Atrial Arrhythmogenic Substrates: The Role of Structure and Molecular Remodeling

Atrial tachyarrhythmias, specifically atrial flutter: AFl) and fibrillation: AF), affect over 2.2 million Americans, leading to more hospitalizations than any other cardiac arrhythmia. These arrhythmias are defined by the presence of reentrant circuits of excitation leading to high atrial rates and uncoordinated activation of the ventricles. The underlying mechanisms of AFl/AF have proven complex and, despite a century of research, no one effective treatment has been developed. Surgical ablation and pharmacological therapies are both fraught with risks and potential pro-arrhythmic side effects. Electrical cardioversion, on the other hand, is extremely effective in terminating these arrhythmias, but the high-energy shocks required for termination cause substantial pain to the patient. In this dissertation, we first investigate the underlying molecular and structural mechanisms of AF in two clinically-relevant models - the human and canine hearts. We identify structural and molecular substrates responsible for the generation and maintenance of AFl/AF. We then explore the application of a novel low-voltage defibrillation therapy to a rabbit model of atrial tachyarrhythmias and show significant reductions in the defibrillation threshold for both AF and AFl. We utilize a variety of experimental techniques, such as high throughput quantitative PCR, optical coherence tomography, and optical mapping. Only truly integrative approaches to arrhythmia research, combining a variety of experimental models and techniques, can continue to unravel the complexities of underlying molecular, structural, and electrophysiological mechanisms and develop effective, safe therapies, as we demonstrate in this dissertation with regards to atrial tachyarrhythmias.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Engineering

Year dc:date.available

2011

Author dc:creator

• Ambrosi, Christina

Contributors dc:contributor

• Igor Efimov

• Biomedical Engineering
• atrial fibrillation
• atrial flutter
• defibrillation
• heart failure
• ion channels
• optical coherence tomography

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K7JQ0Z1G

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-1547