Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. The objectives of this study were to determine the mechanisms and significance of ionic transients in mathematical action potential models, determine the relative contributions of tachycardia-related myocyte remodeling processes to the pathologic features of the remodeled action potential, and to investigate mechanisms of AF maintenance and antiarrhythmic drugs in atrial tissue. / We began by formulating expressions for myocyte Cl- transport processes which allowed us to evaluate model stability and the influence of model equation singularity, and to characterize pacing-induced ionic transients. We found that tissue and model transients are comparable, indicating that any distortion arising from dynamic equation instabilities is not likely to be significant. / We then measured Ca2+-transients in isolated atrial myocytes in control and following tachycardia-induced remodeling and formulated the first atrial action potential model with realistic Ca2+-handling properties. Our results demonstrate that both remodeling of sarcolemmal ionic currents and subcellular Ca2+-handling processes contribute significantly to action potential shortening and loss of rate adaptation as occurs in chronic AF. / Next we developed a two-dimensional model of canine atrial tissue and the first model of AF with realistic ionic and propagation properties. The model provides the first theoretical confirmation of the recent experimentally-determined conception of the mechanisms of AF maintenance, indicating that discrete "driver regions" underlie AF, and that wavelets generated by emanating wavefronts give rise to fibrillation but play a relatively passive role in maintaining AF. / Finally we used our model of AF to determine the mechanisms of AF termination by sodium channel blocking agents (class I antiarrhythmic drugs). In agreement with recent experimental findings, our results demonstrate how sodium channel inhibition first slows and organizes AF, and how the effects of decreased excitability cause AF termination in a way that is independent of wavelength changes, previously thought to be necessary for antiarrhythmic efficacy. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.82903 |
| Date | January 2002 |
| Creators | Kneller, James Ralph William |
| Contributors | Nattel, Stanley (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology and Therapeutics) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001975316, proquestno: AAINQ88499, Theses scanned by UMI/ProQuest. |
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