Multi-scale Approaches to Mechanical Contraction and Electrical Wave Conduction in A 3D Model of Human Atria during Fibrillation

One of the "grand challenges" of integrative biology is to predict the behaviour of an organ that emerges from integrated actions of molecules, ions, cells and tissues operating at multi-physical scales. Cardiac electro-physiology is sufficiently well established for developing a predictive model for the heart. However, successful simulations of cardiac dynamics requires not only well-validated mathematical model of cardiac electro-mechanics and anatomy, but also stable and efficient numerical algorithms for solving these models that are at multiple physical scales, highly complex and non-linear. The aim of this project is to tackle these challenges for human sinoatrial node - atria (SAN-atria) (the upper chambers of the heart), malfunction of that causes morbidity and mortality. We propose to develop a new generation 3D anatomical model of the SAN-atria with coupled electrical and mechanical dynamics, and a new family of numerically stable and efficient algorithms based on discrete element methods. Using the model, we shall quantify the functional impact of pharmacological interventions on atrial electrical and mechanic dynamics. The output of this project will be a family of novel computer models of human SAN-atria and efficient numerical algorithms for cardiac electro-mechanical modelling. The developed model and numerical solvers will be distributed for public access through our local research websites and international depository tools (www.cellML.org and www.fieldML.org).

The proposed project is fundamental research. Its immediate beneficiaries are most likely to be academic. In long term, it may also have potential impacts on economy and public health.

I. Specifically, we identify the following groups of immediate potential beneficiaries:

- Researchers working in mathematical modelling of cardiac arrhythmias.

Benefits: the new numerical method that we shall develop will provide a stable and efficient algorithm to the community that will stimulate further research.

- Cardiac electrophysiology: experimentalists studying re-entrant arrhythmia in cell cultures, tissues and animals.

Benefits: predictions obtained by mathematical modelling using the models we develop are testable experimentally and are potentially relevant for biomedical applications.

- Nonlinear science: researchers working in the theory and applications of excitable media and in the theory of other nonlinear self-organized dissipative structures.

For this group, the benefits will be of a similar kind to the first group above. Excitable media in general, and spiral and scroll waves in particular, have been predicted and observed in a wide variety of spatially extended thermodynamically non-equilibrium systems of various physical, chemical and biological origin. The numerical algorithms we develop here will be easily adaptable to those kinds of models, and most advantages provided by it will be relevant in those applications, too.

- Applied mathematicians and software developers.

This group are also likely beneficiaries, as the practical solutions we will develop may be applicable in other areas.

For the groups above, the ways to ensure the delivery of benefits will be traditional, via providing free access to the algorithm via local and international depository sites, and publications in primary research journals and relevant conferences. The associated time scales are minimal, as the benefits will start immediately upon publication and we choose journals that publish quickly.

II. The impact on public health and wealth creation will be through long-term potential beneficiaries. Speculatively, if our study will lead to the expected improvements in efficiency of anti-arrhythmic drugs, or deeper understanding of the mechanisms underlying the genesis and control of atrial fibrillation, such long-term beneficiaries would be:

- pharmaceutical companies that manufacture antiarrhythmic drugs, who will develop new classes of drugs based on the new understanding of the dynamics of cardiac arrhythmia;

- companies that manufacture electronic pacemakers and implantable defibrillators, who may improve the efficiency or decrease harmful side-effects of atrial conversion protocol of their devices;

- clinicians and the NHS, who will have new more efficient methods of treatment of cardiac arrhythmia at their disposal, with fewer harmful side-effects, and lower treatment and care costs.

- cardiac patients, whose life expectancy and quality of life will improve,

- general public, through tax revenue of the industries involved, lower burden on NHS and prolongation of the active life of the ageing population.

These benefits will be delivered indirectly via subsequent, more applicable research projects, both by other researchers and by ourselves, that will utilize the results of this project. The time scales here are hardly predictable but in any case it will be many years, as is usually the case with new medical treatments.

There is a possibility that some of the results obtained with this project will be directly exploitable. In such cases, we will contact relevant University offices.