血清miR-491-5p和miR-21-5p对急性缺血性卒中患者静脉溶栓后出血转化的预测价值

doi:10.3969/j.issn.1673-5765.2024.12.011

摘要/Abstract

摘要： 目的探讨血清微小RNA（microRNA，miRNA/miR）中miR-491-5p、miR-21-5p对急性缺血性卒中（acute ischemic stroke，AIS）患者静脉溶栓后出血转化的预测价值。
方法回顾性选取2021年1月—2023年2月南阳市中心医院收治的312例AIS静脉溶栓治疗患者为研究对象，按照静脉溶栓后24 h内出血转化发生情况分为出血转化组（66例）和非出血转化组（246例）。实时荧光定量PCR测定血清miR-491-5p、miR-21-5p表达水平。采用多因素logistic回归分析探讨AIS患者静脉溶栓后出血转化的独立危险因素，以ROC曲线分析血清miR-491-5p、miR-21-5p及二者联合对AIS患者静脉溶栓后出血转化的预测价值。
结果出血转化组糖尿病、高血压、心房颤动患者比例以及随机血糖水平、NIHSS评分、血清miR-21-5p表达水平高于非出血转化组（P＜0.001），血清miR-491-5p表达水平低于非出血转化组（P＜0.001）。logistic回归分析结果显示，有糖尿病病史（OR 1.907，95%CI 1.088～3.344）、高血压病史（OR 1.928，95%CI 1.105～3.364）、心房颤动病史（OR 2.375，95%CI 1.356～4.159），随机血糖水平升高（OR 1.826，95%CI 1.062～3.138），NIHSS评分升高（OR 3.894，95%CI 1.568～9.671），血清miR-21-5p表达水平升高（OR 4.237，95%CI 1.643～10.925）是AIS患者静脉溶栓后出血转化的独立危险因素（P＜0.001）；而血清miR-491-5p表达水平升高（OR 0.193，95%CI 0.108～0.347）是AIS患者静脉溶栓后出血转化的保护因素（P＜0.001）。ROC曲线显示，血清miR-491-5p、miR-21-5p表达水平预测AIS患者静脉溶栓后出血转化的AUC值分别为0.784（95%CI 0.731～0.838）和0.785（95%CI 0.722～0.847），对应最佳截断值分别为1.21和2.26，二者联合预测的AUC值提升至0.861（95%CI 0.815～0.907）。
结论血清miR-491-5p表达水平低、miR-21-5p表达水平高是AIS患者静脉溶栓后出血转化的独立危险因素，可作为出血转化的预测指标，联合预测效能良好。

文章导读： 血清miR-491-5p、miR-21-5p可能通过调节免疫炎症反应、内皮细胞损伤等途径参与急性缺血性卒中患者静脉溶栓后出血转化的发生，二者联合预测效能良好。

关键词: miR-491-5p; miR-21-5p; 急性缺血性卒中; 静脉溶栓; 出血转化; 预测价值

Abstract: Objective To investigate the predictive value of serum microRNA-491-5p (miR-491-5p) and microRNA-21-5p (miR-21-5p) for hemorrhagic transformation after intravenous thrombolysis in patients with acute ischemic stroke (AIS).
Methods A total of 312 patients with AIS who underwent intravenous thrombolysis at Nanyang Central Hospital from January 2021 to February 2023 were retrospectively selected as the study objects. They were divided into the hemorrhagic transformation group (66 cases) and the non-hemorrhagic transformation group (246 cases) according to the occurrence of hemorrhagic transformation 24 hours after intravenous thrombolysis. Realtime fluorescence quantitative PCR was used to measure the expression levels of serum miR-491-5p and miR-21-5p. Multivariate logistic regression analysis was used to explore the independent risk factors for hemorrhagic transformation after intravenous thrombolysis in AIS patients. The predictive value of serum miR-491-5p, miR-21-5p, and their combination for hemorrhagic transformation after intravenous thrombolysis in AIS patients was analyzed by ROC curve.
Results The proportion of patients with diabetes mellitus, hypertension, and atrial fibrillation in the hemorrhagic transformation group was higher than that in the non-hemorrhagic transformation group (P<0.001). The levels of random blood glucose, NIHSS score, and serum miR-21-5p expression in the hemorrhagic transformation group were also higher than those in the non-hemorrhagic transformation group (P<0.001), while the expression level of serum miR-491-5p was lower than that in the non-hemorrhagic transformation group (P<0.001). Logistic regression analysis showed that a history of diabetes mellitus (OR 1.907, 95%CI 1.088-3.344), a history of hypertension (OR 1.928, 95%CI 1.105-3.364), a history of atrial fibrillation (OR 2.375, 95%CI 1.356-4.159), elevated random blood glucose level (OR 1.826, 95%CI 1.062-3.138), increased NIHSS score (OR 3.894, 95%CI 1.568-9.671), and elevated expression level of serum miR-21-5p (OR 4.237, 95%CI 1.643-10.925) were independent risk factors for hemorrhagic transformation after intravenous thrombolysis in AIS patients (P<0.001). Conversely, elevated expression level of serum miR-491-5p (OR 0.193, 95%CI 0.108-0.347) was the protective factor for hemorrhagic transformation after intravenous thrombolysis in AIS patients (P<0.001). The ROC curve showed that the AUC values of serum miR-491-5p and miR-21-5p expression levels for predicting hemorrhagic transformation after intravenous thrombolysis in AIS patients were 0.784 (95%CI 0.731-0.838) and 0.785 (95%CI 0.722-0.847), respectively. The corresponding optimal cutoff values were 1.21 and 2.26, respectively. The AUC value predicted by the combination of the two increased to 0.861 (95%CI 0.815-0.907).
Conclusions Low expression level of serum miR-491-5p and high expression level of miR-21-5p are independent risk factors for hemorrhagic transformation after intravenous thrombolysis in AIS patients. They can be used as risk predictors for hemorrhagic transformation, with good combined predictive efficacy.

