The Effects of Gap Junction Modulation on Myocardial Structure and Function

Abstract

The aim of the work in this thesis was to investigate the effects of gap junction modulation during acute myocardial infarction (MI) on ventricular arrhythmogenesis in the settings of acute reperfusion and chronic post-myocardial infarction. Ventricular arrhythmias can occur during reperfusion because of abrupt changes in electrophysiology, whilst arrhythmias occur post-MI because the healed infarct scar forms a substrate for re-entry, with increased inhomogeneity of scarring being associated with greater arrhythmia susceptibility. The effects gap junction modulation on reperfusion arrhythmogenesis were studied in an ex vivo rat model of acute ischaemia-reperfusion. Gap junction modulators were administered to hearts subjected to left anterior descending artery occlusion followed by reperfusion. The electrophysiological changes that accompany ischaemia-reperfusion were studied using optical mapping. Gap junction modulators, AAP10 and carbenoxolone, reduced the incidence of reperfusion arrhythmias. This was associated with the attenuation of the abrupt recovery of conduction during reperfusion, which may underlie their antiarrhythmic effects. A four-week rat chronic myocardial infarction model was developed to study the effects of acute gap junction modulation on late post-MI arrhythmias. Gap junction modulators, rotigaptide and carbenoxolone, were administered acutely for 7 days from the time of surgical MI, and rats were studied at 4 weeks post-MI with ECG-telemetry, programmed electrical stimulation, optical mapping, histomorphometry and connexin43 immunohistochemistry. Enhancing gap junction coupling with rotigaptide acutely during MI reduced heterogeneities in infarct border zone scarring and reduced susceptibility to ventricular arrhythmias on programmed electrical stimulation. Histomorphometric studies support a possible mechanism whereby homogenisation of the acute ischaemic insult and the cell death process may result in more homogeneous scarring and a less arrhythmic healed substrate. Gap junction modulation was anti-arrhythmic in the acute reperfusion setting, and the enhancement of coupling during acute MI may represent a novel therapeutic strategy to modify the morphology of the healed infarct and alter post-infarction arrhythmia susceptibility