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

心房颤动是最常见的心脏病，导致发达国家发病率和死亡率增加，但有效的临床治疗仍然存在问题。心房颤动是一种与年龄相关的疾病，其特征是心房（心脏的上腔室）中的快速和不规则电活动，超越正常起搏并中断正常心律。这种电活动可能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，但其根本原因在很大程度上是未知的。目前迫切需要了解这些原因以有效地诊断和治疗这种疾病。异常的自发电活动（“异位活动”）可以中断正常的心律，并已被认为是房颤起始的机制。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联系的理解是不完整的。钙循环本身取决于复杂的细胞结构和微观尺度上的随机过程，但心房颤动主要是一种器官尺度的现象。因此，跨多个尺度解释行为的方法对于异位活动的详细调查是必不可少的，计算建模提供了跨多个尺度调查生物功能的强大方法。然而，最先进的心脏模型尚未考虑整个器官模型中的微观细节。本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.异位活动在房颤的发生中起什么作用？这将通过开发多尺度的计算模型来实现，其中最详细的模型中观察到的行为将在简化模型中得到解释。首先，详细的心房单细胞模型，它占复杂的结构和疾病状态，将被开发来研究异位活动如何发生。其次，数学技术将被应用于简化模型，同时保留微观尺度上的行为。这些模型将用于模拟多个耦合细胞，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，使得同步行为可以在整个心房的模型中被考虑，以研究起源于单个细胞内的过程对组织行为的影响。该项目将基于复杂系统和统计物理组（曼彻斯特大学）与项目赞助商艾伦·麦凯恩教授。该小组目前使用的数学方法将被应用于实现所概述的项目所需的简化。已经选择了多个实验合作者，以促进该项目，并为模型开发和验证提供必要的实验数据; Mark Cannell教授（布里斯托大学）将提供细胞内心房结构的重建;安东尼沃克曼博士（格拉斯哥大学）将提供关于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）将提供心房解剖结构的高分辨率重建。该项目的成果将是（i）更深入地了解异位活动和房颤的原因和行为，这将有助于有效地诊断和治疗这种疾病，以及（ii）多尺度建模工具，可用于进一步研究心脏疾病，并推广到其他系统中的细胞和器官行为。

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.