Date of Award
Fall 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Electrical & Computer Engineering
Program/Concentration
Biomedical Engineering
Committee Director
Michel Audette
Committee Member
Omer Berenfeld
Committee Member
Venkat Maruthamuthu
Committee Member
Dharmakeerth Nawarathna
Abstract
Long QT syndrome (LQTS) is a genetic or drug-induced electrophysiological disorder in the heart that prolongs the QT interval on the electrocardiogram. LQTS is present in considerable proportions (1:3000 to 1:5000) of the general population. LQTS has a high incidence of malignant ventricular arrhythmias during physical and emotional stress and is a significant cause of sudden death in younger subjects. This poses a substantial medical burden on the healthcare system in terms of morbidity, mortality, and finances. Despite extensive genetic research into LQTS, the mechanisms underlying spontaneous initiation and maintenance of arrhythmias are not fully understood. Beta-blockers are the standard treatment for LQTS but may show reduced effectiveness, particularly in LQTS type 2 (LQT2) and LQTS type 3 (LQT3) subtypes.
Several experimental and clinical studies have implicated the Purkinje cells, the primary cells responsible for the heart’s ventricles synchronized electrical activation, as the likely source of ectopies during LQTS-mediated arrhythmias. However, the exact manner whereby the Purkinje cells contribute to the arrhythmia initiation and its maintenance thereafter has not been well elucidated. This is partly owing to the limited resolution of optical mapping of spatiotemporal patterns of electrical activation and inability to discriminate Purkinje cells from the surrounding myocardium.
Since its emergence, computer modeling of cardiac electrophysiology has been very useful in gaining mechanistic insights into arrhythmia initiation and perpetuation. This dissertation utilizes computational models and simulations of cardiac electrophysiology to elucidate the role of the His-Purkinje system in common and novel mutations that resulted in LQT2 and LQT3. The investigation is extended to also include the role of the His-Purkinje system in arrhythmias in the common clinical setting of drug-induced LQTS.
Myocardial and Purkinje cells exhibited different phenotypic behavior in the presence of the LQTS mutations investigated. Furthermore, the Purkinje cell was found to exhibit a severe phenotype, and the arrhythmia initiation was observed to be greatly dependent on the effect of certain anti-arrhythmic drugs. Overall, findings from this study may help to better understand arrhythmias and therapeutic approaches in the setting of LQTS, either endogenous or brought on by unfavorable pharmacological effects.
Rights
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DOI
10.25777/mxze-4h25
Recommended Citation
Owusu-Mensah, Anthony.
"Roles of the His-Purkinje System in Long QT Syndrome Mediated Arrhythmias"
(2024). Doctor of Philosophy (PhD), Dissertation, Electrical & Computer Engineering, Old Dominion University, DOI: 10.25777/mxze-4h25
https://digitalcommons.odu.edu/biomedengineering_etds/31
ORCID
0000-0002-9770-3356