Quantification of leaflet flutter in bioprosthetic heart valves using fluid-structure interaction analysis

Many studies have indicated that leaflet fluttering and associated bending in biopros-thetic heart valves (BHVs) is an important criterion in determining the durability of BHVimplants. In this thesis work, a computational methodology for the flutter quantificationof BHV leaflets is presented using an immersogeometric fluid–structure interaction (FSI)framework. The proposed approach is based upon displacement tracking of the BHV leafletfree edges. Integrating over the discrete Fourier transform of free edge displacement data,the energy spectral density is computed for a measure of leaflet flutter. This methodologyseeks to improve approaches used in experimental flutter quantification through utiliza-tion of highly accurate simulation solutions and visualizations to capture a measurement ofleaflet flutter. A set of sampling cases with varying valve material thickness are generatedand FSI-based flutter quantification is performed to investigate the effect of leaflet materialthickness on the presence of flutter and bending in BHVs

Extended Duration Simulation and Testing of Cellular and Decellularised Heart Valve Roots

Heart valve disease can affect people of all ages, and can be treated by either valve repair or valve replacement surgery. Currently available replacement heart valves, including mechanical prostheses, bioprostheses, autografts and allografts improve patient survival and quality of life, but have limitations. Key limitations include the risk of immunological reaction and the lack of growth potential and regeneration, which is of particular importance in young patients. To address these limitations, low concentration sodium dodecyl sulphate (SDS) decellularised human aortic, human pulmonary, porcine aortic and porcine pulmonary heart valve roots have been developed. Decellularisation of allografts would potentially reduce the risk of immunological reaction, and the development of a decellularised porcine pulmonary heart valve root would potentially provide an option for right ventricular outflow reconstruction in younger patients who have undergone the Ross Procedure. Before moving to clinical trials, the functional performance of decellularised heart valve roots needs to be pre-clinically assessed appropriately to determine mechanical safety. Whilst there are recommended test methods in place for the in vitro functional performance assessment of newly manufactured and modified surgical replacement heart valves, they need to be optimised or replaced with novel methods suitable for decellularised heart valve roots, due to their time dependent viscoelastic properties. The main aim of this research was to optimise in vitro hydrodynamic and biomechanical performance test methods and develop a novel real time fatigue test method for biological heart valve roots. The secondary aim was to apply the developed in vitro test methods to cellular and decellularised (human and porcine) heart valve roots to evaluate the effect of decellularisation, prior to the decellularised heart valve roots being implanted in patients for clinical trials. In collaboration with NHS Blood and Transplant, Tissue and Eye Services, in vitro biomechanical and hydrodynamic performance of decellularised human aortic and pulmonary heart valve roots was evaluated for the first time in this research. This research determined that the hydrodynamic and functional biomechanical performance of human aortic and pulmonary heart valve roots was not affected by decellularisation treatment. Decellularisation, however, significantly altered some of the directional material properties of pulmonary and aortic heart valve root leaflets. To support clinical translation of decellularised porcine pulmonary heart valve roots, material properties of pulmonary heart valve roots was evaluated following 12 months implantation in sheep. In addition, the effect of the processing steps of cryopreservation and decellularisation on the material properties of porcine pulmonary heart valve roots was investigated. Cryopreservation was shown not to alter the material properties of cellular porcine pulmonary heart valve roots, however, decellularisation did have an effect on the material properties of the porcine pulmonary heart valve root wall. Following 12 months implantation in sheep, the decellularised porcine pulmonary heart valve root wall and leaflets showed a trend for decreasing stiffness and strength; becoming more like the cellular ovine, potentially indicating constructive remodelling. A novel method was developed to investigate the real time fatigue of biological heart valve roots, which was then applied to porcine cellular aortic heart valve roots and porcine decellularised aortic heart valve roots at 120 bpm under physiological cyclic pressures for a maximum of 1.2 million cycles. The results showed no fatigue difference between the cellular and decellularised heart valve roots. Overall, a portfolio of in vitro pre-clinical test methods were developed, optimised and applied to assess the hydrodynamic, biomechanical and fatigue performance of biological heart valve roots including decellularised human and porcine heart valve roots. The in vitro pre-clinical test methods developed in this study will lead to the refinement of in vivo large animal studies and revision of international standards; and the data will help in the development of the next generation of replacement biological heart valve roots, such as decellularised heart valve roots

Mechanics of the tricuspid valve: from clinical diagnosis/treatment, in vivo and in vitro investigations, to patient-specific biomechanical modeling

