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

我们的目的是发现心肌缺血导致致死性室性心律失常和除颤疗效变化的机制。我们期望这一新的见解将有助于优化冠心病患者的除颤治疗。心室颤动引起的心源性猝死是英国死亡的主要原因。在80%的受害者中，心律失常是由冠心病引起的心脏供氧量和需氧量不匹配（心肌缺血）引起的。避免心源性猝死的唯一有效疗法是电除颤：及时对心肌施加电击。然而，尽管大多数接受除颤的患者患有缺血，但研究主要集中在揭示正常心肌除颤的机制。这部分是由于缺血引起的心肌电生理特性改变的复杂性和快速性，这使得对潜在机制的实验评估非常困难。我们将开发一种新的基于解剖的兔局部缺血脑室模型，使用从离子到整个器官水平的实验数据进行验证。然后，我们将进行计算机模拟和实验相结合来研究急性心肌缺血中心律失常和除颤机制的变化。

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.