Abstract:
Congenital heart disease (CHD) remains the most common birth defect, with surgical intervention required in complex cases. Right ventricle (RV) function is known to be a major predictor of sustained cardiac health in these patients; thus, by elucidating the divergent profiles between CHD and the control through tissue analysis, this study aims to identify new avenues of investigation into the mechanisms surrounding reduced RV function. Transcriptomic profiling, in-silico deconvolution and functional network analysis were conducted on RV biopsies, identifying an increase in the mitochondrial dysfunction genes RPPH1 and RMPR (padj = 4.67 × 10-132, 2.23 × 10-107), the cytotoxic T-cell markers CD8a, LAGE3 and CD49a (p = 0.0006, p < 0.0001, and p = 0.0118) and proinflammatory caspase-1 (p = 0.0055) in CHD. Gene-set enrichment identified mitochondrial dysfunctional pathways, predominately changes within oxidative phosphorylation processes. The negative regulation of mitochondrial functions and metabolism was identified in the network analysis, with dysregulation of the mitochondrial complex formation. A histological analysis confirmed an increase in cellular bodies in the CHD RV tissue and positive staining for both CD45 and CD8, which was absent in the control. The deconvolution of bulk RNAseq data suggests a reduction in CD4+ T cells (p = 0.0067) and an increase in CD8+ T cells (p = 0.0223). The network analysis identified positive regulation of the immune system and cytokine signalling clusters in the inflammation functional network, as there were lymphocyte activation and leukocyte differentiation. Utilising RV tissue from paediatric patients undergoing CHD cardiac surgery, this study identifies dysfunctional mitochondrial pathways and an increase in inflammatory T-cell presence prior to reparative surgery.
摘要:
先天性心脏病(CHD)仍然是最常见的出生缺陷,在复杂的情况下需要手术干预。已知右心室(RV)功能是这些患者持续心脏健康的主要预测指标;因此,通过组织分析阐明CHD和对照之间的差异曲线,本研究旨在为RV功能降低的相关机制寻找新的研究途径.转录组学分析,对RV活检进行了计算机反卷积和功能网络分析,确定线粒体功能障碍基因RPPH1和RMPR的增加(padj=4.67×10-132,2.23×10-107),细胞毒性T细胞标志物CD8a,CHD中LAGE3和CD49a(p=0.0006,p<0.0001,p=0.0118)和促炎caspase-1(p=0.0055)。基因集富集鉴定了线粒体功能失调途径,主要在氧化磷酸化过程中发生变化。在网络分析中确定了线粒体功能和代谢的负调节,线粒体复合物形成失调。组织学分析证实了CHDRV组织中细胞体的增加以及CD45和CD8的阳性染色,这在对照中不存在。大量RNAseq数据的去卷积表明CD4+T细胞减少(p=0.0067)和CD8+T细胞增加(p=0.0223)。网络分析确定了炎症功能网络中免疫系统和细胞因子信号簇的正调节。因为有淋巴细胞活化和白细胞分化。利用接受CHD心脏手术的儿科患者的RV组织,这项研究确定了线粒体通路功能失调和修复性手术前炎症T细胞存在的增加.