Obesity is an independent risk factor for cardiac arrhythmias. Although this is an
active field of enquiry, there are several unknowns that have informed the studies
contained in this thesis. First, the effect of increasing adiposity on ventricular
repolarisation abnormalities has not been studied amongst the UK population.
Second, it is unknown if surgical weight reduction reverses any subclinical
proarrhythmic electrophysiological remodelling in arrhythmia-free obese patients.
Third, the mechanisms by which epicardial fat confers higher risks of arrhythmias
has not been studied.
Amongst the UK Biobank population, increasing adiposity and cardiometabolic ill health were associated with QTc prolongation and their effect on QTc interval was
additive when they co-existed. The relationships between QTc interval and
increasing adiposity and cardiometabolic ill-health, respectively, were not modulated
by individuals’ genetics. Ventricular arrhythmias were more prevalent in individuals
with cardiometabolic ill-health, with or without concurrent obesity, compared to
obesity alone.
Non-invasive electrocardiographic imaging in morbidly obese and non-obese
individuals without a history of cardiac arrhythmias showed that total atrial activation
times, dispersion of total atrial activation and atrial activation gradients were greater
in obese patients and persisted after bariatric surgery. By contrast, spatial ventricular
repolarisation gradients reversed after bariatric surgery in obese patients, to the
extent that there was no statistical difference between non-obese and post-operative
obese individuals. Bariatric surgery was also associated with partial improvements in
glycaemic control, autonomic function and regression of left ventricular mass as well
as epicardial fat volume.
Paired human epicardial adipose tissue (EAT) and subcutaneous adipose tissue
(SAT) biopsies were harvested from patients undergoing cardiothoracic surgery and
cultured to generate adipose-conditioned media. EAT-conditioned media was
associated with a higher concentration of profibrotic adipokine Activin A compared to
SAT. Neonatal ventricular myocytes incubated with EAT showed greater conduction
slowing in response to pacing under identical experimental conditions compared to
SAT.
These results show that increasing adiposity and obesity are associated with
abnormal ventricular repolarisation that reverses with weight reduction, although
atrial activation abnormalities may persist even after weight reduction. These
findings may reflect differential mechanisms of remodelling and that are partly
attributable to EAT.