Atrial Fibrillation and Sudden Cardiac Death in Obesity: An Investigation of the Arrhythmogenicity of Epicardial Fat

Abstract

Atrial fibrillation and sudden cardiac death are two burgeoning cardiac disorders caused by arrhythmic events in the heart. Patients with atrial fibrillation are at an increased risk of severe cardiovascular complications, hospitalisation, thromboembolic events, clinical morbidity, and mortality. Premature death resulting from sudden cardiac death is a significant cause of cardiovascular mortality, often occurring in patients without apparent high-risk conditions and with normal heart functions. The emergence of obesity epidemic in the community is implicated in the rising burdens of atrial fibrillation and sudden cardiac death, but this has not been well characterised. More recently, the ectopic cardiac fat depot “epicardial adipose tissue” is postulated to mediate the pro-arrhythmic sequalae of obesity. In this thesis, investigations were undertaken to characterise these relations in a meta-analysis; and to evaluate the cardiac electrophysiological and structural substrates due to epicardial fat in ovine sheep models of chronic weight gain and weight fluctuations. In chapter 2, a comprehensive systematic review of the literature and a meta-analysis were conducted to define the association of the fibrotic biomarker galectin-3 and atrial fibrillation. The findings demonstrated significant associations of high serum galectin-3 and risk and severity of atrial fibrillation. In chapter 3, a comprehensive systematic review of the literature and a meta-analysis were conducted to define the clinical associations of epicardial fat and atrial fibrillation, arrhythmia progression, recurrent atrial fibrillation following curative catheter ablation, and post-operative atrial fibrillation after cardiac surgery. The findings demonstrated significant associations of increased expansions of total cardiac and peri-atrial epicardial adipose tissue with greater risk of atrial fibrillation; severity of atrial fibrillation; atrial fibrillation recurrence post-ablation; and de novo incidence after cardiac surgery. Next, the underlying mechanisms were explored in chronic ovine models and presented in chapters 4 & 5. The results demonstrated that obesity induces expansion of epicardial fat and fibro-fatty replacement of atrial myocytes and deterioration of myocyte contractile apparatus, which may drive impairments of atrial electrical properties. Despite having comparable epicardial fat quantity with reference controls, weight fluctuation, induced similar abnormalities, albeit less severe, with stable obesity, thus highlighting an explanation for the increased atrial arrhythmias risks often seen with periodic fluxes in weight. Chapter 6 reports findings from a systematic review and meta-analysis undertaken to define the association between obesity and sudden cardiac death. The pooled analyses involving over 1.4 million patients demonstrated that, after correcting for traditional high-risk risk factors: underweight body mass index (<18.5 kg.m-2) associates with an increased risk of sudden cardiac death; overweight shows no significant association with sudden cardiac death; obesity (BMI: ≥30 kg.m-2) predicts an exaggerated risk for sudden cardiac death. Similarly, unit increment in body mass index was shown to demonstrate a greater risk for sudden cardiac death, further implicating the role of increased adiposity in the risk of sudden cardiac death. In chapter 7, the molecular and structural substrates for ventricular arrhythmias that lead to sudden cardiac death in a model of chronic obesity are presented. Obesity demonstrated two-and-half-fold expanded ventricular epicardial fat depot with a consequent extensive and severe fat cell infiltrations; significant reduction in ventricular desmosomal cadherin desmoglein-2, which demonstrated significant negative correlation with the degree of fatty infiltration; and induction of diffuse ventricular interstitial fibrosis. The findings further demonstrated that obesity results in significant abnormal modulation of fibrotic pathways, including an alternative component of the central transforming growth factor-beta 1 pathway, angiotensin II, endothelin and aldosterone signalling pathways. The observations of epicardial fat expansion and subsequent fibro-fatty infiltrations are particularly noteworthy. Epicardial fat adds an important extra layer to the stratification of patients at risk of atrial fibrillation and sudden cardiac death. Fibro-fatty infiltrates alone are sufficient to induce re-entrant tachyarrhythmias, leading to atrial fibrillation and sudden cardiac death. Clinical assessment of fibro-fatty infiltrates could help improve sudden cardiac death risk profiling of patients in the low-risk communities, who paradoxically have high absolute mortality rates. More importantly, the fibro-fatty deposits could form a key element in substrate mapping as a guide for ablation of lethal arrhythmias.