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Article(id=1203002061051883692, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203002056400396334, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2023.06.0715, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1648396800000, receivedDateStr=2022-03-28, revisedDate=null, revisedDateStr=null, acceptedDate=1656518400000, acceptedDateStr=2022-06-30, onlineDate=1764747642052, onlineDateStr=2025-12-03, pubDate=1687881600000, pubDateStr=2023-06-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764747642052, onlineIssueDateStr=2025-12-03, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764747642052, creator=13701087609, updateTime=1764747642052, updator=13701087609, issue=Issue{id=1203002056400396334, tenantId=1146029695717560320, journalId=1189873630562394117, year='2023', volume='48', issue='6', pageStart='627', pageEnd='748', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1764747640943, creator=13701087609, updateTime=1764747714497, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1203002364979540735, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203002056400396334, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1203002364979540736, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203002056400396334, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=715, endPage=722, ext={EN=ArticleExt(id=1203002061370650804, articleId=1203002061051883692, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Establishment of a recurrence risk prediction model for patients with nonvalvular atrial fibrillation after ablation based on serum miRNA levels, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore establish a risk prediction model for patients with nonvalvular atrial fibrillation (NVAF) after ablation based on serum miRNA levels. Methods A total of 389 NVAF patients who received ablative therapy in the Second Affiliated Hospital of Fujian Medical University from August 2018 to December 2020 were selected as the study objects. 70.0% (272 cases) were randomly selected as the training set, 20.0% (78 cases) as the test set, and 10.0% (39 cases) as the verification set. The patients were followed up for 1 year, and the Kaplan-Meier cumulative recurrence risk curve was drawn. According to the recurrence of patients during the follow-up period, the patients were divided into recurrence group and non-recurrence group. The factors influencing the risk of recurrence after ablation in the training set of NVAF patients were explored through univariate and multivariate analysis, and the prediction model of recurrence risk after ablation was constructed. The prediction efficiency of this model was further tested by the consistency index (C-index) and receiver operating characteristic (ROC) curve. Then the model effectiveness of the test set is verified. Results As of December 21, 2021, a total of 30 cases were lost to follow-up (18 cases in the training set, 10 cases in the test set, and 2 cases in the validation set), and 359 actual cases were finally included (254 cases in training set, 68 in test set, and 37 in validation set). Of which 58 cases recurred in training set, and the recurrence rate was 22.8%. The baseline epicardial adipose tissue (EAT) volume was higher in recurrent group than that in non-recurrent group (P<0.05). The levels of miRNA-21, miRNA-150 and miRNA-192-5p in relapse group before and at the end of follow-up were higher than those in non-recurrence group, while the levels of miRNA-29 were lower than those in non-recurrence group with statistical significance (P<0.05). Multivariate logistic analysis showed that EAT volume (OR=1.060, 95%CI 1.012-1.109), miRNA-192-5p (OR=1.759, 95%CI 1.135-2.726), miRNA-21 (OR=32.508, 95%CI 9.224-114.577), miRNA-150 (OR=18.704, 95%CI 5.513-63.456) are independent risk factors for recurrence after ablation, miRNA-29b (OR=0.166, 95%CI 0.049-0.560) are protective factors for recurrence after ablation (P<0.05). Based on the above factors, the recurrence risk prediction model predicted that the C-index of NVAF patients after ablation was 0.929 (95%CI 0.890-0.958). ROC curve results of verification set showed that the specificity and sensitivity of this model were 83.2% and 88.0%, and the optimal critical value of area under ROC curve (AUC) was 0.711. The test data showed that the sensitivity, specificity and accuracy of the model were 86.7%, 88.7% and 88.3%. Conclusion The post-NVAF ablation recurrence risk model constructed by EAT volume, miRNA-192-5p, miRNA-29b, miRNA-21, miRNA-150 and other factors has a high predictive value for the recurrence risk after NVAF ablation.

, correspAuthors=Ming-Wei Huang, authorNote=null, correspAuthorsNote=
* E-mail:
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目的 构建基于血清miRNA水平的非瓣膜性房颤（NVAF）患者消融术后复发风险预测列线图模型并对其效能进行评价。方法 选择2018年8月－2020年12月在福建医科大学附属第二医院接受消融治疗的389例NVAF患者作为研究对象，随机选取272例（70.0%）作为训练集，78例（20.0%）作为测试集，39例（10.0%）作为验证集。随访观察1年，绘制Kaplan-Meier累积复发风险曲线，根据随访期间患者复发情况分为复发组与未复发组。通过单因素及多因素分析探求训练集NVAF患者消融术后复发风险的影响因素；构建NVAF消融术后复发风险列线图预测模型，通过一致性指数（C-index）和受试者工作特征（ROC）曲线检验该模型的预测效能，再进一步对测试集的模型效能进行验证。结果 截至2021年12月21日，共30例失访（训练集18例，测试集10例，验证集2例），最终纳入359例（训练集254例，测试集68例、验证集37例）NVAF患者。其中训练集中58例出现复发，复发率为22.8%。复发组基线心外膜脂肪组织（EAT）体积大于与未复发组（P<0.05）；与未复发组比较，复发组消融治疗前、随访结束时miRNA-21、miRNA-150、miRNA-192-5p水平明显升高，miRNA-29水平明显降低，差异有统计学意义（P<0.05）。多因素logistic回归分析显示，EAT体积（OR=1.060，95%CI 1.012～1.109）、miRNA-192-5p（OR=1.759，95%CI 1.135～2.726）、miRNA-21（OR=32.508，95%CI 9.224～114.577）、miRNA-150（OR=18.704，95%CI 5.513～63.456）为消融术后复发的独立危险因素，miRNA-29b（OR=0.166，95%CI 0.049～0.560）为消融术后复发的保护因素（P<0.05）。基于上述因素构建的复发风险预测模型预测NVAF患者消融术后复发的C-index为0.929（95%CI 0.890～0.958）；验证集ROC曲线分析结果显示，该预测模型特异度为83.2%，敏感度为88.0%，ROC曲线下面积（AUC）最佳临界值为0.711；测试集数据显示，该模型敏感度为86.7%，特异度为88.7%，准确率为88.3%。结论 EAT体积及miRNA-192-5p、miRNA-29b、miRNA-21、miRNA-150等为NVAF消融术后复发的独立危险因素，据此建立的列线图模型具有较高的预测价值。

, correspAuthors=黄明伟, authorNote=null, correspAuthorsNote=
黄明伟，E-mail：
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赖文文，医学博士，主治医师，主要从事起搏与电生理等心血管疾病方面的研究

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赖文文，医学博士，主治医师，主要从事起搏与电生理等心血管疾病方面的研究

