In silico Investigation of the Mechanisms of Abnormal Spontaneous Excitation from Cell to Organ - Insights on the Development of Atrial Fibrillation

在发达国家，房颤是导致发病率和死亡率增加的最常见的心脏疾病，但有效的临床治疗仍然存在问题。房颤是一种年龄相关性疾病，表现为心房(心脏上腔)快速而不规则的电活动，凌驾于正常起搏并干扰正常心律。这种电活动可能会导致进一步的并发症，包括心脏病发作和中风。最近的研究在了解房颤的进展方面取得了一些进展，但其潜在原因在很大程度上尚不清楚。为了有效地诊断和治疗这种疾病，迫切需要了解这些原因。异常的自发电活动(异位活动)可以中断正常的心率，并被认为是房颤的一种启动机制。细胞内钙离子循环的缺陷被认为是异位活动的可能原因，但对钙循环和异位活动之间的联系的了解还不完全。钙循环本身在微观尺度上依赖于复杂的细胞结构和随机过程，但心房颤动主要是一种器官尺度的现象。因此，解释多个尺度上的行为的方法对于详细研究异位活动是必不可少的。计算建模为研究多个尺度上的生物功能提供了一种强大的方法。然而，最先进的心脏模型还没有考虑到整个器官模型的微观细节。这个项目的目的是开发新的方法来克服这一限制，并解决以下问题：1.异位活动是如何发生的？2.疾病状态如何促进异位活动？3.异位活动在心房颤动的发展中起什么作用？这将通过在多个尺度上开发计算模型来实现，其中在最详细的模型中观察到的行为将在简化模型中被解释。首先，将开发详细的心房单细胞模型，以研究异位活动是如何发生的，该模型解释了复杂的结构和疾病状态。其次，将应用数学技术来简化模型，同时保留起源于微观尺度的行为。这些模型将被用来模拟多个耦合细胞，以研究异位活动如何同步。最后，将应用技术进一步简化模型，以便可以在整个心房的模型中解释同步行为，以调查单个细胞内起源的过程对组织行为的影响。该项目将设在复杂系统和统计物理组(曼彻斯特大学)，项目发起人艾伦·麦凯恩教授。将应用该小组目前使用的数学方法，以实现概述项目所需的简化。多名实验合作者已被选中，以促进该项目并提供模型开发和验证所需的实验数据；Mark Cannell教授(布里斯托尔大学)将提供细胞内心房结构重建；Antony Workman博士(格拉斯哥大学)将提供有关健康和疾病单细胞的数据集；Jonathan Jarvis教授(利物浦约翰摩尔大学)和Halina Dobryznski博士(曼彻斯特大学)将提供心房解剖的高分辨率重建。该项目的成果将是(I)更深入地了解异位活动和心房颤动的原因和行为，这将有助于有效地诊断和治疗这种疾病，以及(Ii)可用于研究进一步的心脏疾病并推广到其他系统中的细胞和器官行为的多尺度建模工具。

Atrial fibrillation is the most common cardiac disease leading to increased morbidity and mortality in the developed world, yet effective clinical treatment remains problematic. Atrial fibrillation is an age-related disorder identified by rapid and irregular electrical activity in the atria, the upper chambers of the heart, overriding normal pacemaking and interrupting normal heart rhythm. Such electrical activity can lead to further complications including heart attack and stroke. Recent studies have made some progress in understanding the progression of atrial fibrillation, but the underlying causes are largely unknown. There is a pressing need to understand these causes for effective diagnosis and treatment of the disorder.Abnormal spontaneous electrical activity ('ectopic activity') can interrupt normal heart rhythm and has been suggested as a mechanism of atrial fibrillation initiation. Flaws in the cycling of calcium ions within the cell have been suggested as a possible cause of ectopic activity, but understanding of the link between calcium cycling and ectopic activity is incomplete. Calcium cycling itself depends on complex cellular structure and random processes at the microscopic scale, but atrial fibrillation is primarily an organ scale phenomenon. Therefore, approaches which account for behaviour across multiple scales are essential for detailed investigation of ectopic activity.Computational modelling provides a powerful method of investigating biological function across multiple scales. However, state-of-the-art cardiac models do not yet account for microscopic detail in whole organ models. The aim of this project is to develop new approaches to overcome this limitation and address the following questions:1. How does ectopic activity occur?2. How do disease states promote ectopic activity?3. What role does ectopic activity play in the development of atrial fibrillation?This will be achieved through the development of computational models at multiple scales, wherein behaviour observed in the most detailed models will be accounted for in simplified models. Firstly, detailed models of the atrial single cell, which account for complex structure and disease states, will be developed to investigate how ectopic activity occurs. Secondly, mathematical techniques will be applied to simplify the models while preserving behaviour originating at the microscopic scale. These models will be used to simulate multiple coupled cells to investigate how ectopic activity synchronises. Finally, techniques will be applied to further simplify the models, such that the synchronised behaviour can be accounted for in models of the entire atria, to investigate the effect of processes originating within single cells on the tissue behaviour. The project will be based in the Complex Systems and Statistical Physics Group (University of Manchester) with project sponsor Prof. Alan McKane. The mathematical approaches currently used within this group will be applied to achieve the simplifications necessary for the outlined project. Multiple experimental collaborators have been selected to facilitate the project and supply experimental data necessary for model development and validation; Prof. Mark Cannell (University of Bristol) will supply reconstructions of intracellular atrial structure; Dr. Antony Workman (University of Glasgow) will supply datasets concerning healthy and disease single cells; Prof. Jonathan Jarvis (Liverpool John Moores University) and Dr. Halina Dobryznski (University of Manchester) will supply high-resolution reconstructions of atrial anatomy. The outcome of the project will be (i) a deeper understanding of the causes and behaviour of ectopic activity and atrial fibrillation, which will assist in effective diagnosis and treatment of the disorder, and (ii) a multi-scale modelling tool which can be used to investigate further cardiac disorders and generalised to cellular and organ behaviour in other systems.