Integrative computational and experimental study of arrhythmogenesis and defibrillation in acute myocardial ischaemia

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We aim at finding the mechanisms by which myocardial ischaemia results in lethal ventricular arrhythmias and changes in defibrillation efficacy. We expect this new insight will help in optimizing defibrillation therapy in patients suffering from coronary heart disease. Sudden cardiac death subsequent to ventricular fibrillation is the leading cause of mortality in the UK. In 80% of the victims, the arrhythmia arises in consequence of mismatch between cardiac oxygen supply and demand (myocardial ischaemia), caused by coronary heart disease. The only effective therapy to avert sudden cardiac death is electrical defibrillation: timely application of an electric shock to the myocardium. However, although the majority of patients undergoing defibrillation suffer from ischaemia, research has mostly focused on uncovering the mechanisms of defibrillation in the normal myocardium. This is in part due to the complexity and the rapidity of ischaemia-induced alterations in myocardial electrophysiological properties, which render experimental evaluation of the underlying mechanisms very difficult. We will develop a novel anatomically-based rabbit model of the regionally-ischaemic ventricles, validated using experimental data from the ionic to the whole organ level. We then will conduct a combination of computer simulations and experiments to investigate changes in arrhythmia and defibrillation mechanisms in acute myocardial ischaemia.