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Int J Mol Sci, 2020, 21（7）: 2444., articleTitle=Exploratory analysis of circulating miRNA signatures in atrial fibrillation patients determining potential biomarkers to support decision-making in anticoagulation and catheter ablation, refAbstract=null), Reference(id=1203008555768049963, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, doi=null, pmid=null, pmcid=null, year=2020, volume=null, issue=20, pageStart=19, pageEnd=2744, url=null, language=null, rfNumber=[25], rfOrder=26, authorNames=Zhang M, Wang H, Wang X, journalName=Cell Cycle, refType=null, unstructuredReference=Zhang M, Wang H, Wang X, et al. MG53/CAV1 regulates transforming growth factor-β1 signaling-induced atrial fibrosis in atrial fibrillation [J]. Cell Cycle, 2020, 19（20）: 2734-2744., articleTitle=MG53/CAV1 regulates transforming growth factor-β1 signaling-induced atrial fibrosis in atrial fibrillation, refAbstract=null), Reference(id=1203008555847741742, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, doi=null, pmid=null, pmcid=null, year=2018, volume=null, issue=6, pageStart=11, pageEnd=null, url=null, language=null, rfNumber=[26], rfOrder=27, authorNames=Zhou Q, Maleck C, von Ungern-Sternberg SNI, journalName=Circ Arrhythm Electrophysiol, refType=null, unstructuredReference=Zhou Q, Maleck C, von Ungern-Sternberg SNI, et al. Circulating microRNA-21 correlates with left atrial low-voltage areas and is associated with procedure outcome in patients undergoing atrial fibrillation ablation [J]. Circ Arrhythm Electrophysiol, 2018, 11（6）: e006242., articleTitle=Circulating microRNA-21 correlates with left atrial low-voltage areas and is associated with procedure outcome in patients undergoing atrial fibrillation ablation, refAbstract=null), Reference(id=1203008555910656305, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, doi=null, pmid=null, pmcid=null, year=2019, volume=null, issue=6, pageStart=29, pageEnd=3035, url=null, language=null, rfNumber=[27], rfOrder=28, authorNames=Klein C, Brunereau J, Lacroix D, journalName=Eur Radiol, refType=null, unstructuredReference=Klein C, Brunereau J, Lacroix D, et al. Left atrial epicardial adipose tissue radiodensity is associated with electrophysiological properties of atrial myocardium in patients with atrial fibrillation [J]. Eur Radiol, 2019, 29（6）: 3027-3035., articleTitle=Left atrial epicardial adipose tissue radiodensity is associated with electrophysiological properties of atrial myocardium in patients with atrial fibrillation, refAbstract=null), Reference(id=1203008555998736693, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, doi=null, pmid=null, pmcid=null, year=2020, volume=null, issue=1, pageStart=43, pageEnd=145, url=null, language=null, rfNumber=[28], rfOrder=29, authorNames=Zhou M, Wang H, Chen J, journalName=Pacing Clin Electrophysiol, refType=null, unstructuredReference=Zhou M, Wang H, Chen J, et al. Epicardial adipose tissue and atrial fibrillation: possible mechanisms, potential therapies, and future directions [J]. Pacing Clin Electrophysiol, 2020, 43（1）: 133-145., articleTitle=Epicardial adipose tissue and atrial fibrillation: possible mechanisms, potential therapies, and future directions, refAbstract=null), Reference(id=1203008556074234169, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, doi=null, pmid=null, pmcid=null, year=2019, volume=null, issue=11, pageStart=30, pageEnd=2216, url=null, language=null, rfNumber=[29], rfOrder=30, authorNames=Ahn J, Shin SY, Shim J, journalName=J Cardiovasc Electrophysiol, refType=null, unstructuredReference=Ahn J, Shin SY, Shim J, et al. Association between epicardial adipose tissue and embolic stroke after catheter ablation of atrial fibrillation [J]. J Cardiovasc Electrophysiol, 2019, 30（11）: 2209-2216., articleTitle=Association between epicardial adipose tissue and embolic stroke after catheter ablation of atrial fibrillation, refAbstract=null)], funds=[Fund(id=1203008553230495928, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, awardId=2016J01523, language=EN, fundingSource=Natural Science Foundation of Fujian Province(2016J01523), fundOrder=null, country=null), Fund(id=1203008553322770623, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, awardId=2016J01523, language=CN, fundingSource=福建省自然科学基金(2016J01523), fundOrder=null, country=null), Fund(id=1203008553423433922, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, awardId=JS06070, language=EN, fundingSource=Professor Academic Development Foundation of Fujian Medical University(JS06070), fundOrder=null, country=null), Fund(id=1203008553503125701, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, awardId=JS06070, language=CN, fundingSource=福建医科大学教授学术发展基金(JS06070), fundOrder=null, country=null), Fund(id=1203008553566040264, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, awardId=2020QH1113, language=EN, fundingSource=Foundation Project of Fujian Medical University(2020QH1113), fundOrder=null, country=null), Fund(id=1203008553637343436, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, awardId=2020QH1113, language=CN, fundingSource=福建医科大学启航基金(2020QH1113), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1203008548109251476, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, xref=null, ext=[AuthorCompanyExt(id=1203008548113445781, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, companyId=1203008548109251476, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Cardiology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China), AuthorCompanyExt(id=1203008548121834390, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, companyId=1203008548109251476, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=福建医科大学附属第二医院心内一区，福建泉州 362000)])], figs=[ArticleFig(id=1203008551535997033, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Fig.1, caption=

Risk of recurrence after ablation in patients with NVAF in training set（Kaplan-Meier curve）

, figureFileSmall=JP2Tr6uo72o2ESa8f9jeVA==, figureFileBig=FIhN/IK90HfBHBiqf11P1Q==, tableContent=null), ArticleFig(id=1203008551619883117, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=图1, caption=训练集NVAF患者消融术后复发风险（Kaplan-Meier曲线）, figureFileSmall=JP2Tr6uo72o2ESa8f9jeVA==, figureFileBig=FIhN/IK90HfBHBiqf11P1Q==, tableContent=null), ArticleFig(id=1203008551707963507, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Fig.2, caption=

Recurrence prediction nomogram of NVAF patients in training set after ablation

, figureFileSmall=lN7ijU1ARQ7cSB6eUwryJA==, figureFileBig=V4/ZGqSfzhUF6FPs+JAlmQ==, tableContent=null), ArticleFig(id=1203008551808626807, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=图2, caption=训练集NVAF患者消融术后复发风险的列线图模型, figureFileSmall=lN7ijU1ARQ7cSB6eUwryJA==, figureFileBig=V4/ZGqSfzhUF6FPs+JAlmQ==, tableContent=null), ArticleFig(id=1203008551900901499, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Fig.3, caption=

