慢性心功能不全患者单个核细胞微小RNAs差异表达与患者脑血管疾病的关系

Relationship between Differential Expression of MicroRNAs in Mononuclear Cells and Cerebrovascular Diseases in Patients with Chronic Cardiac Insufficiency

目的探讨慢性心功能不全患者外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)微小RNA(microRNAs,miRNAs)差异表达与患者脑血管疾病的关系。方法这是一项对2019年1月至2022年4月期间从西安交通大学第一附属医院出院的274例失代偿性心力衰竭患者的观察性研究。对患者进行随访,直到2023年1月,观察患者缺血性脑血管事件情况。miRNA微阵列用于分析基线循环miRNAs水平。通过实时定量聚合酶链反应(quantitative real time polymerase chain reaction,qRT-PCR)验证差异表达的miRNAs。采用受试者工作特征曲线(receiver operating characteristic curve,ROC)分析候选miRNAs对缺血性脑血管事件的预测价值。结果在随访期间[422(184~939)d],有24例患者发生缺血性脑血管事件。与未发生缺血性脑血管事件的患者相比,发生缺血性脑血管事件的患者服用抗凝剂、维生素K拮抗剂的患者比例显著降低,差异有统计学意义(P<0.05)。在两组基线PBMCs样本中分析了2549个miRNA的表达,并鉴定了20个差异表达的miRNAs(定义为FC>1.3和P<0.05)。qRT-PCR验证结果显示,与非缺血性脑血管事件患者相比,发生缺血性脑血管事件患者的PBMCs样本中hsa-miR-1273g-3p、hsa-miR-2861表达水平显著上调,hsa-miR-483-5p表达水平显著下调,差异有统计学意义(P<0.05)。ROC分析表明,hsa-miR-1273g-3p[曲线下面积(area under the curve,AUC)=0.745]预测心力衰竭患者缺血性脑血管事件的灵敏度和特异度分别为81%、56%,hsa-miR-2861(AUC=0.614)的灵敏度和特异度分别为76%、62%,hsa-miR-483-5p(AUC=0.821)的灵敏度和特异度分别为76%、80%。3种候选miRNAs联合的预测价值优于单独一种miRNA,其AUC、灵敏度和特异度分别为0.941、90%、98%。结论PBMCs中hsa-miR-1273g-3p、hsa-miR-2861表达水平上调和hsa-miR-483-5p表达水平下调可能与心力衰竭患者缺血性脑卒中风险增加有关。

Objectives To explore the relationship between the differential expression of microRNAs(miRNAs)in peripheral blood mononuclear cells(PBMCs)and cerebrovascular diseases in patients with chronic cardiac insufficiency.Methods This was an observational study of 274 patients with decompensated heart failure discharged from The First Affiliated Hospital of Xi′an Jiaotong University from January 2019 to April 2022.The patients were followed up until January 2023 to observe the ischemic cerebrovascular events.MiRNA microarray was used to analyze the level of circulating miRNAs at baseline.The differentially expressed miRNAs were verified by quantitative real time polymerase chain reaction(qRT-PCR).The predictive value of candidate miRNAs for ischemic cerebrovascular events was analyzed by receiver operating characteristic curve(ROC).Results During the follow-up period[422(184-939)d],24 patients had ischemic cerebrovascular events.Compared with patients without ischemic cerebrovascular events,the percentages of patients with ischemic cerebrovascular events taking anticoagulants and vitamin K antagonists decreased significantly(P<0.05).The expression of 2549 miRNAs was analyzed in two groups of baseline PBMCs samples,and 20 differentially expressed miRNAs(defined as FC>1.3 and P<0.05)were identified.RT-qPCR results showed that compared with patients with non-ischemic cerebrovascular events,the expression levels of hsa-miR-1273g-3p and hsa-miR-2861 in PBMCs samples of patients with ischemic cerebrovascular events increased significantly(P<0.05),and the expression level of hsa-miR-483-5p decreased significantly(P<0.05).ROC analysis showed that the sensitivity and specificity of hsa-miR-1273g-3p[area under the curve(AUC)=0.745]in predicting ischemic cerebrovascular events in heart failure patients were 81%and 56%,respectively,while the sensitivity and specificity of hsa-miR-2861(AUC=0.614)were 76%and 62%,respectively.The predictive value of the combination of three candidate miRNAs was better than that of a single miRNA,and its AUC,sensitivity and specificity were 0.941,90%and 98%respectively.Conclusions The upregulation of hsa-miR-1273g-3p,hsa-miR-2861 and down-regulation of hsa-miR-483-5p in PBMCs may be related to the increased risk of ischemic stroke in heart failure patients.