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

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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.