Altered inflammatory state and mitochondrial function identified by transcriptomics in paediatric congenital heart patients prior to surgical repair

Abstract

ObjectiveCongenital 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 in sustained cardiac health in these patients, thus by elucidating divergent profiles between CHD and control through tissue analysis this study aims to identify new avenues of investigation into the mechanisms surrounding reduced RV function. Approach & ResultsTranscriptomic profiling, in silico cellular deconvolution and functional network analysis was conducted on RV biopsies obtained from CHD and control paedatric patients. Analysis identified an increase in mitochondrial dysfunction genes RPPH1 and RMPR (padj = 4.67E-132, 2.23E-107, respectively), Cytotoxic T cell markers CD8a, LAGE3 and CD49a (p = 0.0006, p < 0.0001, p = 0.0118, respectively) and proinflammatory marker Caspase1 (p=0.0055) in CHD compared to control. Gene set enrichment identified mitochondrial dysfunctional pathways, predominately changes to the oxidative phosphorylation processes. Negative regulation of mitochondrial functions and metabolism was identified in functional network analysis, with dysregulation of mitochondrial complex formation. Histological analysis confirmed an increase in cellular bodies with the CHD RV tissue, and positive staining for both CD45 and CD8 in CHD RV tissue, which was absent in control. 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). Network analysis identified positive regulation of the immune system and cytokine signalling clusters within the inflammation functional network as were lymphocyte activation and leukocyte differentiation. ConclusionsUtilizing 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.