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

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.

The mechanisms underlying the initiation and development of atrial fibrillation (AF) are not well understood. Ectopic activity can mediate the development of re-entrant excitation and has been implicated in the genesis and recurrence of AF. This project aims to investigate the mechanistic link between malfunctions of the intracellular calcium handling system and the development of ectopic activity, and their translation into organ scale dynamics.
This will be achieved through the development of mathematical models of the rabbit and human atria in three stages. Firstly, 3D single cell models of the coupled atrial intracellular calcium handling and membrane ion current systems will be developed, incorporating realistic intracellular micro-architecture. A finite element method incorporating Gillespie's algorithm will be implemented. The models will be used to investigate the role of electrical remodelling and sympathetic activity in the genesis of triggered behaviour. Secondly, mesoscopic physics techniques will be applied to reduce the resolution of the single cell models while preserving behaviour originating from stochastic processes at the microscopic scale. This will be achieved primarily through introducing stochastic noise terms to deterministic equations, such that the effect of stochastic processes on localised collections of ion channels and intracellular processes can be accounted for. Multiple cells will then be coupled together to investigate the mechanisms underlying synchronisation of triggered activity. Finally, the mesoscopic approach will be extended to translate synchronised triggered activity into organ-scale models. Combined with realistic reconstructions of atrial anatomy, the role of ectopic activity in the development of AF will be investigated.
The project will produce deep understanding of the mechanisms of AF, facilitating improved treatment of the disorder, as well as a multi-scale framework for the investigation of cardiac arrhythmias.

This research project will improve understanding of the mechanisms of atrial fibrillation (AF), benefiting the health and wellbeing of millions of people around the world. The project results will help to identify markers for the onset and vulnerability of AF, direct forms of clinical treatment (such as catheter ablation therapy and pharmaceutical research) and contribute significantly to the global effort to better understand, prevent and treat the disorder. Because AF is age-related, the benefits will be particularly realised in the aged population. Within this population, improved prevention and treatment of AF will facilitate living an active lifestyle (which AF can inhibit) and therefore will also have benefits on social welfare. Such benefits are expected to be realised over the next 5-20 years.
Project results will suggest potential targets for pharmacological modulation of AF. This will provide a focus for future industrial research, applicable to companies such as AstraZeneca, and contribute to improved non-invasive AF treatment. Translation of project results to pharmaceutical research will not be immediate, and hence benefits are anticipated to be realised over the next two decades. Research projects which follow this one, with a focus on inhibition of the AF mechanisms elucidated within this project, will help to achieve this goal.
Improved treatment and diagnosis of AF will also have significant benefits to the NHS, increasing its efficiency. Because AF predisposes to further heart conditions as well as stroke, improved treatment of AF will significantly relieve NHS resources. Moreover, AF directly accounts for just under 1% of the total annual costs to the NHS; this figure is increased to 3-5% if the indirect consequences, such as heart failure and stroke, are accounted for. Improved efficacy in treatment as well as prevention of further disorders developing will significantly reduce this cost, providing economic benefits.
The approach of the project, rather than the project results, will also have wider impact in the research community as well as wider society, including schools. The project uses a significant interdisciplinary approach - drawing on skills in mathematics, physics, biology and computational science, as well as including both modelling and cutting- edge experimental techniques. This approach is generalisable to other systems of excitable cell, and therefore provides a multi-scale modelling framework to facilitate research in multiple fields. Furthermore, such an approach can be used to enthuse school children (and the wider public) about interdisciplinary research and demonstrate the application of STEM courses to solve medical problems. This will therefore encourage more students to undertake STEM courses at higher education levels as well as encouraging interdisciplinary thinking and approaches from a young age. This will help keep the UK at the cutting-edge of scientific research, in a world where the boundaries between disciplines are becoming increasing blurred. Such an approach will also help with public engagement with science, and increase awareness of both AF and the fact that STEM subjects can be used in medical research. Benefits will range from the immediate (within just a few years) to the long term (the next generation of scientists). This too will therefore have economic impacts and improve the competitiveness of the UK. Raising awareness about the application of physics and mathematics to medical research will also inform policy makers and encourage further investment into schemes focusing on this type of research, such as many of those offered by the MRC, which are becoming an increasingly important factor in systems biology approaches to biomedical research.
Finally, the use of the developed models as 'virtual cells' for experimental work could significantly contribute to a reduction of animal use in biomedical research.