Computational modelling of normal and hypertrophic cardiac electromechanics from diffusion tensor imaging and histology

Cardiac hypertrophy is a disease in which the heart is enlarged, and is associated with an increased risk of ventricular fibrillation, an often fatal arrhythmia where the normal electrical and mechanical activity of the heart is disturbed and the heart stops pumping blood.
The aim of this project is to develop computer models of the heart that can be used to investigate the causes of ventricular fibrillation during hypertrophy, and potential ways of reducing the risk of such arrhythmias occurring.
The shape and structure of the heart in both normal and hypertrophic conditions will be determined using a technique known as diffusion tensor magnetic resonance imaging (DT-MRI). As little is known about how the structure of the heart varies between individuals, or from species to species, libraries of heart shape and structure will be produced that will allow comparisons to be made.
Using this information, along with more data obtained using the techniques of histology and immunohistochemisrty, mathematical descriptions of the heart‘s electrical and mechanical activity will then be developed. The resulting electromechanical models will contract and change shape, something that current models do not do.
These models will then be used to examine ventricular fibrillation in the hypertrophied heart.

Aims and Objectives.
Individuals with cardiac hypertrophy have a significantly increased risk of ventricular fibrillation, an often fatal arrhythmia. Computational cardiac models provide tools for examining the mechanisms underlying the onset of such arrhythmias and interventions aimed at either preventing this onset or restoring normal sinus rhythm, as the data they provide can be dissected in time and space, and by parameters. The aims of this project are to develop biophysically detailed, contracting electromechanical continuum models of the ventricles, and use these models to evaluate the mechanisms of ventricular fibrillation development in hypertrophy, and the electromechanical consequences of such an arrhythmia.

Design and Methodology.
Diffusion tensor magnetic resonance imaging (DT-MRI) will be used to obtain libraries of normal and hypertrophic ventricular geometries and architectures. DT-MRI gives diffusion tensors throughout a tissue, from which can be computed fibre and sheet orientations along with tissue anisotropies. Electrophysiological heterogeneities throughout the ventricular myocardium will be mapped using histology and immunohistochemistry. Analysis of these data will reveal the inter- and intra-species variations in the organisation of the cardiac architecture and the spatial distribution of the electrophysiological heterogeneities. Biophysically detailed electromechanical continuum models of the ventricles will then be developed that incorporate spatially heterogeneous membrane excitation, excitation-contraction coupling and normal/abnormal intracellular calcium dynamics, the resultant deformation, and mechanoelectric feedback, with both normal and hypertrophic excitation and contraction parameters, geometries and architectures. The models describing electrophysiology will be high order systems of nonlinear ordinary differential equations to simulate excitation in cells, or reaction-diffusion partial differential equations to simulate propagation through tissue; the mechanics and deformation of the heart will be described by continuum mechanics and modelled using finite element methods. The geometries and architectures of the developed models will be extracted from the libraries obtained using DT-MRI. Simulation, visualisation and analysis of ventricular fibrillation in hypertrophy will carried out on high performance computing resources utilising novel parallelisation and integration methods.

Scientific and Medical Opportunities of the Study.
It is anticipated that the results will significantly contribute to the understanding of cardiac electrophysiology and mechanics, and the mechanisms underlying the onset of ventricular fibrillation in hypertrophy. Datasets and models will be made publicly available for use by other researchers.