Investigating Myocardial Infarct Scars as a Focal Arrhythmogenic Substrate Using Advanced Computational Modelling Based-On High-Resolution Imaging

尽管越来越多的人在心脏病发作后幸存下来，但在他们的心肌中留下的疤痕使他们在初次发作后发生致命性心律失常（心脏异常跳动）的风险增加。关于疤痕的存在与心律失常死亡增加之间的潜在过程，人们知之甚少。具体来说，目前尚不清楚疤痕是否参与了心律失常的实际产生，或者它是否只是帮助稳定由另一种与疤痕本身无关的机制产生的心律失常发作。因此，对这些患者的诊断和治疗计划并不理想，并且由于心律失常事件引起的猝死率在这一人群中仍然很高。目前的临床工具可以提供有用的信息关于疤痕患者曾遭受心脏病发作。临床磁共振成像为分析患者疤痕的位置和形状提供了一种重要的非侵入性手段。此外，分析心律失常时的临床心电图（ECG）记录不仅可以提示心律失常的类型，还可以提示疤痕在心律失常发作中可能起的作用。特别是，仔细分析前几次心律失常的心电图痕迹的形状表明，在许多情况下，疤痕本身极有可能是导致心律失常的异位活动的实际来源。基础科学研究表明，疤痕内部和周围的组织结构是高度多样化的，其功能电学特性也与正常健康的心脏组织不同。因此，疤痕如何产生致命的心律失常被认为涉及高度复杂的过程，但尚未得到很好的理解。我们的目标是使用计算机建模以及高分辨率的动物和临床图像，以深入了解直接从心脏疤痕内产生致命性心律失常的潜在过程。通过使用疤痕的高分辨率动物图像，我们将生成非常详细的计算模型，以研究疤痕内结构和功能多样性之间的相互作用如何促进心律失常的产生。这将使我们了解疤痕和周围组织的精细特性如何使其容易受到心律失常的影响，确定关键的“热点”区域，这些区域代表心律失常活动最危险的潜在来源。然后，我们将利用这些知识与患者MR和心律失常发生率数据进行比较，朝着将这些发现转化为临床迈出重要的一步，帮助为临床数据中发现的潜在观察关系提供机制解释。总的来说，这项研究的发现将为改善心脏疤痕患者的风险分层铺平道路，并开发新的临床有用的治疗方法，针对作为心律失常产生来源的疤痕。由于英国每年的心脏病发病率很高（12.4万例），以及心脏病发作后心律失常对个体造成的重大风险，这项研究的潜在受益者将是广泛的。因此，这项工作也有可能减少相关死亡和疾病的健康和经济成本。

Although an increasing number of people survive heart attacks, the scar left in their heart muscle leaves them at an increased risk of developing lethal cardiac 'arrhythmias' (abnormal beating of the heart) following the initial attack. Little is known about the underlying processes linking the presence of scars to increased death from cardiac arrhythmias. Specifically, it is not well understood whether the scar is involved in the actual generation of the arrhythmia, or whether it just helps to stabilise an arrhythmic episode generated by another mechanism, unrelated to the scar itself. As a result, diagnosis and therapy planning is non-optimal for these patients, and the rate of sudden death due to arrhythmic events is still high within this population.Current clinical tools can provide useful information regarding scars within patients who have suffered prior heart attacks. Clinical magnetic resonance (MR) imaging gives an important non-invasive means of analysing the location and shape of scars in patients. In addition, analysis of clinical electrocardiogram (ECG) recordings during arrhythmia can suggest not only the type of arrhythmia, but also the role the scar may play in such episodes. In particular, careful analysis of the shape of the ECG trace in the first few arrhythmic beats has suggested that, in many cases, the scar itself is highly likely to be the actual source of the ectopic activity responsible for generating the arrhythmia.Basic science investigations have shown that the structure of the tissue in and around the scar is highly diverse, and that the functional electrical properties are also changed from that of the normal, healthy cardiac tissue. As such, how the scar may act to generate lethal arrhythmia is thought to involve highly complex processes, which are not yet well understood.Our goal is to use computer modelling alongside high-resolution animal and clinical images to gain an in-depth understanding of the underlying processes involved in the generation of lethal arrhythmias directly from within cardiac scars.By using high-resolution animal images of scars, we will generate exceptionally-detailed computational models to investigate how the interaction between structural and functional diversity within a scar may encourage the generation of arrhythmia. This will allow us to understand how the fine-scaled properties of the scar and surrounding tissue make it susceptible to arrhythmias, identifying key 'hot spot' regions which represent the most dangerous potential sources of arrhythmic activity.We will then use this knowledge in comparison with patient MR and arrhythmia incidence data to make an important step towards translating these findings into the clinic, helping provide a mechanistic explanation of the underlying observed relationships uncovered in the clinical data.Overall, the findings from this research will pave the way for improved of risk stratification in patients with cardiac scars, and the development of novel clinically-useful therapies targeting the scar as a source of arrhythmia generation. The potential beneficiaries from this research will be extensive due to the high incidence of heart attacks annually in the UK (124,000), and the significant risk posed by arrhythmia to individuals following a heart attack. Consequently, this work also has the potential to reduce the health and economic costs of associated death and illness.