Correction curve of the recurrence prediction nomogram for NVAF patients in training set after ablation

, figureFileSmall=XPhVJHeHcfvmh0RkHrpKxQ==, figureFileBig=chIPx/TmhGPCelsSZ6ysVw==, tableContent=null), ArticleFig(id=1203008551972204674, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=图3, caption=训练集NVAF患者消融术后复发预测列线图校正曲线, figureFileSmall=XPhVJHeHcfvmh0RkHrpKxQ==, figureFileBig=chIPx/TmhGPCelsSZ6ysVw==, tableContent=null), ArticleFig(id=1203008552051896455, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Fig.4, caption=

ROC curve of the recurrence prediction model for NVAF patients in validation set after ablation

, figureFileSmall=8n4y3+SiafqRXn8v787vaw==, figureFileBig=qePI6luf+sjTgI7vNakY9w==, tableContent=null), ArticleFig(id=1203008552127393930, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=图4, caption=验证集NVAF患者消融术后复发预测模型ROC曲线, figureFileSmall=8n4y3+SiafqRXn8v787vaw==, figureFileBig=qePI6luf+sjTgI7vNakY9w==, tableContent=null), ArticleFig(id=1203008552219668623, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Tab.1, caption=

Comparison of the clinical data of NVAF patients between training set and validation set

, figureFileSmall=null, figureFileBig=null, tableContent=
项目训练集（n=272）验证集（n=39）χ2/tP
性别[例（%）]
 男136（50.0）20（51.3）0.0220.881
 女136（50.0）19（48.7）
年龄（岁，$\bar{x}±s$）63.2±11.362.9±11.10.1570.876
体重指数（kg/m2，$\bar{x}±s$）22.72±1.6722.51±1.730.7120.480
心功能[例（%）]
 Ⅰ－Ⅱ级144（52.9）19（48.7）0.2440.621
 Ⅲ－Ⅳ级128（47.1）20（51.3）
病程（年，$\bar{x}±s$）6.61±1.326.62±1.350.0430.996
卒中史[例（%）]20（7.4）4（10.3）0.4040.525
吸烟史[例（%）]172（63.3）26（66.7）0.1740.677
饮酒史[例（%）]195（71.7）27（69.2）0.1010.751
合并疾病[例（%）]
 冠心病95（34.9）15（38.5）0.1870.666
 糖尿病82（30.2）13（33.3）0.1630.686
 高血压78（28.7）12（30.8）0.0730.788
服用他汀类药物[例（%）]106（39.1）13（33.3）0.4590.498
服用ACEI/ARB[例（%）]103（37.9）14（35.9）0.0560.812
房颤类型[例（%）]  1.4820.224
 阵发性房颤245（96.5）36（92.3）
 持续性房颤9（3.5）3（7.7）  
), ArticleFig(id=1203008552307749011, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=表1, caption=

训练集与验证集NVAF患者临床资料比较

, figureFileSmall=null, figureFileBig=null, tableContent=
项目训练集（n=272）验证集（n=39）χ2/tP
性别[例（%）]
 男136（50.0）20（51.3）0.0220.881
 女136（50.0）19（48.7）
年龄（岁，$\bar{x}±s$）63.2±11.362.9±11.10.1570.876
体重指数（kg/m2，$\bar{x}±s$）22.72±1.6722.51±1.730.7120.480
心功能[例（%）]
 Ⅰ－Ⅱ级144（52.9）19（48.7）0.2440.621
 Ⅲ－Ⅳ级128（47.1）20（51.3）
病程（年，$\bar{x}±s$）6.61±1.326.62±1.350.0430.996
卒中史[例（%）]20（7.4）4（10.3）0.4040.525
吸烟史[例（%）]172（63.3）26（66.7）0.1740.677
饮酒史[例（%）]195（71.7）27（69.2）0.1010.751
合并疾病[例（%）]
 冠心病95（34.9）15（38.5）0.1870.666
 糖尿病82（30.2）13（33.3）0.1630.686
 高血压78（28.7）12（30.8）0.0730.788
服用他汀类药物[例（%）]106（39.1）13（33.3）0.4590.498
服用ACEI/ARB[例（%）]103（37.9）14（35.9）0.0560.812
房颤类型[例（%）]  1.4820.224
 阵发性房颤245（96.5）36（92.3）
 持续性房颤9（3.5）3（7.7）  
), ArticleFig(id=1203008552379052183, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Tab.2, caption=

Comparison of the clinical data of NVAF patients with and without relapse in training set

, figureFileSmall=null, figureFileBig=null, tableContent=
项目复发组（n=58）未复发组（n=196）χ2/tP
性别[例（%）]
 男35（60.3）101（51.5）1.3980.237
 女23（39.7）95（48.8）
年龄（岁，$\bar{x}±s$）63.3±11.262.4±10.70.5430.588
体重指数（kg/m2，$\bar{x}±s$）22.63±1.6522.37±1.711.0450.298
心功能[例（%）]
 Ⅰ—Ⅱ级34（58.6）110（56.1）0.1140.736
 Ⅲ—Ⅳ级24（41.4）86（43.9）
病程（年，$\bar{x}±s$）6.52±1.296.20±1.381.6330.106
卒中史[例（%）]10（17.2）10（20.4）0.2840.594
吸烟史[例（%）]42（72.4）130（66.3）0.7580.384
饮酒史[例（%）]46（79.3）149（76.0）0.2720.602
合并疾病[例（%）]
 冠心病20（34.5）75（38.3）0.2740.601
 糖尿病15（25.9）67（34.2）1.4180.234
 高血压22（37.9）56（28.6）1.8430.175
服用他汀类药物[例（%）]20（34.5）86（43.9）1.6250.202
服用ACEI/ARB[例（%）]21（36.2）82（41.8）0.5880.443
房颤类型[例（%）]  0.5840.445
 阵发性房颤55（94.8）190（96.9）
 持续性房颤3（5.2）6（3.1）  
), ArticleFig(id=1203008552467132572, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=表2, caption=

