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Genetic Cardiac Arrhythmias in the Young: From Population Trends to Cellular Mechanisms
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- Author / Creator
- Roston, Thomas Michael
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Arrhythmic heart disease in the young often has a hereditary genetic basis and may carry a lifelong burden of increased morbidity and mortality. The presenting rhythm can be atrial and/or ventricular origin, and both the age of onset and associated risk of sudden cardiac death vary markedly. This is influenced in part by the genetic driver(s) of disease. Atrial fibrillation is one of the most malignant atrial arrhythmias that can negatively impact quality of life and lead to an increased risk of stroke, but generally not sudden death. Although ample research efforts have been dedicated to understanding the different facets of the more common acquired atrial fibrillation in older adults, relatively little is known about atrial fibrillation presenting in young patients with no known risk factors for acquired atrial fibrillation. The latter is thought to represent a potentially genetic arrhythmia condition. In contrast, ventricular-predominant arrhythmia syndromes classically presenting <40 years of age consist mainly of inherited conditions that can cause sudden death. These syndromes may be under-recognized due to their low prevalence, often non-specific and initially innocuous presentations, and concealed nature despite standard clinical testing. Once recognized and diagnosed, which may include cascade family screening, these patients can be treated by targeting the molecular mechanisms of the underlying ion channel dysfunction. There is increasing recognition that the mechanisms of genetic atrial and ventricular arrhythmias in the young are overlapping, making their combined study logical. This dissertation includes six retrospective studies and one systematic review and meta-analysis that collectively examine the incidence, disease mechanisms, and therapeutic outcomes of potentially genetic arrhythmia conditions in the young. First, we report a population study investigating the incidence of atrial fibrillation/flutter in young Canadians. We show a strong sex-predilection to lone AF in young males, but worse outcomes in affected females. By developing a rigorous definition of lone/idiopathic atrial fibrillation, we conclude that this population-level approach may be an effective methodology to identify young AF patients who may benefit from genetic discovery. Next, the focus turns to a population-level study of syncope in the young, as this is a very common symptom in genetic arrhythmia syndromes. Amongst 11,488 children with syncope presenting for emergency care, there was a low rate of hospitalization (2%) but a high burden of comorbidities and likelihood of re-presentation. Cardiac conditions were common, but mortality was extremely low (one potentially cardiac death amongst 11,488 syncopal patients at 1-year). These findings suggest that although syncope can be the sentinel symptom of a genetic arrhythmia syndrome, this population approach using administrative coding is likely too non-specific to be useful in identifying those rare children predisposed to sudden death. Finally, using a large international registry cohort, we examine a rare form of genetic ventricular-predominant arrhythmia caused by cardiac ryanodine receptor dysfunction, called catecholaminergic polymorphic ventricular tachycardia. We show that implantable cardioverter defibrillators are paradoxically associated with increased harm, chronotropic incompetence during exercise is a risk factor for arrhythmic events, and homology mapping is a useful tool to predict RyR2 variant pathogenicity in this disorder. Through deeper phenotypic analysis of the registry, we further identify one of the first cases of a novel genetic arrhythmia syndrome related to the ryanodine receptor, now being termed cardiac ryanodine receptor release deficiency syndrome.Collectively, the studies comprising this dissertation provide a comprehensive overview of the methodologies needed to address key question in this diverse and challenging population. Future efforts should focus on leveraging the centralized nature of the single-payer healthcare system in Canada to better link population level cardiac outcomes to deeply phenotyped and genotyped arrhythmia registry cohorts.
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- Graduation date
- Spring 2020
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.