Key words: miR-491-5p; miR-21-5p; Acute ischemic stroke; Intravenous thrombolysis; Hemorrhagic transformation; Predictive value

中图分类号:

王笑寒, 潘燕, 张小林, 刘坦. 血清miR-491-5p和miR-21-5p对急性缺血性卒中患者静脉溶栓后出血转化的预测价值[J]. 中国卒中杂志, 2024, 19(12): 1441-1447.

WANG Xiaohan, PAN Yan, ZHANG Xiaolin, LIU Tan. Predictive Value of Serum miR-491-5p and miR-21-5p on Hemorrhagic Transformation after Intravenous Thrombolysis in Acute Ischemic Stroke Patients[J]. Chinese Journal of Stroke, 2024, 19(12): 1441-1447.

参考文献

[1] WEI L，CHEN C，DAI Y Q，et al. Serum 25-hydroxyvitamin D deficiency predicts poor outcomes among acute ischemic stroke patients receiving intravenous thrombolysis[J]. Chin Med J（Engl），2019，132（4）：491-494.
[2] 孙若楠，赵源征，朱迎慧，等. 溶栓前血清钙和尿酸水平对急性缺血性脑卒中静脉溶栓后出血转化的预测价值[J]. 中华老年心脑血管病杂志，2021，23（6）：617-620.
SUN R N，ZHAO Y Z，ZHU Y H，et al. Value of serum calcium and UA levels before thrombolysis for predicting HT in AIS patients after intravenous thrombolysis[J]. Chin J Geriatr Heart Brain Vessel Dis，2021，23（6）：617-620.
[3] HUANG X J，CAI Q K，XIAO L L，et al. Influence of procedure time on outcome and hemorrhagic transformation in stroke patients undergoing thrombectomy[J]. J Neurol，2019，266（10）：2560-2570.
[4] 罗婷，邵祥忠，谢海洋，等. 进展性缺血性脑卒中病人外周血miRNA的表达水平及临床意义[J]. 中西医结合心脑血管病杂志，2021，19（13）：2272-2275.
LUO T，SHAO X Z，XIE H Y，et al. Expression level and clinical significance of peripheral blood miRNA in patients with progressive ischemic stroke[J].Chinese Journal of Integrative Medicine on Cardio-Cerebrovascular Disease，2021，19（13）：2272-2275.
[5] SONG X D，LIU J F，WANG Y N，et al. Serum microRNA miR-491-5p/miR-206 is correlated with poor outcomes/spontaneous hemorrhagic transformation after ischemic stroke：a case control study[J/OL]. Brain Sci，2022，12（8）：999[2023-08-22]. https://doi.org/10.3390/brainsci12080999.
[6] 王蓉，王凤，陈星宇，等. 血清miR-221、miR-210、miR-21-5p与老年急性脑梗死颈动脉粥样硬化斑块性质相关性及对预后预测价值分析[J]. 临床军医杂志，2022，50（12）：1313-1316.
WANG R，WANG F，CHEN X Y，et al. Analysis of the correlation between serum miR-221，miR-210，miR-21-5p and the properties of carotid atherosclerotic plaque in elderly patients with acute cerebral infarction and its predictive value for prognosis[J]. Clin J Med Offic，2022，50（12）：1313-1316.
[7] 中华医学会神经病学分会，中华医学会神经病学分会脑血管病学组. 中国急性缺血性脑卒中诊治指南2018[J]. 中华神经科杂志，2018，51（9）：666-682.
Chinese Society of Neurology，Chinese Stroke Society. Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018[J]. Chin J Neurol，2018，51（9）：666-682.
[8] LARRUE V，VON KUMMER R R，MÜLLER A，et al. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator：a secondary analysis of the European-Australasian acute stroke study（ECASS Ⅱ）[J]. Stroke，2001，32（2）：438-441.
[9] ESKIOGLOU E，HUCHMANDZADEH MILLOTTE M，AMIGUET M，et al. National institutes of health stroke scale zero strokes[J]. Stoke，2018，49（12）：3057-3059.
