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.