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Title: Enhancing gap junction coupling in reperfused myocardium
Author: Debney, Michael Thomas
ISNI:       0000 0004 5367 5650
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The work in this thesis sought to examine the effects of enhancing cardiac gap junction coupling using the pharmacological agent Rotigaptide in clinically applicable models of acute myocardial infarction. Specifically, the studies in this thesis investigated the effect of Rotigaptide on ventricular arrhythmogenesis and structural remodelling of the reperfused substrate, with particular emphasis on the development, application and histological validation of diffusion tensor magnetic resonance imagine (DTI) as a novel imaging modality to describe and quantify structural remodelling post-infarction. An ex vivo rat model of acute regional ischaemia-reperfusion was characterised and used to study the effect of Rotigaptide on ventricular arrhythmogenesis during acute ischaemia and reperfusion. Arrhythmias occurred during ischaemia in a monomodal distribution with a peak incidence between 12-15 minutes after ischaemia. The incidence of reperfusion arrhythmias was dependent on the preceding duration of ischaemia with a progressive reduction as ischaemic time extended from 15 to 60 minutes. Rotigaptide pre-treatment afforded a significant reduction in ischaemia-induced arrhythmias compared to administration at the onset of ischaemia or at the time of reperfusion. An in vivo rat model of infarction-reperfusion, mimicking clinical reperfusion in the setting of acute MI was characterised and Rotigaptide administered prior to reperfusion and for a week post-MI. At four-weeks post-MI animals were studied with 6-lead ECG, ambulatory telemetry, programmed electrical simulation (PES), optical mapping, DTI and histology. Rotigaptide reduced the susceptibility to arrhythmias induced by PES and partially restored DTI-derived indices of tissue disruption in infarcted myocardium.
Supervisor: Peters, Nicholas ; Lyon, Alexander Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available