| dc.description.abstract | Despite its prevalence, the underlying aetio-pathogenesis of atrial fibrillation (AF) remains incompletely understood. One area of novel interest lies in the adipose tissue that directly overlies the myocardium, namely epicardial adipose tissue (EAT). EAT acts as a local depot of immune cells and mediators that can infiltrate the myocardium given the lack of fascial interruption between the tissues. However, a comprehensive immune characterisation of EAT is currently lacking with human tissue studies sparse and patients typically poorly matched for baseline clinical characteristics. The aim of this thesis was to systematically define the immunological signature of EAT in a propensity-matched cohort of cardiac surgical patients with a prior history of AF, those in sinus rhythm and patients who developed de novo post-operative AF. Adaptive immune cells were found to be enriched in the EAT with T cells in particular the predominant immune cell type. T cell subset analysis revealed an increase in both EAT-resident CD4+ and CD8+ memory T cell populations in AF patients. CD4+ tissue-resident memory T cells (TRMs) in EAT correlated with the production of the pro-inflammatory cytokines interferon-γ and interleukin-17. On a single cell level, EAT was compared with paired atrial tissue specimens and both tissues exhibited similar immune cell populations with a shared core TRM signature, TRM subsets and the same T cell clones present in the underlying atrial myocardium as the EAT. Spatial transcriptomics analysis confirmed regional tissue gene alterations and cellular differences consistent with histological data demonstrating the EAT/atrial tissue border region to be a hotspot of inflammatory and fibrotic activity. Physiologically, TRM populations added to induced pluripotent stem cell-derived atrial cardiomyocytes were able to differentially modulate calcium signalling compared with non-TRM populations. Moreover, RNA-sequencing analysis from these cardiomyocytes confirmed differential activation of inflammatory and apoptotic pathways in the TRM co-cultured cardiomyocytes. Taken together, these results demonstrate that EAT acts as the immune reservoir of the heart and sampling it can thus provide an accurate readout of the immune landscape of the underlying cardiac tissue. AF patients exhibit a unique EAT-resident T cell population, which can directly modulate vulnerability to arrhythmia and hence may be a potential novel immune-therapeutic target in AF. | en_US |
