Structure-function relationships in the aortic valve

Abstract

Globally, heart valve dysfunction constitutes a large portion of the cardiovascular disease load, causing high rates of mortality in European and industrialized countries. This is reflected in the database of the American Heart Association and the UK Valve Registry, showing a progressive increase in the number and age of patients in need of surgical interventions. Aortic valve (AV) dysfunction is significantly more prevalent than pathologies associated with other heart valves, accounting for approximately 43% of all patients having valvular disease. These statistics highlight the essential need for efficient and long term substitutes. However, the two types of replacement valves currently available in practice, i.e. mechanical and bioprosthetic valves, have only an estimated lifetime of around 10 years, after which the associated problems necessitate re-operation in at least 50-60% of the patients. Moreover, for patients under 35, the failure rate is nearly 100% within 5 years of the valve replacement surgery. The significant numbers of patients suffering from AV dysfunction, shortcomings to currently available valve substitutes, and the market demands for replacement valves has prompted increasing interest in the study of AV biomechanics. A fundamental study of the AV structure-function biomechanics is presented in this thesis. The mechanical behaviour of the AV is characterised at the tissue level, and the associated microstructural mechanisms established. In addition to the experiments, in depth mathematical models are developed and presented, to explain the observed experimental data and elucidate the micromechanics of the AV constituents and their contribution to the tissue behaviour. Tissue-level results indicate that the AV shows ‘shear-thinning’ behaviour, as well as anisotropic time-dependent characteristics. The microstructural experimental data indicates that there is no direct translation of tissue level mechanical stimuli to the ECM, implying that strain transfer is non-affine. Modelling micro-structural mechanics has confirmed that collagen fibres do not need to become fully straight before they contribute to load bearing, while the elastin network has been shown to contribute to load bearing even at high strains, further exacerbating the non-linear stress-strain relationship of the valve. The structural mechanisms underlying time-dependent behaviour of the tissue can be explained at the fibre level, stemming from fibre sliding and the dissipative effects arising due to fibre-fibre and fibre-matrix frictional interactions, suggesting a unified structural mechanism for both the stress-relaxation and creep phenomena. These outcomes contribute to an improved understanding of the physiological biomechanics of the native AV, and may therefore assist in optimising the design processes for substitute valves and selecting appropriate materials to effectively mimic the native valve function. Understanding AV micromechanics also helps quantify the mechanical environment perceived by the residing cells, which can have significant implications for cell-mediated tissue engineering strategies.