Proper tricuspid valve (TV) function is essential to unidirectional blood flow through the right side of the heart. Alterations to the tricuspid valvular components, such as the TV annulus, may lead to functional tricuspid regurgitation (FTR), where the valve is unable to prevent undesired backflow of blood from the right ventricle into the right atrium during systole. Various treatment options are currently available for FTR; however, research for the tricuspid heart valve, functional tricuspid regurgitation, and the relevant treatment methodologies are limited due to the pervasive expectation among cardiac surgeons and cardiologists that FTR will naturally regress after repair of left-sided heart valve lesions. Recent studies have focused on (i) understanding the function of the TV and the initiation or progression of FTR using both in-vivo and in-vitro methods, (ii) quantifying the biomechanical properties of the tricuspid valve apparatus as well as its surrounding heart tissue, and (iii) performing computational modeling of the TV to provide new insight into its biomechanical and physiological function. This review paper focuses on these advances and summarizes recent research relevant to the TV within the scope of FTR. Moreover, this review also provides future perspectives and extensions critical to enhancing the current understanding of the functioning and remodeling tricuspid valve in both the healthy and pathophysiological states

Production and characterisation of acellular porcine pulmonary heart valve conduits

Cardiac valve replacement is the second most common heart operation. Currently available replacement heart valves all have limitations. This study aimed to produce and characterise a decellularised, biocompatible porcine pulmonary root conduit for use in the Ross procedure. A process for the decellularisation of porcine pulmonary roots was developed incorporating trypsin (2.25 × 104 Unit.ml-1) digestion of the adventitial surface of the scraped pulmonary artery and sequential treatment with: hypotonic Tris buffer (HTB; 10mM Tris pH 8.0, 0.1% (w/v) EDTA, 10KIU aprotinin), 0.1% (w/v)SDS in HTB, two cycles of DNase and RNase, and sterilisation with 0.1% (v/v) peracetic acid. Histology confirmed an absence of cells and retention of the gross histoarchitecture. DNA levels were reduced by >90 % throughout the decellularised tissue and functional genes were not detected using PCR. Immunohistochemistry showed a lack of α-gal epitopes and confirmed cell removal but a loss of collagen IV. In vitro biocompatibility studies indicated the decellularised leaflets were not cytotoxic while the pulmonary wall was shown to reduce 3T3 cells viability in 3 out of 6 samples. Uniaxial tensile testing to failure demonstrated no significant difference in the tensile properties between the fresh and decellularised leaflets and pulmonary walls in the circumferential and radial directions with the exception of the elastin phase slope of the pulmonary artery in both directions which showed a significant decrease in the decellularised tissue. Pulsatile flow testing indicated the decellularised pulmonary roots had excellent hydrodynamic function and leaflet kinematics in comparison to the fresh tissue. Initial attempts to culture fresh pulmonary roots in a heart valve bioreactor were unsuccessful, indicating a need to develop the physiological culture system further. Overall the decellularised porcine pulmonary roots have excellent potential for development of a tissue engineered solution for right ventricular out flow tract reconstruction during the Ross procedure

Computed tomography and positron emission tomography in the assessment of aortic valve disease

