Left atrial transcriptional changes associated with atrial fibrillation susceptibility and persistence.
Left atrial transcriptional changes associated with atrial fibrillation susceptibility and persistence.
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DOI：
10.1161/circep.114.001632
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发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Chung MK
中科院分区：
文献类型：
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作者：
Deshmukh A;Barnard J;Sun H;Newton D;Castel L;Pettersson G;Johnston D;Roselli E;Gillinov AM;McCurry K;Moravec C;Smith JD;Van Wagoner DR;Chung MK
先前的心房颤动（AF）转录研究仅限于特定的转录本、动物模型、慢性AF、右心房或小样本。我们试图描述人类房颤左心房转录组的特征，以区分与房颤易感性和持续性相关的变化。选择来自239名患者的左心耳，按冠状动脉疾病、瓣膜疾病和AF病史（无AF病史、手术时窦性心律的AF病史、手术时AF病史）分层，进行全基因组mRNA微阵列分析。检测转录本与AF表型组的差异表达。在3个基因集合中检测差异表达基因的富集：转录因子（TF）集合，由共享的保守顺式调控基序定义; miRNA集合，由共享的3′UTR基序定义;和分子功能集合，由共享的Gene-Ontology分子功能定义。房颤易感性与CREB/ATF家族、HSF 1、ATF 6、SRF和E2 F1 TF的靶点表达降低相关。持续性AF活动与离子通道功能相关基因和基因集表达降低相关，与报告的功能变化一致。房颤易感性与炎症、氧化和细胞应激反应相关的几种转录因子的靶点表达降低有关。相反，离子通道表达的变化与房颤活动相关，但在房颤易感性方面受到限制。我们的研究结果表明，显著的转录重塑标志着对AF的易感性，而离子通道表达的重塑发生在AF进展的后期或作为AF的结果。
Prior transcriptional studies of atrial fibrillation (AF) have been limited to specific transcripts, animal models, chronic AF, right atria, or small samples. We sought to characterize the left atrial transcriptome in human AF to distinguish changes related to AF susceptibility and persistence. Left atrial appendages from 239 patients stratified by coronary artery disease, valve disease and AF history (No AF history, AF history in sinus rhythm at surgery, AF history in AF at surgery) were selected for genome-wide mRNA microarray profiling. Transcripts were examined for differential expression with AF phenotype group. Enrichment in differentially expressed genes was examined in 3 gene set collections: A transcription factor (TF) collection, defined by shared conserved cis-regulatory motifs; a miRNA collection, defined by shared 3′UTR motifs; and a molecular function collection, defined by shared Gene-Ontology molecular function. AF susceptibility was associated with decreased expression of the targets of CREB/ATF family, HSF1, ATF6, SRF, and E2F1 TFs. Persistent AF activity was associated with decreased expression in genes and gene sets related to ion channel function consistent with reported functional changes. AF susceptibility was associated with decreased expression of targets of several transcription factors related to inflammation, oxidation, and cellular stress responses. In contrast, changes in ion channel expression were associated with AF activity, but were limited in AF susceptibility. Our results suggest that significant transcriptional remodeling marks susceptibility to AF, while remodeling of ion channel expression occurs later in the progression or as a consequence of AF.