q-Exactive MS操作以正离子模式进行。全扫描的分辨率设定为35,000，扫描范围为m/z70-300。补充表1显示了氨基酸分析的详细MS参数。
补充表1、氨基酸分析的详细MS参数
AE组和No AE组的26个氨基酸的血浆水平的差异显示在补充表2中。与No AE受试者相比，AE受试者中异亮氨酸，亮氨酸，酪氨酸，苯丙氨酸，鸟氨酸，谷氨酸，肌酸，肌酸酐，丝氨酸，尿素，犬尿氨酸和甘氨酸均较高。AE组中谷氨酰胺，精氨酸和组氨酸的水平降低。在两组之间的其他氨基酸之间未观察到显着差异。
补充表2、AE组和No AE组26个氨基酸的血浆水平差异
氨基酸与院内临床结果的关联主成分分析(PCA)确定了六个有意义的代谢组学因子(表4)，包括因子1(鸟氨酸，甘氨酸，丝氨酸)，因子2(支链氨基酸，亮氨酸，异亮氨酸和缬氨酸)，因子3(苯丙氨酸)，因子4(尿素，肌酸酐)，因子5(牛磺酸)和因子6(苏氨酸)。
表4、通过主成分分析(PCA)确定的六个有意义的代谢组学因子
接下来，我们通过单变量和多变量逻辑回归模型分析了六个因素与临床结果的关联。如表5所示，在调整临床协变量后(包括年龄，BMI，症状发作至再灌注时间，Gensini评分，前壁MI，高血压病史，糖尿病史，当前吸烟史)，因素1,2和3与心血管死亡或AHF的主要结果风险增加显着相关(因素1：优势比[OR]＝1.73[95％置信区间＝1.12-2.66，P＝0.013]，因子2：OR＝3.36[95％CI＝1.98-5.69，P<0.001]，因子3：OR＝2.35[95％CI＝1.52-3.61，P<0.001]。
表5、六个因子与临床结果的关联
关于次要结果，因子2与急性心力衰竭(AHF)和心血管死亡增加有关(OR＝2.07[95％CI＝1.34-3.19，P＝0.001])(OR＝2.22[95％CI＝1.23-4.00，P＝0.008])。值得注意的是，因子1和因子3与心血管死亡风险不相关，因子1与AHF风险不相关。
随机森林生存分析也确定了相同的六种代谢组学因子；其中，因子2具有区分AE受试者和非AE受试者的最高值(图1)。
与因子2中最低三分位数的受试者相比，最高三分位数的患者AE发生率增加9.45倍(调整OR：9.45；95％CI＝3.18-28.09，P＝0.001)(图2)。
这些分析表明，因素2与PCI后STEMI患者的心血管死亡和AHF显着相关。
实施例2、其他生物标志物的测定以及联合分析
入院时从STEMI患者收集血液样本。使用OCD Vitros 5600(Ortho ClinicalDiagnostics)cTnI ES系统测定cTnI标志物浓度；使用商业检测试剂盒OCD Vitros 5600(Ortho Clinical Diagnostics)NT-proBNP ES系统测定NT-pro BNP标志物浓度。
AE组的NT-pro BNP(298.5±119.4ng/L对214.3±80.8ng/L；P<0.001)和TnI(7.7±19μg/ml对8.8±6.9μg/ml，P＝0.001)的显著着高于No AE组。
TnI和NT-pro BNP用于诊断和预测心肌梗塞的公认的生物标志物，将其与因子2联合，在单变量和多变量逻辑回归模型(调整年龄，BMI，症状发作至再灌注时间，Gensini评分，前壁MI，高血压病史，糖尿病史和当前吸烟史)中，NT-pro BNP和因子2均被保留作为主要结果的预测因子。调整后的NT-pro BNP和因子2的OR分别为2.14(95％CI＝1.652-3.00，P<0.001)和3.36(95％CI＝1.98-5.69，P<0.001)。在本工作中，TnI未被确定为预测因子，OR＝1.29(95％CI＝0.89-1.29，P＝0.089)(补充表4)。
补充表4、因子2和TnI和NT-pro BNP指标组合用于预测心肌梗塞
为了确定NT-pro BNP和因子2联合区分AE与无AE患者的能力，我们计算了受试者ROC曲线的AUC下的面积。分析显示因子2的预测值略高于NT-pro BNP(AUC：0.69对比AUC：0.74)(图3)。NT-pro BNP和因子2的组合对于主要结果的预测值有所增加(AUC 0.82，P<0.001)(补充图3)。
GRACE风险评分的预测是指南推荐的院内风险评估工具。我们评估了因子2的加入是否比单独的GRACE风险评分改进了风险预测。将NT-pro BNP加入GRACE风险评分中，C统计量从0.702(95％CI，0.625-0.778)改进到0.760(95％CI，0.692-0.829，P＝0.069)。净重分类指数NRI为0.646(95％CI，0.378-0.914，P<0.001)，综合判别改善指数IDI为0.095(95％CI，0.053-0.136，P<0.001)。将因子2加入GRACE评分后，c统计量得到改善，为0.814(95％CI，0.753-0.876，P<0.001)。NRI和IDI分别为0.729(95％CI，0.466-0.992，P<0.001)和0.186(95％CI，0.131-0.240，P<0.001)。在GRACE评分中，使用NT-pro BNP中加入因子2进一步改善了风险预测，c-统计量进一步增加至0.869(95％CI，0.818-0.920，P<0.001)。NRI为1.000(95％CI，0.756-1.244，P<0.001)，IDI为0.306(95％CI，0.241-0.371，P<0.001)(表3)。
表3、不同参数的GRACE风险评分
最后需要说明的是，以上实施例仅帮助本领域技术人员理解本发明的实质，不用做对本发明保护范围的限定。
Claims (4)
1.一组分子标志物在制备预测或辅助预测ST段抬高型心肌梗死(STEMI)患者经皮冠状动脉介入治疗(PCI)后院内心血管不良事件发生的产品中的应用，
所述的分子标志物组包括：颉氨酸，亮氨酸，异亮氨酸；
更进一步的，所述的分子标志物组还包括：NT-pro BNP(脑钠肽前体N端)。
2.根据权利要求1所述的应用，其特征在于，所述的院内心血管不良事件包括但不限于，心肌缺血和缺血再灌注损伤、心内破裂，恶性心律失常和心力衰竭(HF)，以及由上述不良事件导致的死亡。
3.一种检测试剂盒，所述的检测试剂盒中包括检测权利要求1所述分子标志物组的检测试剂，
所述的检测试剂包括但不限于：
(1)特异性结合所述分子标志物的抗体，所述的抗体包括但不限于多克隆抗体、单克隆抗体、单链抗体、功能性抗体片段、抗体Fab区，纳米抗体、嵌合抗体、多特异性抗体等；
(2)特异性结合所述分子标志物的配体蛋白或多肽；
(3)特异性识别所述分子标志物的非蛋白类化合物。
4.根据权利要求3所述的试剂盒，其特征在于，所述的检测试剂盒是，
(1)酶联免疫法检测试剂盒；
(2)胶体金试纸检测试剂盒；
(3)化学发光检测试剂盒；
(4)流式细胞仪检测试剂盒。
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| CN111323521A (zh) * | 2020-04-20 | 2020-06-23 | 中国人民解放军北部战区总医院 | 色氨酸分解代谢中的犬尿氨酸/色氨酸比值的改变在st段抬高型心肌梗死预后中的应用 |
| CN113549688A (zh) * | 2021-08-27 | 2021-10-26 | 河北医科大学第二医院 | 一组诊断冠状动脉疾病的分子标志物 |
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