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

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.

Electrical defibrillation by timely application of a strong shock to the myocardium is the only effective therapy to prevent sudden cardiac death subsequent to ventricular fibrillation. However, although the majority of patients undergoing defibrillation suffer from coronary heart disease, little is known about the ischaemic tissue response to the delivery of defibrillation shocks. The main focus of the proposed research is to unravel the mechanisms underlying changes in defibrillation efficacy during the first 45 min of acute myocardial ischaemia. We hypothesize that (i) stretch of ischaemic border zone tissue plays a key role in arrhythmogenesis and defibrillation failure at 15-45min post-occlusion, when altered calcium dynamics favour occurrence of afterdepolarizations; (ii) elevated defibrillation threshold in acute regional ischaemia stems from heterogeneous tissue responses to the shock resulting from heterogeneous ischaemic electrophysiological substrate. This project is based on direct and multiple level iteration between experimental and computational research, coordinated by the Applicant. A mathematical model of the rabbit ventricles in regional ischaemia will be developed with realistic representation of ischaemia-induced effects. Experiments will provide the electrophysiological and anatomical data required to develop the model and to validate the model predictions. Computer simulations will be conducted using the ventricular model to examine changes in defibrillation threshold at several timings post-occlusion for both electrically-induced and spontaneous arrhythmias secondary to regional ischaemia. The Applicant will be directly involved in all aspects of the research, and will put special emphasis in acquiring expertise in the experimental techniques used in cardiac electrophysiology. The interdisciplinary training gained by the Applicant through the proposed studies will set the basis for an efficient and rigorous use of experimental and computational techniques in the study of cardiac arrhythmogenesis and anti-arrhythmia therapies during her Research Career. The combination of the Applicant‘s expertise, local experimental and theoretical know-how at Oxford, computational resources available through association with the UK e-science program, and established collaboration with Prof. Efimov will offer a unique opportunity to provide the mechanistic insight into arrhythmogenesis and defibrillation during acute ischaemia. This is hoped to ultimately advance the development of new or improved anti-arrhythmia interventions with increased success rates of cardiac defibrillation, which could reduce mortality /morbidity from sudden cardiac death. Finally and most importantly, patients with coronary heart disease could benefit from more efficient therapies, improved quality of life and prolonged life expectancy. Thus, the proposed research would contribute to reduce the burden of cardiovascular disease on the community.