Mechanistic investigation into the arrhythmogenic role of transmural heterogeneities in regional ischaemia phase 1A
1 Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, CSEB 216, Baltimore, MD 21218, USA; 2 Computing Laboratory, Oxford University, Wolfson Building, Parks Road, Oxford OX1 3QD, UK; 3 Physics and Engineering Department, Washington and Lee University, Lexington, VA 24450, USA
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 IK(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 IK(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 IK(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.
Key Words: Ischaemia, Arrhythmogenesis, Transmural heterogeneites, Re-entry, Simulation
* Corresponding author. Tel: +1 410 516 4116; fax: +1 410 516 5294. E-mail address: ntrayanova{at}jhu.edu
These authors contributed equally.
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