Introduction Native and bioprosthetic aortic valve diseases are an increasingly common clinical challenge as a consequence of the ageing demographic and the expansion of new valve technology. In both conditions, there remains substantial scope to broaden our understanding of the pathophysiology, improve diagnostic sensitivity and accuracy, and develop new markers of disease activity with which to measure therapeutic effect. Computed tomography (CT) and positron emission tomography (PET) are non-invasive imaging assessments that combine high resolution anatomical detail with real-time functional information about disease activity, and as such are ideally suited to complement echocardiography in the investigation of native and bioprosthetic aortic valve diseases. Methods Aortic Stenosis Volunteers with aortic stenosis (n=143) across a range of severity underwent echocardiography, CT aortic valve calcium scoring and contrast-enhanced CT angiography. Aortic valve fibrosis and calcification were quantified to produce two novel measures: the fibro-calcific ratio and fibro-calcific burden. From the same study population, a subset of 15 volunteers underwent hybrid 18F-fluoride PET/CT on two separate occasions and we investigated different methods of image analysis to optimise accuracy and reproducibility. Bioprosthetic Valves Explanted degenerated bioprosthetic valves (n=16) were examined ex vivo using histopathology and preclinical 18F-fluoride PET/CT. Patients with bioprosthetic aortic valves (n=78) were then recruited into two cohorts, with and without prosthetic valve dysfunction, and underwent in-vivo contrast-enhanced CT angiography, 18F-fluoride PET, and serial echocardiography over 2 years of follow-up. Results Aortic Stenosis Contrast-enhanced CT calcium volume correlated closely with conventional CT calcium score in the aortic valve (r=0.86, p=<0.001). Fibrosis dominated in mild aortic stenosis while calcification dominated in severe stenosis (fibro-calcific ratio: 1.33 [0.91-2.4]) versus 0.53 [0.35-1.05] respectively; p=0.001). Males exhibited more calcium than fibrosis, with the reverse true for females (fibro-calcific ratio: 0.89 [0.45-1.54] versus 1.49 [0.82-5.74] respectively; p=0.001). The fibro-calcific burden demonstrated the strongest correlation with peak aortic-jet velocity (r=0.71, p<0.001), especially in women (r=0.77, p=0.001) where it outperformed CT calcium score (p=0.027). In our investigation of 18F-fluoride-PET/CT, contrast-enhanced, ECG-gated PET/CT provided superior spatial localisation of 18F-fluoride uptake. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in variability from 25% to <10%. Bioprosthetic Valves In degenerated bioprosthetic valves ex vivo, calcification was the most prevalent pathological feature (87%), whilst thrombus (40%) and pannus overgrowth (47%) were other common findings. All valves exhibited 18F-fluoride uptake on PET, with a strong positive correlation between 18F-fluoride uptake and calcium volume (r=0.73, p=0.0031). 18F-Fluoride uptake was highest in regions of leaflet calcification but also localised to regions of organised thrombus, fibrosis and features of matrix degradation on histopathology. In the cohort study of patients with bioprosthetic aortic valves, all those with recognised valve dysfunction exhibited abnormalities on CT and high 18F-fluoride uptake. In the 71 patients without valve dysfunction, 20% had leaflet pathology on CT and 34% had increased 18F-fluoride uptake (target-to-background ratio 1.55 [1.44-1.88]). Patients with increased 18F-fluoride uptake exhibited more rapid deterioration in valve function than those without (annualised change in peak transvalvular velocity: 0.30 [0.13-0.61] versus 0.01 [-0.05-0.16] ms-1/year, p<0.001). 18F-Fluoride uptake correlated with deterioration in all echocardiographic measures of valve function (e.g. change in peak velocity, r=0.72; p<0.001) and, on multivariable analysis, was the only independent predictor of future bioprosthetic dysfunction. Conclusions In both native aortic valve disease and bioprosthetic valve disease, CT and 18F-fluoride PET afford valuable insights into disease mechanisms, inform patient risk stratification and prognosis, and provide biomarkers of disease activity that may be used for the development of future therapeutic interventions

The Mechanical Properties of Native Porcine Aortic and Pulmonary Heart Valve Leaflets

Aortic heart valves and their replacements fail in vivo for reasons that are not fullyunderstood. Mechanical evaluation and simulations of the function of native aorticvalves and their replacements have been limited to tensile and biaxial tests that seek toquantify the behavior of leaflet tissues as a homogenous whole. However, it is widelyunderstood that valvular tissues are multi-layered structures composed of collagen,elastin, and glycosaminoglycans. The mechanical behavior of these layers within intactvalve leaflet tissues and their interactions are unknown. In addition, pulmonary valveshave been used as substitutes for diseased aortic valves without any real understanding ofthe mechanical differences between the aortic and pulmonary valves. The pulmonaryvalve operates in an environment significantly different than that of the aortic valve and,thus, mechanical behavioral differences between the two valve leaflets may exist. In thisstudy, we sought to determine the mechanical properties of the porcine aortic andpulmonary valves in flexure, and to determine the mechanical relationship between theleaflet layers: the fibrosa, spongiosa, and ventricularis. This was accomplished bydeveloping a novel flexure mechanical testing device that allowed for the determinationof the flexural stiffness of the leaflet tissue was determined using Bernoulli-Eulerbending. Moreover, transmural strains were quantified and used to determine thelocation of the neutral axis to determine if differences existed in the layer properties ofthe fibrosa and ventricularis. To contrast the flexural studies, biaxial experiments werealso performed on the aortic and pulmonary valves to determine the mechanicaldifferences in the tensile behavior between the two leaflets.Results indicated that the pulmonary valve is stiffer than the aortic valve inflexure but less compliant than the aortic valve in biaxial tensile tests. The interactionsbetween the layers of the leaflets suggest an isotropic mechanical response in flexure, butdo so through mechanisms that are not fully understood. For heart valve leafletreplacement therapy, this study illustrates the biomechanical differences between theaortic and pulmonary valve leaflets and emphasizes the need to fully characterize the twoas separate but related entities. Understanding the interactions of microscopic structuressuch as collagen and elastin fibers is critical to understanding the response of the tissue asa whole and how all these elements combine to provide a functioning component of theorgan system