训练集复发与未复发NVAF患者的临床资料比较

, figureFileSmall=null, figureFileBig=null, tableContent=
项目复发组（n=58）未复发组（n=196）χ2/tP
性别[例（%）]
 男35（60.3）101（51.5）1.3980.237
 女23（39.7）95（48.8）
年龄（岁，$\bar{x}±s$）63.3±11.262.4±10.70.5430.588
体重指数（kg/m2，$\bar{x}±s$）22.63±1.6522.37±1.711.0450.298
心功能[例（%）]
 Ⅰ—Ⅱ级34（58.6）110（56.1）0.1140.736
 Ⅲ—Ⅳ级24（41.4）86（43.9）
病程（年，$\bar{x}±s$）6.52±1.296.20±1.381.6330.106
卒中史[例（%）]10（17.2）10（20.4）0.2840.594
吸烟史[例（%）]42（72.4）130（66.3）0.7580.384
饮酒史[例（%）]46（79.3）149（76.0）0.2720.602
合并疾病[例（%）]
 冠心病20（34.5）75（38.3）0.2740.601
 糖尿病15（25.9）67（34.2）1.4180.234
 高血压22（37.9）56（28.6）1.8430.175
服用他汀类药物[例（%）]20（34.5）86（43.9）1.6250.202
服用ACEI/ARB[例（%）]21（36.2）82（41.8）0.5880.443
房颤类型[例（%）]  0.5840.445
 阵发性房颤55（94.8）190（96.9）
 持续性房颤3（5.2）6（3.1）  
), ArticleFig(id=1203008552571990178, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Tab.3, caption=

Comparison of laboratory and imaging indexes between the two groups of NVAF patients in training set（$\bar{x}±s$）

, figureFileSmall=null, figureFileBig=null, tableContent=
项目复发组（n=58）未复发组（n=196）tP
实验室指标
 PLT（×109/L）205.11±30.26212.01±32.981.4940.138
 PDW（%）13.03±2.1512.72±2.090.9710.334
 MPV（fl）10.11±1.6610.34±1.250.9760.332
 LDL-C（mmol/L）3.33±0.823.12±0.711.7640.081
 TC（mmol/L）4.29±1.214.18±1.300.5980.551
 TG（mmol/L）2.56±0.782.61±0.810.4250.672
 hs-CRP（mg/L）14.63±2.6914.21±3.850.9380.350
 CK-MB（U/L）30.26±3.2129.68±3.581.1760.242
 cTnI（ng/ml）3.25±0.713.14±0.801.0060.317
影像学指标
 LAD（mm）33.65±3.2532.97±3.081.4160.160
 LVEF（%）58.26±8.9660.25±9.361.4710.145
 EAT体积（cm3）100.43±12.6094.70±9.663.1970.002
 LAVI（ml）152.32±30.26153.98±32.870.3600.720
 LVEDd（mm）48.26±3.9649.23±4.011.6340.106
), ArticleFig(id=1203008552685236390, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=表3, caption=

训练集两组NVAF患者实验室及影像学指标比较（$\bar{x}±s$）

, figureFileSmall=null, figureFileBig=null, tableContent=
项目复发组（n=58）未复发组（n=196）tP
实验室指标
 PLT（×109/L）205.11±30.26212.01±32.981.4940.138
 PDW（%）13.03±2.1512.72±2.090.9710.334
 MPV（fl）10.11±1.6610.34±1.250.9760.332
 LDL-C（mmol/L）3.33±0.823.12±0.711.7640.081
 TC（mmol/L）4.29±1.214.18±1.300.5980.551
 TG（mmol/L）2.56±0.782.61±0.810.4250.672
 hs-CRP（mg/L）14.63±2.6914.21±3.850.9380.350
 CK-MB（U/L）30.26±3.2129.68±3.581.1760.242
 cTnI（ng/ml）3.25±0.713.14±0.801.0060.317
影像学指标
 LAD（mm）33.65±3.2532.97±3.081.4160.160
 LVEF（%）58.26±8.9660.25±9.361.4710.145
 EAT体积（cm3）100.43±12.6094.70±9.663.1970.002
 LAVI（ml）152.32±30.26153.98±32.870.3600.720
 LVEDd（mm）48.26±3.9649.23±4.011.6340.106
), ArticleFig(id=1203008552777511080, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Tab.4, caption=

Comparison of serum miRNA levels of NVAF patients in training sets（$\bar{x}±s$）

, figureFileSmall=null, figureFileBig=null, tableContent=
血清miRNA水平复发组（n=58）未复发组（n=196）tP
消融治疗前
 miRNA-291.39±0.461.62±0.343.5330.001
 miRNA-212.88±0.372.34±0.429.457<0.001
 miRNA-1502.61±0.442.16±0.347.180<0.001
 miRNA-192-5p3.22±1.062.61±0.844.025<0.001
随访结束时
 miRNA-291.38±0.451.62±0.323.788<0.001
 miRNA-212.89±0.362.31±0.4110.430<0.001
 miRNA-1502.62±0.432.17±0.327.388<0.001
 miRNA-192-5p3.23±1.052.62±0.824.072<0.001
), ArticleFig(id=1203008552882368683, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=表4, caption=

训练集NVAF患者血清miRNA水平比较（$\bar{x}±s$）

, figureFileSmall=null, figureFileBig=null, tableContent=
血清miRNA水平复发组（n=58）未复发组（n=196）tP
消融治疗前
 miRNA-291.39±0.461.62±0.343.5330.001
 miRNA-212.88±0.372.34±0.429.457<0.001
 miRNA-1502.61±0.442.16±0.347.180<0.001
 miRNA-192-5p3.22±1.062.61±0.844.025<0.001
随访结束时
 miRNA-291.38±0.451.62±0.323.788<0.001
 miRNA-212.89±0.362.31±0.4110.430<0.001
 miRNA-1502.62±0.432.17±0.327.388<0.001
 miRNA-192-5p3.23±1.052.62±0.824.072<0.001
), ArticleFig(id=1203008552974643373, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=EN, label=Tab.5, caption=

Multivariate logistic regression analysis of recurrence risk in NVAF patients in training set after ablation

, figureFileSmall=null, figureFileBig=null, tableContent=
变量βSEWaldχ2POR（95%CI）
EAT体积0.0580.0236.1990.0131.060（1.012～1.109）
miRNA-192-5p0.5650.2246.3820.0121.759（1.135～2.726）
miRNA-29b–1.7930.6208.3780.0040.166（0.049～0.560）
miRNA-213.4820.64329.34<0.00132.508（9.224～114.577）
miRNA-1502.9290.62322.079<0.00118.704（5.513～63.456）
), ArticleFig(id=1203008553066918066, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002061051883692, language=CN, label=表5, caption=

