凝血酶调节蛋白联合中性粒细胞肽酰基精氨酸脱亚氨酶4预警非瓣膜性房颤合并急性缺血性脑卒中患者缺血事件复发

Thrombin regulatory protein combined with neutrophil peptidyl arginine deiminase-4 predicts risk of ischemic event recurrence in patients with nonvalvular atrial fibrillation complicated with acute ischemic stroke

目的研究凝血酶调节蛋白(TM)联合中性粒细胞肽酰基精氨酸脱亚氨酶4(PAD4)预警非瓣膜性心房颤动(NVAF)合并急性缺血性脑卒中(AIS)患者缺血事件复发风险。方法纳入2020年8月至2023年2月期间于天津市西青医院就诊的NVAF合并AIS患者164例为患者组,男71例,女93例,年龄51~83岁。采用Shine i2900型全自动化学发光免疫分析仪测定血浆TM水平;采用TECAN Sunrise酶标仪测定血清PAD4水平。以Kruskal-Wallis H检验进行多组间比对,以Mann-Whitney U检验进行两组间数据比对;用Friedman秩和检验进行同组内各时间节点数据比较;用ROC曲线分析诊断性能;用Logistic回归进行关联性分析;用Kaplan-Meier曲线进行生存分析,Cox比例风险回归模型获得HR值。结果在治疗前和治疗后,复发组血浆TM水平均高于未复发组(P值均<0.001);未复发组在治疗后血浆TM水平显著低于治疗前(P<0.001),复发组治疗后TM水平与治疗前差异无统计学意义(P=0.166)。AIS患者组在治疗前、后的血清PAD4水平均显著高于健康对照组(P值均<0.001)。治疗前,未复发组血清PAD4水平与复发组间的差异无统计学意义(P=0.093);治疗后,复发组显著高于未复发组(P<0.001);未复发组在治疗后血清PAD4水平低于治疗前(P<0.001),复发组在治疗后显著高于治疗前间(P<0.001)。治疗前,血浆TM的ROC曲线下面积(AUC^(ROC))为0.885,临界值为13.04TU/mL;治疗后,AUC^(ROC)为0.909,临界值为10.52TU/mL。治疗前,血清PAD4的AUC^(ROC)为0.606,临界值为11.45ng/mL;治疗后,AUC^(ROC)为0.939,临界值为10.00ng/mL。TM与PAD4联合评估的治疗前AUC^(ROC)为0.877,治疗后AUC^(ROC)为0.976。用Logistic回归做多元分析,AIS患者治疗后的TM和PAD4水平均与充血性心力衰竭和高血压有显著相关性(P<0.05)。生存分析显示,治疗后,TM、PAD4以及两项指标联合评估,均可有效预测患者在随访期内缺血事件复发的累积风险(Log-rankχ^(2)分别为20.597、5.836和27.786,P值分别为<0.001、0.016和<0.001)。Cox回归模型显示,TM与PAD4联合评估可有效预测AIS患者随访期内的缺血事件复发风险(HR=1.397)。结论NVAF并发AIS患者TM和PAD4水平显著增高,并随病情发展趋势而改变,通过对上述两项指标的动态监测和联合评估,可有效预警AIS患者缺血事件复发的风险,为临床早期识别和及时干预提供依据。

Objective To explore the significance of detections for thrombin regulatory protein(TM)combined with neutrophil peptidyl arginine deiminase 4(PAD4)to predict the risk of ischemic event recurrence in patients with nonvalvular atrial fibrillation(NVAF)complicated with acute ischemic stroke(AIS).Methods A total of 164 patients with NVAF and AIS admitted to Tianjin Xiqing Hospital from August 2020 to February 2023 were enrolled into the patient group,including 71 males and 93 females,aged from 51 to 83 years.The levels of plasma TM were measured by Shine i2900 automatic chemiluminescence immuno-analyzer,and the levels of serum PAD4 were determined by TECAN Sunrise enzyme-labeler.Kruskal-Wallis H test was used for comparison among multiple groups,and Mann-Whitney U test was used for the comparison between two groups.Friedman rank sum test was used to compare the data of each time points in the same group.The diagnostic performance was analyzed by ROC curve.Logistic regression was used for correlation analysis.Kaplan-Meier curve was used for survival analysis and Cox proportional risk regression model was used to obtain HR values.Results The plasma TM level in the relapsed group was higher than that in the non-relapsed group before and after treatment(all the P<0.001).The plasma TM level after treatment was significantly lower than that before treatment in the non-relapsed group(P<0.001).Compared with those before treatment,no significant difference of the plasma TM level after treatment was found in the relapse group(P=0.166).The serum PAD4 levels in the AIS patients before and after treatment were significantly higher than those in healthy controls(P<0.001).Before treatment,no significant dfference of serum PAD4 level was found between the non-relapsed group and the relapsed group(P=0.093).After treatment,the serum PAD4 levels in the recurrence group was significantly higher than that in the non-recurrence group(P<0.001).After treatment,the serum PAD4 level in the non-relapsed group was lower than that before treatment(P<0.001),but it was significantly higher than that before treatment in the relapsed group(P<0.001).Before treatment,the area under the ROC curve(AUC^(ROC))was O.885 and the threshold value of plasma TM was 13.04 TU/mL.The AUC^(ROC) was 0.909 after treatment and the plasma TM cut-ff value was 10.52 TU/mL.Before treatment,the AUC^(ROC) was 0.606 and the critieal value ofserumPAD4 was1145ng/mLTheAUC^(ROC) was 939 and thesermPAD4cutffvalue was1000ng/mLafertreat ment.The AUC^(ROC) assessed by the combination of TM and PAD4 was 0.877 before treatment,and it was 0.976 after treatment.Multivariate analysis by Logistic regression showed that both the levels of TM and PAD4 after treatment were significantly correlated with age,congestive heart failure and hypertension in AIS patients(P<0.05).The results of survival analysis showed that after treatment,all the levels of TM and PAD4 as well as the combined evaluation for the two indicators may effectively predict the cumulative risk of recurrent ischemic events during the follow-up period(Log-rank χ^(2) was 20.597,5.836 and 27.786,P<0.001,0.016 and<0.001).Cox regression models showed that the combined assessment for the levels of TM and PAD4 may effectively predict the risk of ischemic event recurrence during follow-up in AIS patients(HR=1.397).Conclusion The plasma levels of TM and PAD4 in the patients with NVAF complicated with AIS were significantly increased and changed with the trend of the disease progression.Dynamic monitoring and combined evaluation for the levels of TM and PAD4 could effectively early warn the risk of ischemic event recurrence in the patients with AIS,and provide a basis for early identification and timely intervention in clinical practice.