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Title: Murine gap junction remodelling induced by subdiaphragmatic pacing
Author: Kontogeorgis, Andrianos
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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This thesis aims to adapt and develop a mouse model for stable dyssynchronous pacing and systematic investigation of mechanisms of structural gap-junctional remodelling (GJR) and correlation to functional changes. GJR, an altered abundance or localisation of connexin proteins strongly correlates with arrhythmogenic substrates. Wild type Cx43+/+ and heterozygous Cx43 knockout Cx43+/- (66% mean reduction in Cx43) mice were paced in vivo subxiphisternally at 10-15% above anaesthetised sinus rates for one to six hours avoiding intubation, vascular access, thoracic or mediastinal disruption. In Cx43+/+ mice, pacing resulted in electrical and mechanical dyssynchrony. Echocardiographic (ECHO) and electrocardiogram (ECG) indices, ventricular effective refractory period (VERP) and arrhythmia inducibility were not significantly altered. Pacing attenuated transmural gradients of Cx43 immunosignal in the LV free wall. Significant reductions in Cx43 mRNA abundance at the LV free wall occurred. Cx43, its isoforms and interacting protein expression were unchanged. Fractionation studies of 6hr-paced hearts demonstrated reduced Cx43 in membrane fractions while cytosolic fractions increased significantly. Cx43 degradation studies demonstrated substantially increased ubiquitinated forms with pacing. Cx43 protein expression in paced and unpaced Cx43+/- mice hearts was unchanged. In contrast to Cx43+/+ cells, Cx43+/- mice demonstrated significantly shorter action potential durations (APD), increased steady-state (Iss) and inward rectifier (IK1) potassium currents. Pacing prolonged action potential duration (APD) at 50ms and 90ms increased VERP at 80ms/100ms and significantly reduced Iss in Cx43+/- vs. unpaced Cx43+/- hearts. Pacing induces electro-mechanical dyssynchrony in wildtype Cx43 (Cx43+/+) hearts, results in remodelling of the cardiac gap junctions without sustained measurable effects or increased arrhythmia inducibility. Transgenic hearts (Cx43+/-) respond quite differently to pacing, which may be relevant in cardiac disease, where Cx43 is focally reduced. Pacing could lead to the remodelling of repolarisation currents in regions of reduced Cx43, enhancing dispersion of refractoriness and potentially creating a substrate for arrhythmia re-entry.
Supervisor: Peters, Nicholas; Kaba, Riyaz Sponsor: British Heart Foundation ; National Institutes of Health (U.S.) ; American Heart Association
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available