训练集NVAF患者消融术后复发风险的多因素logistic回归分析

, figureFileSmall=null, figureFileBig=null, tableContent=
变量βSEWaldχ2POR（95%CI）
EAT体积0.0580.0236.1990.0131.060（1.012～1.109）
miRNA-192-5p0.5650.2246.3820.0121.759（1.135～2.726）
miRNA-29b–1.7930.6208.3780.0040.166（0.049～0.560）
miRNA-213.4820.64329.34<0.00132.508（9.224～114.577）
miRNA-1502.9290.62322.079<0.00118.704（5.513～63.456）
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基于血清miRNA水平的非瓣膜性房颤患者消融术后复发风险预测列线图模型的构建与评价
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赖文文 , 赵文安 , 张志龙 , 卢辉耀 , 蔡克锋 , 许朝祥 , 黄明伟 *
解放军医学杂志 | 临床研究 2023,48(6): 715-722
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解放军医学杂志 | 临床研究 2023, 48(6): 715-722
基于血清miRNA水平的非瓣膜性房颤患者消融术后复发风险预测列线图模型的构建与评价
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赖文文, 赵文安, 张志龙, 卢辉耀, 蔡克锋, 许朝祥, 黄明伟*
作者信息
  • 福建医科大学附属第二医院心内一区，福建泉州 362000

    • 赖文文，医学博士，主治医师，主要从事起搏与电生理等心血管疾病方面的研究

通讯作者:

黄明伟，E-mail：
Establishment of a recurrence risk prediction model for patients with nonvalvular atrial fibrillation after ablation based on serum miRNA levels
Wen-Wen Lai, Wen-An Zhao, Zhi-Long Zhang, Hui-Yao Lu, Ke-Feng Cai, Chao-Xiang Xu, Ming-Wei Huang*
Affiliations
  • Department of Cardiology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China
出版时间: 2023-06-28 doi: 10.11855/j.issn.0577-7402.2023.06.0715
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摘要
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目的 构建基于血清miRNA水平的非瓣膜性房颤（NVAF）患者消融术后复发风险预测列线图模型并对其效能进行评价。方法 选择2018年8月－2020年12月在福建医科大学附属第二医院接受消融治疗的389例NVAF患者作为研究对象，随机选取272例（70.0%）作为训练集，78例（20.0%）作为测试集，39例（10.0%）作为验证集。随访观察1年，绘制Kaplan-Meier累积复发风险曲线，根据随访期间患者复发情况分为复发组与未复发组。通过单因素及多因素分析探求训练集NVAF患者消融术后复发风险的影响因素；构建NVAF消融术后复发风险列线图预测模型，通过一致性指数（C-index）和受试者工作特征（ROC）曲线检验该模型的预测效能，再进一步对测试集的模型效能进行验证。结果 截至2021年12月21日，共30例失访（训练集18例，测试集10例，验证集2例），最终纳入359例（训练集254例，测试集68例、验证集37例）NVAF患者。其中训练集中58例出现复发，复发率为22.8%。复发组基线心外膜脂肪组织（EAT）体积大于与未复发组（P<0.05）；与未复发组比较，复发组消融治疗前、随访结束时miRNA-21、miRNA-150、miRNA-192-5p水平明显升高，miRNA-29水平明显降低，差异有统计学意义（P<0.05）。多因素logistic回归分析显示，EAT体积（OR=1.060，95%CI 1.012～1.109）、miRNA-192-5p（OR=1.759，95%CI 1.135～2.726）、miRNA-21（OR=32.508，95%CI 9.224～114.577）、miRNA-150（OR=18.704，95%CI 5.513～63.456）为消融术后复发的独立危险因素，miRNA-29b（OR=0.166，95%CI 0.049～0.560）为消融术后复发的保护因素（P<0.05）。基于上述因素构建的复发风险预测模型预测NVAF患者消融术后复发的C-index为0.929（95%CI 0.890～0.958）；验证集ROC曲线分析结果显示，该预测模型特异度为83.2%，敏感度为88.0%，ROC曲线下面积（AUC）最佳临界值为0.711；测试集数据显示，该模型敏感度为86.7%，特异度为88.7%，准确率为88.3%。结论 EAT体积及miRNA-192-5p、miRNA-29b、miRNA-21、miRNA-150等为NVAF消融术后复发的独立危险因素，据此建立的列线图模型具有较高的预测价值。

预测模型  /  非瓣膜性房颤  /  消融术  /  microRNA  /  复发

Objective To explore establish a risk prediction model for patients with nonvalvular atrial fibrillation (NVAF) after ablation based on serum miRNA levels. Methods A total of 389 NVAF patients who received ablative therapy in the Second Affiliated Hospital of Fujian Medical University from August 2018 to December 2020 were selected as the study objects. 70.0% (272 cases) were randomly selected as the training set, 20.0% (78 cases) as the test set, and 10.0% (39 cases) as the verification set. The patients were followed up for 1 year, and the Kaplan-Meier cumulative recurrence risk curve was drawn. According to the recurrence of patients during the follow-up period, the patients were divided into recurrence group and non-recurrence group. The factors influencing the risk of recurrence after ablation in the training set of NVAF patients were explored through univariate and multivariate analysis, and the prediction model of recurrence risk after ablation was constructed. The prediction efficiency of this model was further tested by the consistency index (C-index) and receiver operating characteristic (ROC) curve. Then the model effectiveness of the test set is verified. Results As of December 21, 2021, a total of 30 cases were lost to follow-up (18 cases in the training set, 10 cases in the test set, and 2 cases in the validation set), and 359 actual cases were finally included (254 cases in training set, 68 in test set, and 37 in validation set). Of which 58 cases recurred in training set, and the recurrence rate was 22.8%. The baseline epicardial adipose tissue (EAT) volume was higher in recurrent group than that in non-recurrent group (P<0.05). The levels of miRNA-21, miRNA-150 and miRNA-192-5p in relapse group before and at the end of follow-up were higher than those in non-recurrence group, while the levels of miRNA-29 were lower than those in non-recurrence group with statistical significance (P<0.05). Multivariate logistic analysis showed that EAT volume (OR=1.060, 95%CI 1.012-1.109), miRNA-192-5p (OR=1.759, 95%CI 1.135-2.726), miRNA-21 (OR=32.508, 95%CI 9.224-114.577), miRNA-150 (OR=18.704, 95%CI 5.513-63.456) are independent risk factors for recurrence after ablation, miRNA-29b (OR=0.166, 95%CI 0.049-0.560) are protective factors for recurrence after ablation (P<0.05). Based on the above factors, the recurrence risk prediction model predicted that the C-index of NVAF patients after ablation was 0.929 (95%CI 0.890-0.958). ROC curve results of verification set showed that the specificity and sensitivity of this model were 83.2% and 88.0%, and the optimal critical value of area under ROC curve (AUC) was 0.711. The test data showed that the sensitivity, specificity and accuracy of the model were 86.7%, 88.7% and 88.3%. Conclusion The post-NVAF ablation recurrence risk model constructed by EAT volume, miRNA-192-5p, miRNA-29b, miRNA-21, miRNA-150 and other factors has a high predictive value for the recurrence risk after NVAF ablation.

