Growth and Remodelling in the Porcine Heart-- Pushing Mathematics through Experiments

Cardiovascular disease (CVD) is the leading cause of disability and death in the UK and worldwide, with an estimated £19bn annual economic impact. The prevalence of acquired heart disease (e.g. coronary heart disease, which can lead to myocardial infarction), particularly in the elderly population, means that this is the dominant public health problem in our society. Scope remains for more effective clinical management of CVDs, in part due to the poor correlation between symptoms and causation. Significant potential exists in developing novel and innovative solutions to lead towards patient-specific interventions, which have already achieved enhanced outcomes within other clinically-demanding specialities.
Computational modelling provides a platform for forward and inverse analysis of cardiac mechanics. Soft tissue modelling enables integration of multi-scalar structure-function and FSI, and presents an emerging opportunity for investigating CVD-based, patient-specific interventions and is already being exploited to improve knowledge of myocardial infarction, evaluation of novel graft materials and assessing the vulnerabilities of atherosclerotic arteries to the plaque. The value of such simulations is a function of accurately representing tissue behaviour, via constitutive models. Existing models consider the tissue's anisotropic, hyperelastic response, but with limited studies on growth and remodelling (G&R) and data derived age-specific behaviour. Recent adult myocardium experimental studies also demonstrated the importance of viscoelastic tissue properties, which are generally ignored in heart modelling. This study will deliver experimentally based G&R laws with viscoelasticity that increase the accuracy of age-specific, cardiac tissue-behaviour simulations. Twinned with increasing computational capabilities, this is an important next-step towards realising patient-specific cardiac treatments.
We have designed an experimental programme that provides data for generating new G&R constitutive laws, from porcine tissue across 6 G&R stages. We will measure critical structural parameters including collagen and cardiomyocyte fibre orientation and dispersion, and biomechanical parameters including bi-axial, simple shear and stress-relaxation. We will also biochemically and biologically analysis these tissues, to allow cross-mapping to human studies. These data will then enable generation of new constitutive models, based on the framework developed by the Glasgow group. These have been used successfully to simulate the 3D dynamic finite strain LV mechanics, using the structure-based HO constitutive law, coupled with cardiac active contraction and FSI. We will hypothesis-test the new G&R laws by acquiring in vivo porcine ultrasound data, to allow derivation of p-v curves, blood flow rate and pressure. We will also map this behaviour to equivalent phases of human maturation.
The experimentally based G&R laws will represent significant progress versus the existing international capabilities of modelling in cardiac tissues. It should bring nearer the ambition of achieving patient-specific surgeries to enable more effective treatment of acquired heart disease and other CVDs. Our work will also set a foundation and reference for subsequent studies focused on G&R in disease progressions and potential clinical intervention. Our approach will provide a platform for others to exploit these principles and methodologies across a broader research area, which could include monitoring and managing progression of general heart diseases. Our work will also contribute towards worldwide academic basic and applied sciences, as well as the translational (healthcare) domain. We will provide the first combined experimental and theoretical approach to G&R of a natural porcine heart, establishing a database of structural and biomechanical changes mapped to human physiology, which will be available for interrogation to support further research.

The research proposed here would have a combination of short- and long-term beneficiaries, and with continued effort, will offer long-term social and economic benefit.

Academic impact: The most direct impact will be the training of the two PDRAs, as well as training of PhD, MSc and final year undergraduate project students across the three universities. This research, defining viscoelastic G&R laws for the healthy heart, will also provide a valuable reference that scientists and clinicians can use to plan and develop new intervention strategies. For example, our work will provide a valuable database of the key changes in geometry and material properties associated with growth and, by modelling, we can show: how this evolution will affect the stress and strain distributions within the heart; what drives the growth laws; and what parameters changes (e.g. myocyte alignment) are strongly associated with ageing. Using such a multidisciplinary approach for such a topical medical problem, the project will broaden the base of researchers engaged in CVD treatment and diagnostics through a combination of project-associated seminar programme, and SofTMech bi-monthly meetings. Outside the three universities, researchers engaged in heart research will gain access to our open source software, as well as journal publications and conference presentations.

Socio-Economic impact: CVDs and chronic heart disease, in particular, cause nearly 74k deaths each year in the UK, equivalent to an average of nearly 200 people dying every day. They also cause a £19bn annual economic impact. Myocardial infarction in younger adults, particularly in women is currently a hot topic in cardiovascular medicine. The current proposal aims to provide new insights into the consequences of, and patient-specific interventions to assist, ageing myocardial tissue. Identification of specific G&R laws in healthy and diseased hearts can result in novel treatments. This is because cells within the tissue are balanced in homeostasis. Ageing or diseases disturb this, and cells remodel to reach a new state of homeostasis. One questions is when the fibroblast cells deposit and remodel collagen, do they act as over-stretched (strain-driven), or over-stressed (stress-driven)? These different scenarios are the same for a linear elastic material but not for the anisotropic myocardium. Clarifying the two mechanisms will lead to novel treatments: for strain-driven processes, therapies that restrain deformation are crucial; for stress-driven processes, control of pressure and stiffness are more effective. Our work will lay the foundation for future work on heart diseases, e.g. myocardial infarction in young and aged-subjects. We will organize a special Heart-day meeting at which our clinical collaborators, as well as researchers from other user groups (e.g. from Golden Jubilee National Hospital Glasgow Royal Infirmary, Vascutek, Wolfram Research), will be invited to participate, with the aim to identify new partners for further research.

User engagement: The team is ideally placed to maximise the impact generated from the research, with clinical input hardwired into the project. Prof Berry, a clinical academic and Consultant Cardiologist, is a co-investigator and will ensure that this work remains grounded within clinical reality. Strong clinical links also exist between the applicants and the other clinical groups at theBHF Glasgow Cardiovascular Research Centre and the Golden Jubilee Hospital, via the GlasgowHeart project. The project proposed here also draws upon a substantial body of UK and international expertise outside Glasgow.

Other public engagement will include Glasgow Science Festival activities, School open days, Family/Patient groups, production of YouTube videos, displaying posters and animations in lay language in the Glasgow Kelvingrove Museum, and broadcasting our work in the University of Glasgow Research Radio show.