Understanding the impact of the microvasculature on quantification of fibre orientation in the heart using Diffusion Spectrum MRI and computer models

The heart is a highly efficient and effective electro-mechanical pump for supplying the continue flow of blood that is essential for life. The critical importance of its function is represented by the very high number of deaths associated with heart disease both in the UK and the western world. The pump function crucially depends on the complex architecture of the heart: individual muscle cells are arranged in chains often referred to as muscle fibres. These muscle fibres are ordered in complex three-dimensional (3D) arrangements, joined together by non-muscle 'connective' tissue. In addition, an extended network of blood vessels is embedded within the heart muscle to provide vital blood supply to the individual cells. It is this micro-structural architecture that fundamentally defines both the electrical conductivity and mechanical stiffness of the muscle wall, and thus determines the function of the heart.
This central role of cardiac micro-structure in both, health and disease has motivated the development of non-invasive techniques to image cardiac structure. Particularly, Magnetic Resonance Imaging (MRI), which allows for increasingly detailed insight into the structure and function of tissues and organs. The value of MRI data means this type of imaging has gained rapid acceptance within both the pre-clinical and clinical domains. Even though these recordings are not yet sufficiently detailed to reliably identify fibre orientation in hearts of individual patients, major research efforts are underway to achieve this goal.
Underpinning these efforts is that a precise understanding of detailed cardiac tissue architecture will be of great importance for an accurate diagnosis of cardiac diseases, prediction of their progression, and identification of useful treatment approaches. The key role of the heart's structure also means that MRI data are increasingly being used to validate computer models, which describe the electrical conductivity and mechanical function of the heart. These computer models of the heart are not only essential in basic science research, but will also play a fundamental role in personalized medicine where doctors can use these models to assess treatment options, and predict treatment outcomes for a specific individual before the patient even enters the operating theatre.
However, there is a fundamental question that has to be answered before this technique can be considered as a reliable tool for structural assessment in the heart: is the reading of MRI indeed reflecting the orientation of the muscle-fibres, or is it dominated by the many (small) blood vessels supplying the heart muscle with nutrients? The answer to this question is of particular relevance for the diseased heart, where the highly regular micro-structure (fibres and blood vessels) of the muscle is distorted.
This proposed project exactly aims to answer this open question by combining the expertise of leading teams in cardiac MRI (Cardiovascular Medicine at the John Radcliffe Hospital Oxford), and image analysis and computational modelling (Department of Bioengineering, Kings College London). The teams will jointly develop techniques and validate them in small rodents models, with the vision that all algorithms can in future be adapted to the investigation of human hearts.

Several areas/groups of beneficiaries of the proposed project can be identified:
Firstly, the project will facilitate and benefit pre-clinical research. Given the multi-disciplinary nature of the project, the two PIs and their Departments represent large sections of this group, including basic bio-research, image analysis/modelling of biological systems, cardiovascular medicine, and magnetic resonance imaging. Furthermore, the PIs have strong network collaborations at national and international levels (as partially reflected in this proposal). Because the outcome of this proposal is of direct relevance for the research of our teams and their collaborators in areas such as structure-function studies, structural-vascular interactions research, (for an illustration, see lists of publications of the PIs) we anticipate the impact of our work to be rapidly disseminated across this network.
Secondly, in the longer run, the project will serve the medical community by paving the way for development of new tools and models to aid the diagnoses, patient selection, planning and optimisation of interventions, and tailoring of treatments. This work will ultimately improve prognosis for patients with heart disease, whether congenital or acquired.
Thirdly, the project embraces the concept of the 3Rs (Reduction, Refinement, and (partial) Replacement of animal-based research). Advancing MR techniques to be applicable, non-invasively, to high-fidelity structure-function studies enables a reduction in the number of animals required for research. This finds reflection in our study design, where each heart serves as its own control (using multiple imaging modalities; going from in vivo to ex vivo). Stringent intra-individual control and validation provides more powerful statistical analyses in an otherwise highly inhomogeneous biological model. The development and cross-validation of computer models further helps to reduce the use of animals for research, development, and teaching.
Fourth, it is clear that there is significant potential for commercial benefit. This includes manufacturers of preclinical magnetic resonance systems, who will be able to assess the benefit of newly developed MRI techniques; providers of biomedical image analysis and visualisation software who will have access to new image alignment and structure extraction tools; and - in the longer run - pharmaceutical companies who will eventually benefit from the availability of new technologies to test the efficacy and side effects of drugs using either the newly developed imaging techniques or the computational models that will arise.
Last but not least, considering the burden heart disease places on individuals, their families, the economy, and the social and health systems in the developed world, the techniques and tools provided by this proposal will be of general societal benefit, as the outcome of this work will fundamentally contribute to the understanding of normal and patho-physiological structural-mechano-interaction in the heart.