prediction model  /  non-valvular atrial fibrillation  /  ablation  /  microRNA  /  relapse
赖文文, 赵文安, 张志龙, 卢辉耀, 蔡克锋, 许朝祥, 黄明伟. 基于血清miRNA水平的非瓣膜性房颤患者消融术后复发风险预测列线图模型的构建与评价. 解放军医学杂志, 2023 , 48 (6) : 715 -722 . DOI: 10.11855/j.issn.0577-7402.2023.06.0715
Wen-Wen Lai, Wen-An Zhao, Zhi-Long Zhang, Hui-Yao Lu, Ke-Feng Cai, Chao-Xiang Xu, Ming-Wei Huang. Establishment of a recurrence risk prediction model for patients with nonvalvular atrial fibrillation after ablation based on serum miRNA levels[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (6) : 715 -722 . DOI: 10.11855/j.issn.0577-7402.2023.06.0715
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非瓣膜性房颤（nonvalvular atrial fibrillation，NVAF）作为心房颤动（简称房颤）的常见类型，具有较高的住院率、致残率及病死率[1]，而消融术为房颤维持窦性心律的治疗方法[2]。但消融术后复发率仍较高，为20%～61%[3]。心房结构和电重构是NVAF发生发展的基础，但驱动这种重构的机制尚未完全明确，近年来，NVAF复发在分子水平上的基因调控引起了研究者的极大关注。微小RNA（microRNA，miRNA）是由约22个核糖核苷酸组成的小型非编码RNA[4]，大多数miRNA通过信使RNA的裂解或翻译抑制作为靶基因产物的负调节因子，也可在转录后调节基因表达；多种miRNA被证实与心脏肥大、高血压、心律失常等心血管疾病有关[5-6]；另有研究证实，miRNA与NVAF诱导的离子通道重塑及纤维化有关[7]。miRNA-192、miRNA-150、miRNA-21、miRNA-29等为目前研究较多的与房颤相关的miRNA，其中miRNA-192可使参与组织器官纤维化的小窝蛋白1表达降低[8]，高表达miRNA-150可抑制平滑肌α肌动蛋白、胶原蛋白Ⅰ的表达[9]，miRNA-21、miRNA-29则广泛参与心肌细胞肥大，凋亡坏死、成纤维细胞增殖及内皮细胞转化[10]。了解上述血清miRNA在NVAF患者中的表达水平，或可从miRNA水平上为NVAF的治疗提供病理生理学依据。本研究构建基于血清miRNA水平的NVAF消融术后复发风险预测模型，旨在为预防NVAF消融术后复发提供理论依据。
1 资料与方法
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1.1 研究对象
纳入2018年8月－2020年12月在福建医科大学附属第二医院接受消融治疗的389例NVAF患者进行前瞻性研究。诊断标准：参照美国心脏病协会2012年发布的房颤管理指南中NVAF的诊断标准[11]，经超声心动图或24 h动态心电图检查确诊。纳入标准：（1）符合手术指征且首次接受射频消融治疗；（2）年龄>18岁。排除标准：（1）合并严重的缓慢型心律失常；（2）合并肥厚型心肌病等其他心脏疾病、心源性休克；（3）左心房或左心耳血栓形成；（4）既往行冠脉介入术或搭桥术者。剔除随访丢失者、精神障碍、运动障碍者。本研究经福建医科大学附属第二医院伦理委员会批准（2021-109），且所有患者或家属签订知情同意书。随机选取272例（70.0%）作为训练集，78例（20.0%）作为测试集，39例（10.0%）作为验证集。根据随访复发情况分为复发组与未复发组。
1.2 预测模型的建立及验证
（1）建模：收集训练集患者临床资料，对消融术后复发风险行单因素和多因素logistic回归分析，筛选与复发相关的因素，将筛选后各独立因素绘制风险预测模型的列线图；（2）内部验证：采用Bootstrap抽样法重复抽样1000次，绘制校准曲线并计算C-index及95%CI，进一步采用受试者工作特征（ROC）曲线对模型进行内部验证；（3）外部验证：在测试集对建立的模型进行外部验证。
1.3 治疗方案
所有患者均行正规抗凝治疗至少3周，术前行经食管超声心动图排除左心房及左心耳血栓。术前停用抗心律失常药物至少5个半衰期。所有患者均行全身或局部麻醉，在心脏三维标测系统（CARTO）指引下完成射频消融术。穿刺两侧股静脉，置入冠状窦电极；左心房行肺静脉造影，右股静脉置入Swartz鞘，将鞘管送入磁导航大头消融导管并固定于推送器，进行左心房建模；行双侧肺静脉隔离，设置前、后壁功率分别为40～45 W、35～40 W，每次消融20～30 s或A波振幅下降80%后酌情停止。持续性房颤者加行左心房顶部线性消融，合并房扑者加行三尖瓣峡部线性消融。若患者术后房颤持续发作，可行体外电复律以恢复窦性心律，术后若无大出血、心包填塞等表现，则恢复抗凝治疗并维持3个月，后期根据CHA2DS2-VASc[C：心力衰竭；H：高血压；A：年龄≥75岁；D：糖尿病；S：血栓栓塞、卒中或短暂性脑缺血发作；V：血管性疾病（心肌梗死、外周动脉血管病或主动脉瓣疾病）；A：年龄65～74岁；Sc：性别]积分情况决定是否继续抗凝治疗；术后3个月内，阵发性房颤暂停抗心律失常药物，持续性房颤服用胺碘酮或普罗帕酮，3个月后根据房颤是否复发及现状决定是否使用抗心律失常药物。
1.4 检测指标
1.4.1 一般资料
消融治疗前收集所有患者的临床资料[年龄、性别、病程、体重指数、心功能、高血压、糖尿病、冠心病、卒中史及术前他汀类、血管紧张素转化酶抑制剂（ACEI）和血管紧张素Ⅱ受体阻滞剂（ARB）服用情况]。
1.4.2 实验室检测指标
消融治疗前抽取空腹肘静脉血5 ml，采用DxH 600型全自动血细胞分析仪检测平均血小板体积（MPV）、血小板计数（PLT）、血小板分布宽度（PDW）；采用迈瑞BS-280型生化分析仪检测高敏C反应蛋白（hs-CRP）、低密度脂蛋白胆固醇（LDL-C）、胆固醇（TC）、三酰甘油（TG）水平，采用荧光免疫分析仪（FIA-102）检测心肌肌钙蛋白I（cTnI）和肌酸激酶同工酶（CK-MB）水平。
1.4.3 影像学指标
消融治疗前采用iE Elite型心脏超声诊断仪及配套探头测量左房前后径（LAD）、左心房容积（LAVI）、左室射血分数（LVEF）、左心室舒张末期直径（LVEDd）等心脏超声参数。采用64层螺旋CT测量心外膜脂肪组织（EAT）体积：设置扫描参数，经肘静脉以4.0～5.0 ml/s速率注入造影剂，造影剂示踪，于主动脉根部选一感兴趣区监测CT值，当CT值增幅>100 HU时，延迟6 s扫描，在患者屏气时进行扫描，范围从气管隆突至心尖部。工作站重建EAT图像，层厚0.75 mm。安排经验丰富的放射科医师应用Volumer软件逐层勾勒心外膜边界，设定–50～–200 HU的CT值为脂肪组织，自动计算EAT体积。
