BACKGROUND Tetralogy of Fallot (ToF) and Atrial Septal Defects (ASD) are the most common types of congenital heart diseases and a major cause of childhood morbidity and mortality. Cardiopulmonary bypass (CPB) is used during corrective cardiac surgery to support circulation and heart stabilization. However, this procedure triggers systemic inflammatory and stress response and consequent increased risk of postoperative complications. The aim of this study was to define the molecular bases of ToF and ASD pathogenesis and response to CPB and identify new potential biomarkers. METHODS Comparative transcriptome analysis of right atrium specimens collected from 10 ToF and 10 ASD patients was conducted before (Pre-CPB) and after (Post-CPB) corrective surgery. Total RNA isolated from each sample was individually hybridized on Affymetrix HG-U133 Plus Array Strips containing 38,500 unique human genes. Differences in the gene expression profiles and functional enrichment/network analyses were assessed using bioinformatic tools. qRT-PCR analysis was used to validate gene modulation. RESULTS Pre-CPB samples showed significant differential expression of a total of 72 genes, 28 of which were overexpressed in ToF and 44 in ASD. According to Gene Ontology annotation, the mostly enriched biological processes were represented by matrix organization and cell adhesion in ToF and by muscle development and contractility in ASD specimens. GSEA highlighted the specific enrichment of hypoxia gene sets in ToF samples, pointing to a role for hypoxia in disease pathogenesis. The post-CPB myocardium exhibited significant alterations in the expression profile of genes related to transcription regulation, growth/apoptosis, inflammation, adhesion/matrix organization, and oxidative stress. Among them, only 70 were common to the two disease groups, whereas 110 and 24 were unique in ToF and ASD, respectively. Multiple functional interactions among differentially expressed gene products were predicted by network analysis. Interestingly, gene expression changes in ASD samples followed a consensus hypoxia profile. CONCLUSION Our results provide a comprehensive view of gene reprogramming in right atrium tissues of ToF and ASD patients before and after CPB, defining specific molecular pathways underlying disease pathophysiology and myocardium response to CPB. These findings have potential translational value because they identify new candidate prognostic markers and targets for tailored cardioprotective post-surgical therapies.

中文翻译：

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转录组分析定义了ToF和ASD儿童的心肌基因标志，并揭示了针对心肺转流手术的疾病特异性分子重编程。

背景技术法洛（ToF）和房间隔缺损（ASD）的四联症是先天性心脏病的最常见类型，并且是儿童发病率和死亡率的主要原因。心脏矫正手术期间使用体外循环（CPB）以支持血液循环和心脏稳定。但是，此过程会触发全身性炎症和压力反应，并因此增加术后并发症的风险。这项研究的目的是确定ToF和ASD发病机理以及对CPB的反应的分子基础，并确定新的潜在生物标志物。方法在校正前（CPB前）和校正后（CPB后）对10例ToF和10例ASD患者的右心房标本进行了转录组分析。从每个样品中分离出的总RNA在含有38,500个独特人类基因的Affymetrix HG-U133 Plus Array Strips上单独杂交。使用生物信息学工具评估基因表达谱和功能丰富/网络分析的差异。qRT-PCR分析用于验证基因调节。结果CPB前样品显示总共72个基因的显着差异表达，其中28个在ToF中过表达，在ASD中44个过表达。根据基因本体论注释，ToF中基质组织和细胞粘附以及ASD标本中的肌肉发育和收缩性代表了最丰富的生物学过程。GSEA强调了ToF样品中缺氧基因组的特异性富集，指出缺氧在疾病发病机理中的作用。CPB后心肌在与转录调节，生长/凋亡，炎症，粘附/基质组织和氧化应激有关的基因表达谱中表现出显着变化。其中，这两个疾病组只有70个常见，而ToF和ASD分别是110和24个。通过网络分析预测差异表达的基因产物之间的多功能相互作用。有趣的是，ASD样品中的基因表达变化遵循一个普遍的缺氧特征。结论我们的结果提供了在CPB前后，ToF和ASD患者右心房组织中基因重编程的全面视图，定义了疾病病理生理学和心肌对CPB反应的特定分子途径。