Pericardial adiposity and cardiac arrhythmia vulnerability

Completed under a Cotutelle arrangement between the University of Melbourne and University of Birmingham© 2020 Simon Philip WellsBackground: The cellular mechanisms that predispose to arrhythmia include heterogeneic conduction slowing and/or changes in repolarisation time (e.g. regional alterations in transmural electrophysiology). Augmented pericardial adiposity is an independent risk factor for atrial and ventricular fibrillation, but the cellular mechanisms are unknown. Very limited data indicate pericardial adipose tissue exhibits paracrine characteristics, secreting factors which modulate cardiac electrophysiology. Recent evidence demonstrates pericardial adipose tissue can synthesise oestrogens which are known to affect cardiomyocyte function. It is hypothesised that augmented pericardial adiposity promotes epicardial conduction slowing and/or repolarisation prolongation through paracrine mechanisms to predispose to arrhythmia. Research aims: (relevant chapters in brackets) 1. Establish that transmural electrophysiology is modulated in the context of elevated cardiac adiposity. (3) 2. Compare electrophysiology of cardiomyocyte cultures from different origins as prelude to examining the paracrine influences of pericardial adipose tissue. (4) 3. Ascertain that obesity and epicardial adiposity associate with cardiac electrophysiological remodelling which may increase arrhythmia vulnerability. (5) 4. Identify that sex steroids can modulate atrial electrophysiology, indicating their potential as paracrine regulators of arrhythmia vulnerability. (6) Methods: Cardiac electrophysiology was assessed in both atrial and ventricular tissues utilising multiple in vitro methodologies. To establish the effects of adiposity on transmural electrophysiology, male rats were fed a high fat diet, then tangential left ventricular slices were electrophysiologically mapped. To optimise cardiomyocyte culture conditions, neonatal rat ventricular myocyte (NRVM) and human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) electrophysiology was compared. Fragments of epicardial adipose tissue were co-cultured with hiPSC-CMs to assess the paracrine influence on cardiomyocyte electrophysiology. The effects of obesity on left atrial electrophysiology were determined using male mice fed a Western diet. Left atrial electrophysiology was also assessed in male and female chow-fed mice in the absence/presence of sex steroids. Results: Some of the overall findings of this investigation include: 1. Augmented pericardial adiposity likely disrupts ventricular transmural conduction gradients through putative local actions on the epicardium. 2. hiPSC-CM and NRVM cultures display similar electrophysiology and exhibit good capacity to detect changes in repolarisation via experimental intervention. 3. Obesity associates with prolonged epicardial atrial action potential duration. This is caused by a paracrine influence of pericardial adipose tissue on cardiomyocytes. 4. Oestrogen and testosterone prolong repolarisation and slow conduction in the left atrium, indicating their potential as paracrine regulators of arrhythmia vulnerability. Conclusions: Pericardial adipose tissue has capacity to selectively prolong epicardial activation and repolarisation. This is at least in part, mediated through a paracrine mechanism. Prolonged repolarisation and slowed conduction predispose to triggered and reentrant arrhythmias, respectively. Together, these data indicate that augmented cardiac adiposity has a causative effect on cardiomyocyte electrophysiology to increase arrhythmia likelihood