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Interactions Between Activation And Repolarisation In Predisposition Towards Cardiac Arrhythmia

Finlay, M; (2014) Interactions Between Activation And Repolarisation In Predisposition Towards Cardiac Arrhythmia. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The lethal cardiac arrhythmias ventricular fibrillation (VF) and ventricular tachycardia (VT) are a leading cause of death in heart disease. We hypothesised that dynamic activation and repolarisation interactions will vary according to autonomic tone and the nature of the myocardial substrate as affected by disease states. This hypothesis was tested in a series of human and murine experiments. Incorporation of data from human electrophysiological studies into a linear computer model was able to predict activation dynamics of sequential extrastimuli. This served as a validation of the concept of dynamic interactions between activation and repolarisation in man. A human model of mental stress demonstrated that activation and repolarisation dynamics are altered by intrinsic autonomic stimulation. Specifically, a reduction in activation potential duration and an increase in dispersion of repolarisation occurred at short coupling intervals during stress. A weak increase in conduction velocity and excitability was also observed. Patients with early-stage arrhythmogenic right ventricular cardiomyopathy (ARVC) were seen to exhibit conduction changes prior to the onset of structural disease. This was used to determine potential diagnostic criteria based on surface ECG correlates of intracardiac observations. These criteria are able to distinguish early ARVC from benign right ventricular outflow tract tachycardia. Finally, the mechanism of modulation of tissue level activation dynamics were further studied using a novel thin-tissue slice murine model. Conduction velocity and excitability were modulated by both sympathetic and parasympathetic stimuli, parasympathetic modulation is demonstrated to be dependent on the Gαi2 regulatory pathway at the tissue level. The tissue slice method provides a novel tissue-level platform for the study of cardiac electrophysiology in genetically modified mice. In conclusion, this work demonstrates that modulations of activation and repolarisation dynamics are seen in pro-arrhythmic states, specifically in sympathetically active states and in arrhythmogenic right ventricular cardiomyopathy.

Type: Thesis (Doctoral)
Title: Interactions Between Activation And Repolarisation In Predisposition Towards Cardiac Arrhythmia
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Cardiac Arrhythmia, Mental Stress, Arrhythmogenic Right Ventricular Cardiomyopathy, Arrhythmogenisis
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng
URI: https://discovery.ucl.ac.uk/id/eprint/1429926
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