Metabolical: understanding the role of epicardial fat and obesity in atrial fibrillation

The risk of developing atrial fibrillation (AF), the most common cardiac arrhythmia worldwide, is increased by obesity and other metabolic diseases, such as diabetes mellitus and metabolic syndrome. Expansion of the fat layer surrounding the heart, epicardial adipose tissue (EAT), is associated with both AF and obesity. Furthermore, EAT has been implicated as an acute trigger for arrhythmogenesis. This thesis aimed to examine acute mechanisms of EAT-induced arrhythmogenesis, with a specific focus on the involvement of both acute metabolic stress and chronic obesity.

Using an in vitro isolated right atrial trabecula model, human trabeculae (n = 21) were exposed to 24-hour cultured secretome of human EAT from either non-obese (BMI < 30 kg/m²; n = 6) or obese (BMI > 30 kg/m²; n = 7) participants. EAT biopsies were bisected and either left untreated (EATsec) or treated with an acute metabolic stress cocktail of hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia (EAT-MSsec). Neither the EATsec nor EAT-MSsec increased the proportion of trabeculae that developed spontaneous contractions (SCs) compared to baseline (Pre-EATsec) measurements (EATsec: 6/21 & EAT-MSsec: 5/21 vs. Pre-EATsec: 8/21, P = 0.70). Similarly, there was no difference in the SC propensity induced by EATsec from non-obese (2/7) and obese participants (4/14, P = 0.56). The EATsec induced a distinctly negative inotropic (F_dev: 2.6 ± 0.7 mN/mm² vs. Pre-EATsec: 4.0 ± 0.9 mN/mm², P < 0.0001) and lusitropic (-dF/dt_max: -26.2 ± 6.0 mN/mm²/s vs. Pre-EATsec: −35.1 ± 7.1 mN/mm²/s, P = 0.01) effect, however this was unchanged by either metabolic stress or obesity.

To identify differential expression of adipokines induced by the acute metabolic stress cocktail, chronic obesity, or a combination of the two, EATsec and EAT-MSsec samples from non-obese (n = 7) and obese (n = 7) participants underwent proteomic analysis. This study is the first to identify alterations in adipokine expression in the EAT secretome in obesity and provided the novel finding of increased expression of S100 proteins S100A, S100A11, and S100B in obesity. Acute metabolic stress altered the expression of some, but not many, adipokines, however the response to acute metabolic stress differed in EAT from obese compared to non-obese participants.

With the aim of attaining a more accurate cross-sectional area (CSA) metric for normalisation of the previously collected functional data, trabeculae (N=25) were fixed, sectioned, and immuno-stained to determine their cardiomyocyte and fibrotic CSAs. While normalisation of force parameters to cardiomyocyte CSA was not superior to estimated CSA using a light microscope, the structural composition of trabeculae was highly variable and reflective of diversity in participant clinical characteristics.

Overall, my thesis has expanded on the pre-existing knowledge base surrounding AF, obesity, and EAT by providing mechanistic data describing the acute paracrine relationship between the EAT secretome and the atrial myocardium in humans, and how this is informed by acute metabolic stress and chronic obesity. These data can inform future research investigating alternative mechanisms behind obesity-induced and EAT-mediated AF, namely chronic processes rather than acute, and the role of newly identified adipokine targets in EAT and the myocardium.