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dc.contributor.advisorWittert, Gary Allenen
dc.contributor.authorAbed, Hany Samyen
dc.description.abstractBackground Epidemiological evidence identifies obesity as an independent risk factor for atrial fibrillation (AF). Additionally, therapeutic outcomes for AF appear to be adversely affected by the presence of obesity. Conditions associated with AF such as hypertension, obstructive sleep apnea, coronary disease and cardiac failure have common salient atrial electro-structural features, predisposing to arrhythmias. Many of these conditions are also associated with obesity and atrial hypertension. However, the degree by which obesity itself, independent of confounding hemodynamic changes, results in atrial electro-structural changes favoring arrhythmogenesis remains unknown. Aims The aim of our first study was to determine, using an ovine model, the electro-structural changes resulting from weight gain and obesity, and the contribution of the accompanying hemodynamic abnormalities. Following characterization of the obesity related atrial “substrate”; we investigated, in humans with atrial fibrillation, whether weight loss with cardio-metabolic risk factor management reduces arrhythmia burden, disease severity and structural correlates of reverse remodeling. Hypotheses: (I) Progressive weight gain promotes pro-arrhythmic atrial changes. (ii) Weight reduction combined with effective management of obesity-related co morbidities has favorable effects on AF severity and burden. (iii) Weight reduction and risk factor management has a favorable effect on atrial remodeling and pericardial fat volume (PFV). Methods Atrial structural (cardiac MRI), histological (tissue infiltrates and pro-fibrotic mediators) and electrical (tissue conduction and excitability) changes accompanying progressive weight gain over 8 months through ad-libitum calorie-dense feeding, were determined in male sheep sampled at baseline, 4 and 8 months (10/group). The clinical study was conducted as a single center randomized prospective trial, to investigate the effect of weight and cardio-metabolic risk factor management on AF severity, AF burden, atrial structure, myocardial mass and pericardial fat volume. The study utilized a physician-led weight and risk factor management program. This was compared to a parallel control group provided with brief lifestyle counseling and daily supplementation with marine triglycerides. Results The pre-clinical work showed that diet-induced obesity was accompanied by a progressive increase in atrial size, tissue inflammatory, lipid and fibrotic infiltrates. Molecular markers of pro-fibrotic mediators were also increased. There was slowing in conduction velocity, heterogeneity of conduction dispersion and greater AF burden. The electrical abnormalities persisted following statistical adjustment for systemic and atrial hypertension and the changes were more profound with greater increase in weight. The clinical work demonstrated an effective reduction in AF burden and severity, using a standardized validated AF severity questionnaire and ambulatory rhythm monitoring. In addition, there was a reduction in atrial size and ventricular wall thickness accompanying a favorable cardio-metabolic risk profile. There was a favorable reduction in PFV, height-indexed atrial volumes and myocardial mass. On post-hoc analysis PFV was predictive of the reduction in AF severity scores. Conclusion Diet induced obesity resulted in atrial conduction and structural abnormalities independent of systemic and left atrial hypertension, suggesting an obesity-specific effect. Our translational work shows that the burden of AF may be reduced through effective weight loss and appropriate management of the underlying metabolic derangement. Moreover, pericardial fat volume is independently predictive of AF severity and this depot is amenable to lifestyle intervention. Subsequent investigation requires further analysis of inflammatory markers, molecular pathways regulating fibrogenesis and myocardial electrical activity and the effect of pharmacological inhibition of key mediators. Long-term outcome studies to determine maintenance of benefit are also required.en
dc.subjectobesity; atrial fibrillation; remodelingen
dc.titleObesity and atrial electrical and mechanical remodeling: implications for atrial fibrillation.en
dc.contributor.schoolSchool of Medicineen
dc.provenanceCopyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.en
dc.description.dissertationThesis (Ph.D.) -- University of Adelaide, School of Medicine, 2013en
Appears in Collections:Research Theses

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