1.4.4 血清miRNA水平测定
消融治疗前、随访结束时取5 ml空腹静脉血，4 ℃下1500 r/min（离心半径6 cm）离心8 min后取上层血清继续16 000 r/min（离心半径6 cm）离心10 min，将上层液体分装在EP管中–80 ℃保存备用。采用德国QIAGEN公司提供的QIAGEN miRNeasy Serum/Plasma Kit试剂盒提取miRNA，并将miRNA反转录成cDNA。引物序列：miR NA-29b，5'-GCTAGCTTATCAGACTGATGTTGA-3'；miRNA-21，5'-UAGCUUAUCAGACUGAUGUUG A-3'；miRNA-150，5'-GUCCAGUUUUCCCAGG AAUCCCU-3'；miRNA-192-5p，5'-GATCCTTCA AGAGATTTTTTG-3'。扩增引物购自上海生工生物工程股份有限公司。采用ABI Vii7型实时荧光定量PCR仪（美国Applied Biosystems公司）进行检测。反应条件：95 ℃预变性10 min；95 ℃变性10 s、60 ℃退火30 s、72 ℃延伸30 s，45个循环。实验重复3次。结果以2–ΔΔCt表示。
1.5 随访及复发标准
随访观察1年，于门诊定期复查，必要时通过微信或电话方式随访。随访截止时间为2021年12月21日。记录患者术后的症状变化并进行心电图及24 h动态心电图检查，若术后3个月空白期之后出现房性心动过速、房扑、房颤持续时间>30 s则判断为复发[12]。
1.6 质量控制
在确保患者资料真实可信的基础上，严格执行纳入、排除标准，经专门人员收集患者临床资料并核对是否与患者身份信息匹配，对数据进行平行双录入及统计分析（基于Epidate软件），以确保数据导入的准确性。
1.7 统计学处理
采用SPSS 22.0软件进行统计分析。计量资料先行正态性检验，呈正态分布者以$\bar{x}±s$表示，组间比较采用两独立样本t检验；计数资料以例（%）或构成比表示，采用χ2检验比较组间差异；绘制Kaplan-Meier累积复发风险曲线，对所有变量进行共线性诊断且对不存在共线性的变量行多因素logistic回归分析，P<0.05为差异有统计学意义。使用R语言建立复发风险列线图预测模型，用一致性指数（C-index）量化模型的预测性能，并进行Bootstrap内部验证，绘制校正曲线，评价模型的预测校准度和鉴别效度，采用Medcalc绘制ROC曲线验证预测模型的内部效能，使用构建的模型对测试集患者进行外部验证。
2 结果
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2.1 训练集和验证集NVAF患者基线资料比较
训练集与验证集患者的性别、年龄、体重指数、心功能分级、病程、吸烟史、卒中史、饮酒史、合并疾病、服用药物类型、房颤类型差异均无统计学意义（P>0.05，表1）。
2.2 训练集NVAF患者消融术后复发风险
截至末次随访时间2021年12月21日，训练集中18例失访，最终纳入254例，其中58例（22.4%）复发，归为复发组，196例（77.7%）未复发归为未复发组。Kaplan-Meier累积复发风险曲线显示，伴随着时间的推移，累积复发风险逐渐增加（图1）。
2.3 训练集NVAF患者临床资料比较
训练集中复发组与未复发组患者在年龄、性别、体重指数、病程、心功能、合并疾病、卒中史、饮酒、吸烟，服用他汀类药物、服用ACEI/ARB及房颤类型方面差异均无统计学意义（P>0.05，表2）。
2.4 训练集NVAF患者实验室及影像学指标比较
复发组EAT体积明显大于未复发组，差异有统计学意义（P<0.05），两组其他指标PLT、MPV、PDW、LDL-C、TC、TG、hs-CRP、cTnI、CK-MB、LAD、LVEF、LAVI、LVEDd差异均无统计学意义（P>0.05）（表3）。
2.5 训练集NVAF患者血清miRNA水平比较
组内消融治疗前、随访结束时miRNA-29、miRNA-21、miRNA-150、miRNA-192-5p水平比较差异均无统计学意义（P>0.05），复发组消融治疗前、随访结束时miRNA-21、miRNA-150、miRNA-192-5p水平较未复发组高，miRNA-29水平较未复发组低（P<0.05）（表4）。
2.6 消融术后复发风险的多因素logistic回归分析
以是否复发作为因变量（复发=1，未复发=0），将上述差异有统计学意义的变量作为自变量进行logistic回归分析，EAT体积及miRNA-192-5p、miRNA-29b、miRNA-21、miRNA-150水平为连续变量，以实测值纳入回归分析中，变量筛选采用逐步法（α入=0.05，α出=0.1）。多因素logistic回归分析显示，EAT体积（OR=1.060，95%CI 1.012～1.109）、miRNA-192-5p（OR=1.759，95%CI 1.135～2.726）、miRNA-21（OR=32.508，95%CI 9.224～114.577）、miRNA-150（OR=18.704，95%CI 5.513～63.456）为消融术后复发的独立危险因素，miRNA-29b（OR=0.166，95%CI 0.049～0.560）为消融术后复发的保护因素（P<0.05）（表5）。
2.7 NVAF患者消融术后复发风险列线图模型的构建与评估
将影响NVAF患者消融术后复发风险的独立相关因素纳入列线图模型，各指标分值之和对应的概率即为NVAF患者消融术后复发风险的预测值（图2）。预测复发相关因素的C-index为0.929（95%CI 0.890～0.958），提示列线图具有良好的区分度，且校准曲线斜率接近1，该列线图预测NVAF患者消融术后风险的一致性良好（图3）。验证集ROC曲线结果显示，该预测模型特异度为83.2%，敏感度为88.0%，AUC最佳临界点值为0.711（图4）。
2.8 基于测试集对预测模型效果的验证
最终测试集纳入68例，15例复发，53例未复发，验证结果显示，该模型的敏感度为86.7%，特异度为88.7%，准确率为88.3%。
3 讨论
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NVAF及其症状的有效治疗可通过房颤消融实现，但这种侵入性治疗常伴有相对较高的房颤复发率[13]。Stabile等[14]对冷冻球囊消融术后心房颤动复发情况的观察显示，25%（923/3681）的患者在术后12个月内至少发生一次房颤复发，Chew等[15]发现，导管消融1年以内的房颤患者中有36%出现复发，而本研究训练集患者中22.4%出现复发。目前认为，房颤的进展机制较为复杂，NVAF的发生及维持是因心房结构重构所致，此种重构主要以心房肌细胞凋亡、肌原纤维溶解、心房肌纤维化等为表现[16]。最近的研究发现，心房组织中表达的几种miRNA与心房电生理特性有关，从而使血清miRNA水平预测NVAF患者消融术后复发风险的潜在价值受到了临床的关注[17]。