[10] YAGHI S，WILLEY J Z，CUCCHIARA B，et al. Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke：a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association[J/OL]. Stroke，2017，48（12）：e343-e361[2023-08-22]. https://doi.org/10.1161/STR.0000000000000152.
[11] 吕亚星，姜超，梁朝辉，等. 中、重度脑白质疏松与急性缺血性脑卒中患者静脉溶栓出血转化及预后的关系[J]. 中华神经医学杂志，2020，19（9）：873-881.
LYU Y X，JIANG C，LIANG C H，et al. Correlations of moderate to severe leukoaraiosis with hemorrhagic transformation and prognoses of patients with acute ischemic stroke after intravenous thrombolysis[J]. Chin J Neuromed，2020，19（9）：873-881.
[12] 郝静峰，郭鹏，张自艳，等. 血清微RNA-497对预测急性缺血性脑卒中治疗后出血转化的价值[J]. 安徽医药，2023，27（5）：1010-1015.
HAO J F，GUO P，ZHANG Z Y，et al. Value analysis of serum miR-497 in predicting post-treatment hemorrhage transformation in patients with acute ischemic stroke[J]. Anhui Medical and Pharmaceutical Journal，2023，27（5）：1010-1015.
[13] BALIAN N R，ALONZO C B，ZURRÚ M C，et al. Clinical predictors of hemorrhagic transformation in non lacunar ischemic stroke[J]. Medicina（B Aires），2017，77（2）：100-104.
[14] 陈燕，张秋，尤年兴. 急性缺血性脑卒中静脉溶栓后神经功能恢复及脑出血转化发生的影响因素分析[J]. 中华危重病急救医学，2020，32（11）：1340-1345.
CHEN Y，ZHANG Q，YOU N X. Analysis of influencing factors of neurological function recovery and cerebral hemorrhage transformation after intravenous thrombolysis in patients with acute ischemic stroke[J]. Chin Crit Care Med，2020，32（11）：1340-1345.
[15] 常青，杨宇英，薛茜，等. NLR，MMP-9对急性缺血性脑卒中静脉溶栓患者出血转化的诊断价值[J]. 中国老年学杂志，2022，42（9）：2077-2081.
CHANG Q，YANG Y Y，XUE Q，et al. Diagnostic value of NLR，MMP-9 for hemorrhagic transformation in patients with intravenous thrombolysis in acute ischemic stroke[J]. Chinese Journal of Gerontology，2022，42（9）：2077-2081.
[16] 朱壮，佟晴，顾宁，等. 氨基末端脑利钠肽前体与急性缺血性脑卒中患者静脉溶栓后出血转化及预后的相关性[J]. 临床神经病学杂志，2023，36（1）：7-12.
ZHU Z，TONG Q，GU N，et al. Correlation between N-terminal pro-brain natriuretic peptide and hemorrhagic transformation and prognosis in patients with acute ischemic stroke after intravenous thrombolysis[J]. J Clin Neurol，2023，36（1）：7-12.
[17] 侯丽淳，杨慧，关雪莲，等. miRNA-145与miRNA-146a在缺血性脑卒中的表达研究[J]. 中风与神经疾病杂志，2019，36（2）：124-126.
HOU L C，YANG H，GUAN X L，et al. Study on the expression of miRNA-145 and miRNA-146a in ischemic stroke[J]. J Apoplexy and Nervous Diseases，2019，36（2）：124-126.
[18] 杨利强，关欣，徐伟杰，等. microRNA在缺血性脑卒中发生发展及其诊断治疗中的作用研究进展[J]. 中国老年学杂志，2022，42（10）：2540-2543.
YANG L Q，GUAN X，XU W J，et al. Progress of research on the role of microRNA in the occurrence，development of ischemic stroke and its diagnosis and treatment[J]. Chinese Journal of Gerontology，2022，42（10）：2540-2543.
[19] 苏梓健，詹晨阳，张婷，等. 外泌体microRNA对缺血性脑卒中调控机制的研究进展[J]. 中风与神经疾病杂志，2022，39（10）：933-935.
SU Z J，ZHAN C Y，ZHANG T，et al. Progress of exosomal microRNA regulation mechanism in ischemic stroke[J]. J Apoplexy and Nervous Diseases，2022，39（10）：933-935.
[20] WANG W，LI D B，LI R Y，et al. Diagnosis of hyperacute and acute ischaemic stroke：the potential utility of exosomal microRNA-21-5p and microRNA-30a-5p[J]. Cerebrovasc Dis，2018，45（5/6）：204-212.