Meta-Gene Analysis of Atrial Fibrillation: Unravelling Immune and Signalling Pathways through Transcriptomics
Creators: name: Elijah, Stone,
Publisher: name: Torrens University Australia
Year: 2025
Subjects: classificationCode: 320101
subject: Cardiology (incl. cardiovascular diseases)

description: <b>Background</b>The existence of a relationship between AF and systemic inflammation is widely known, however the underlying cellular mechanisms contributing to AF-onset in a pro-inflammatory state are poorly understood. This thesis aims to provide a better understanding of the cellular relationship between AF and inflammation at a cellular level, while discussing the practical implications of this relationship.<b>Methods:</b>In Chapter 2 (Machine learning based deconvolution of microarray atrial samples from AF patients reveals increased fractions of follicular CD4+ T cells and gamma-delta T cells), we used softwarebased microarray data analysis to identify atrial tissue samples with AF and sinus rhythm controls. We then used Cibersoft gene analysis to assess the relationship between each atrial tissue sample and gene expression of key-mediators in the inflammatory process, including follicular CD4 T cells, gamma-delta T cells, dendritic Cells and neutrophilsIn Chapter 3 (Cardiac and Immune cell Analysis Reveals Altered Neutrophil Dynamics in Chronic Atrial Fibrillation), we used the same method of atrial tissue selection; however, in addition to comparing AF/non-AF control groups, we also assessed different phases of AF (i.e. acute, chronic, persistent). We then used Cibersoft to assess the relationship between each atrial tissue sample and gene expression of pro-inflammatory markers, including naïve B cells, memory B cells, plasma cells (or plasmablasts), cytotoxic T cells (CD8), helper T cells (CD4 naïve, memory and follicular), regulatory CD4 T cells, gamma-delta T cells, natural killer cells (NK cells; resting and activated), dendritic cells (resting and activated), monocytes, macrophages (M0, M1 and M2), mast cells (resting and activated), eosinophils and neutrophils.In Chapter 4 (Atrial distribution of gene expression in the PV-LA), we similarly used software-based microarray data analysis to identify LAA/LA-PV samples from paired AF patients and sinus rhythm control patients. After isolating these regional areas, we then used Cibersoft gene analysis to review the prevalence of various upregulated/downregulated genes within LAA/LA-PV samples of AF patients compared with sinus rhythm controls.<br><b>Results and Discussion:</b><br>In chapter 2, we noted a significant AF association with atrial tissue follicular CD4+ T cells and gamma-delta T cells – this demonstrates a potential follicular CD4 T cell phenotype expression in human atrial tissue in patients with permanent AF.In chapter 3, we found a significant difference in expressed immune cell sub-types in AF compared with SR control tissue. We analysed this further and compared neutrophil expression across specific phases of acute vs chronic/persistent AF. In doing so, we found that persistent AF appears a more prolonged phase of inflammation whereas permanent AF is associated with a reduction in neutrophils and a return to baseline levels of mast cells, natural killer cells and angiogenesis markers such as endothelial cells and pericytes.In chapter 4, we demonstrated upregulated integrin pathways in the PV-LA region of atrial tissue. This may provide an explanation for integrin-based disruption of cell-cell adhesion causing tissue remodelling and electrical conduction abnormalities, overall contributing to the development or perpetuation of AF. Unsurprisingly, in keeping with our previous findings, TGF-beta, signalling by BMP along with tight and cell-cell junction pathways were significantly downregulated in LA-PV tissue.