虽然房颤与传统心血管风险因素的暴露时间、暴露强度密切相关，但房颤复发风险很大程度上是已知风险因素无法解释的，最近的研究显示，遗传或表观遗传因素可能有助于易患此种心律失常的基质发育。miRNA是一种短的内源性非编码RNA，可通过与mRNA的3'非翻译区的互补序列结合，导致miRNA的翻译抑制，从而发挥调控基因表达的作用[18]。此外，miRNA在循环中很容易被检测到，并可能为急性心肌梗死、心力衰竭和房颤等急慢性心血管疾病的治疗提供靶点[19-20]。miRNA-29家族因为其抑制细胞外基质的合成，以及展现出的抗纤维化作用而备受关注。Li等[21]分析miRNA-29的目标基因发现，该基因具有多种胶原合成潜力，可通过抑制COL1A1、COL1A2等胶原合成，参与抗纤维化过程，而心肌纤维化是心肌重构的重要特征，可导致心肌舒张和收缩力下降，也可对心脏传导功能造成影响，Quah等[22]的一项研究发现，在复发NVAF患者血浆及心房肌组织中miRNA-29b的表达明显低于非复发者，与本研究结果一致。因此，笔者认为与miRNA-29b可能与心肌细胞外基质胶原成分的变化有关。
miRNA-192为进化高度保守的miRNA，其基因位于人类染色体11q13，产生miR-192-5p、miR-192-3p两条成熟链，其中miR-192-5p是p53的直接作用靶基因，也是p53信号通路的调控基因，在多种疾病的病理生理中发挥作用[23]。Kiyosawa等[24]发现，miR-192-5p在房颤患者的心房组织中表达上调，并可调节心脏钠通道基因SCN5A的表达。此外，已知miR-192可降低小窝蛋白1的表达水平，而一项全基因组关联研究发现小窝蛋白1与房颤相关[25]。本研究结果显示，miRNA-192为NVAF消融术后复发的危险因素，可能与miRNA-192-5p可下调SCN5A基因表达而促进心律失常有关。
miRNA-21可参与房颤的心房重构，是房颤治疗的潜在靶点。有研究发现，miRNA-21水平下降可降低房颤风险[26]。与miRNA-21类似，本研究中房颤复发者血清中的miRNA-150水平低于非复发者，且miRNA-150与1年内房颤复发明显相关，多因素logistic回归分析进一步发现miRNA-150、miRNA-21均为消融术后复发的独立危险因素。由于采用列线图可将复杂的回归方程转换为可视化图形，使预测模型更具可读性，因此，本研究采用miRNA-192、miRNA-150、miRNA-21等因素构建列线图模型，结果显示，该模型可预测NVAF患者消融术后复发风险，C-index为0.929（95%CI 0.890～0.958），ROC曲线分析显示该预测模型特异度为83.2%，敏感度为88.0%，提示本研究构建的预测模型具有较好的临床应用价值，可有效辅助临床医师高效识别高危人群。
EAT与房颤之间存在复杂的病理生理机制：EAT可产生多种细胞因子，其中炎性因子、基质金属蛋白酶等均为房颤发生机制中的危险因素[27]；房颤患者CRP、IL-6等炎性因子水平明显升高，且基质金属蛋白酶在心肌中表现活跃，EAT体积增大可促使胆碱能神经和外周肾上腺素能神经增加，而胆碱能神经激活可造成动作电位时限缩短，短时间内大量的Ca2+在动作电位时程3相晚期进入细胞内，导致3相晚期的早后除极，引起肺静脉及心肌的触发激动，进而导致房颤。Zhou等[28]发现，EAT体积对术后“空白期”复发有一定的预测价值，Ahn等[29]发现EAT体积可预测术后复发，且术后“空白期”复发与远期复发呈正相关，与本研究结果一致。笔者认为，EAT参与术后“空白期”复发的机制有两点：（1）心脏射频消融术中射频能量刺激EAT分泌各种炎性因子作用于心肌细胞，引发剧烈的局部炎性反应；（2）射频能量可对EAT中的自主神经节造成一定损伤，进而降低了心房肌的自律性。因此，心脏CT评估EAT体积可筛查消融术后易发生心律失常的人群，为术后早期干预提供了理论依据。
综上所述，EAT体积、miRNA-192-5p、miRNA-29b、miRNA-21、miRNA-150为NVAF消融术后复发的独立危险因素，据此构建的预测模型具有较高的应用价值。本研究也存在一定不足，不同类型的房颤具有不同的潜在机制，且术后复发存在差异性，不仅需探索更多的miRNA，还应区分房颤类型；其次消融术后也可能会出现无症状房颤发作，虽未能在本研究随访时捕捉到，但这可能会对研究结果造成一定影响，后期仍需更多研究来探讨。因此，对复发高危患者除予以常规治疗外，还应从房颤发生的上游进行干预，积极治疗导致心房重构的高血压、心肌病等原发疾病，并在术后采用更为积极的个性化措施来防止复发。
基金
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  • 福建省自然科学基金(2016J01523)
  • 福建医科大学教授学术发展基金(JS06070)
  • 福建医科大学启航基金(2020QH1113)
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2023年第48卷第6期
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doi: 10.11855/j.issn.0577-7402.2023.06.0715
  • 接收时间：2022-03-28
  • 首发时间：2025-12-03
  • 出版时间：2023-06-28
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  • 收稿日期：2022-03-28
  • 录用日期：2022-06-30
基金
Natural Science Foundation of Fujian Province(2016J01523)
福建省自然科学基金(2016J01523)
Professor Academic Development Foundation of Fujian Medical University(JS06070)
福建医科大学教授学术发展基金(JS06070)
Foundation Project of Fujian Medical University(2020QH1113)
福建医科大学启航基金(2020QH1113)
作者信息
    福建医科大学附属第二医院心内一区，福建泉州 362000

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黄明伟，E-mail：
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