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Title: Gap junction remodelling and conduction abnormalities in the heart
Author: Chowdhury, Rasheda Amin
ISNI:       0000 0004 2706 7731
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Electrical coupling between mammalian cardiac myocytes allows orderly spread of excitation and is mediated by gap junction (GJ) channels composed of connexin (Cx) proteins. In normal myocardium, gap junctions within the intercalated disc allow intercellular transfer of ions and represent low resistance pathways for electrical propagation. GJ remodelling describes either a change in connexin expression and/or redistribution toward the lateral cell borders. This remodelling is thought to play a crucial role in arrhythmogenesis. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. AF becomes more persistent over time (“AF begets AF”). This self perpetuating nature of AF is poorly understood and may be associated with GJ remodelling. The aim of this thesis was to characterise the GJ structural remodelling that occurs alongside electrical changes in AF and to investigate the role of gap junction modulation on changes in electrical propagation, using animal and cell models. The findings of the in vivo goat burst-pacing model suggest that late AF-induced electrical remodelling occurs with a similar time course to connexin remodelling. These consistencies in the timescale of remodelling suggest that structural GJ remodelling is a likely determinant of the development of persistent AF. Although electrical remodelling is unaffected by the angiotensin receptor blocker, candesartan, its administration does attenuate GJ remodelling. HL-1 is a cardiac muscle cell line with a phenotype that is similar to atrial myocytes, particularly in connexin expression. Rapid pacing did not induce a change in the pattern of activation. GJ uncoupling with carbenoxolone resulted in reversible slowing of conduction and could be used as a method of modifying conduction. This thesis provides an insight into the role of gap junctions in conduction propagation both in the intact myocardium in an animal model of AF and in an in vitro cell model.
Supervisor: Peters, Nicholas ; Dupont, Emmanuel Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral