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Type: Thesis
Title: The Impact of Weight Fluctuation on Atrial Substrate and the Prevention of Atrial Remodelling With the Use of Anti-Fibrotics
Author: Twomey, Darragh Joseph
Issue Date: 2016
School/Discipline: Adelaide Medical School
Abstract: Atrial fibrillation (AF) is the commonest sustained arrhythmia in humans and is responsible for a significant socioeconomic burden. Affected individuals can suffer significant symptoms and are at risk of potentially life-threatening complications. Obesity is increasingly recognised as risk factor for the development of this arrhythmia. Weight fluctuation is common during attempted weight loss and has detrimental cardiovascular effects in human cohort studies, including patients with AF. However, the pathophysiological mechanisms by which this occurs are unclear. The first aim of this thesis is to characterise the electrophysiological effects of weight fluctuation using an obese ovine model. Previous studies have demonstrated that obesity promotes the development of atrial fibrosis as well as the upregulation of profibrotic factors in atrial tissue. The second major aim of this thesis is to investigate the effect of blockade of these profibrotic receptors on obesity-related atrial remodelling. Chapter 2 describes the use a fluctuating weight model in order to study the electrophysiological changes over time. Weight fluctuation was associated with progressive changes in atrial electrophysiology. This group demonstrated reduction in conduction velocity when compared to a lean control group, particularly following a second cycle of weight gain followed by weight loss. These changes were less severe when compared to an obese group. Additionally, the changes in conduction were more heterogeneous than in animals with persistent obesity. This resulted in an increased propensity to AF when compared with lean controls. Chapter 3 investigates the role of endothelin receptor blockade in the prevention of atrial substrate in obesity. Obesity was again induced in ovine subjects and two groups were compared. One was treated with the endothelin receptor antagonist (ERA) bosentan whilst the other acted as a control group. Animals treated with bosentan had attenuation of obesity-related conduction slowing. This was seen on both endocardial and epicardial surfaces. Importantly, there was no effect on either haemodynamics or refractory periods. AF inducibility was also reduced by ERA treatment. Examination of atrial demonstrated reduced fibrosis and downregulation of pro-fibrotic factors with ERA treatment. Importantly, this effect was independent of the TGF-β pathway. Chapter 4 examines the effect of the TGF-β receptor antagonist tranilast on the obese ovine atrium. A similar model of induced obesity was used to compare tranilast treatment with a control group. Animals receiving tranilast demonstrated attenuation of conduction slowing. Endo and epicardial mapping showed this slowing was heterogeneous across atrial sites, perhaps suggesting a predominantly local mechanism in the development of these electrophysiological changes.
Advisor: Sanders, Prashanthan
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2017
Keywords: Atrial fibrilation
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
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