Mechanistic investigation into the arrhythmogenic role of transmural heterogeneities in regional ischaemia phase 1A

AIMS: Studies of arrhythmogenesis during ischemia have focused primarily on reentrant mechanisms manifested on the epicardial surface. The goal of this study was to use a physiologically-accurate model of acute regional ischemia phase 1A to determine the contribution of ischaemia-induced transmural electrophysiological heterogeneities to arrhythmogenesis following left anterior descending artery occlusion. METHODS AND RESULTS: A slice through a geometrical model of the rabbit ventricles was extracted and a model of regional ischaemia developed. The model included a central ischaemic zone incorporating transmural gradients of I(K(ATP)) activation and K+o, surrounded by ischaemic border zones (BZs), with the degree of ischaemic effects varied to represent progression of ischaemia 2-10 min post-occlusion. Premature stimulation was applied over a range of coupling intervals to induce re-entry. The presence of ischaemic BZs and a transmural gradient in I(K(ATP)) activation provided the substrate for re-entrant arrhythmias. Increased dispersion of refractoriness and conduction velocity in the BZs with time post-occlusion led to a progressive increase in arrhythmogenesis. In the absence of a transmural gradient of I(K(ATP)) activation, re-entry was rarely sustained. CONCLUSION: Knowledge of the mechanism by which specific electrophysiological heterogeneities underlie arrhythmogenesis during acute ischaemia could be useful in developing preventative treatments for patients at risk of coronary vascular disease.