Flow Characterization Under Idealized Stenosis Geometry and Performance Assessment of the Hemodynamic Flow Facility

It is well known that regions inside the human arterial network susceptible to atherosclerosis experience a complex flow environment. Endothelial Cells (ECs) lining the inner wall of arteries are sensors to spatially and temporally varying shear stress (i.e. wall shear stress gradients). This complex force-loading can disrupt local cell-to-cell attachment regions triggering a cascade of biological events leading to the formation of atherosclerotic lesions. Consequently, researchers predominantly use a Parallel Plate Flow Chamber (PPFC) to study the hemodynamic-cell cycle relationship due to its simplicity and ability to achieve a two-dimensional fully-developed steady laminar flow across the cell monolayer. Researchers also resort to a PPFC with a vertical step to disrupt the incoming steady and/or pulsatile flow and, thus, generate a complex force-loading on the live ECs. The present study is focused on the development and validation (by means of quantifying all elements of the design, performance and experimental uncertainty) of a hemodynamic flow facility allowing two-component ( ) Laser Doppler Velocimetry (LDV) measurements as close as 40 µm from the cell monolayer inside the PPFC. The study uses a backward-facing step (BFS) with 50% area reduction to model an idealized stenosis and, hence, disturb the incoming steady and pulsatile laminar flow. To provide insight not only into the fluid dynamic comparison but also on how the BFS models wall shear stress (WSS) and its spatial and temporal gradient (along with the oscillatory shear index, OSI) in a stenosed tube representing an artery, a detailed quantitative comparison with more realistic models of stenosis is provided (i.e. carotid artery phantom). To the best of the author’s knowledge such a quantitative comparison is not available in the literature. In addition, the present study provides mean flow and turbulence statistics downstream of the BFS, thereby adding knowledge to stenosed cases (away from the wall in the developing shear layer) allowing Computational Fluid Dynamics (CFD) modelers to reference experimental data when simulating intermittent turbulent flows. The results indicate that despite the simplicity of the chosen geometry, the measured flow downstream of the BFS under steady and pulsatile flow exhibits a number of features that are documented in previous work with more realistic configurations of stenoses (i.e. asymmetric tube stenosis). The author believes this simple geometry will set the stage for more advanced studies in the PPFC with more realistic geometrical configurations of stenoses. Lastly, additional work with live ECs cultured inside the PPFC can be undertaken under disturbed flow conditions reported in the present investigation

Development of a haemodynamic model for improving clinical treatment of vascular disease

Atherosclerosis is a chronic artery disease that leads to heart attack and stroke; affecting millions of people worldwide. It tends to develop in locations where disturbed flow patterns occur, such as the carotid artery, left coronary artery and abdominal aorta. The causative factors leading to atherosclerosis still remain relatively poorly understood. Conventional diagnosis of arterial disease relies on a combination of history, clinical examination and clinical imaging derived from CT, MRI, etc. To address some of the important factors related to arterial haemodynamics, Computational Fluid Dynamics (CFD) studies were performed on in-vitro models using physiologically relevant conditions. The flow disturbances in terms of wall shear stress and oscillatory shear index were examined. Based on the current research, new insights from a haemodynamics point of view were provided. This study aims to enrich and complement the current arterial disease research, and contribute to promoting the diagnosis accuracy and efficiency in the future. This thesis is composed by six parts of work. Firstly, a comprehensive literature review was performed to identify the research gaps between the current relevant numerical studies with real clinical application. Secondly, the proposed CFD model was validated with published experimental work using particle image velocimetry (PIV) approach. A downstream impedance model was then developed to improve numerical simulation accuracy for image-based artery bifurcations. The numerical results were correlated with a clinical indicator to provide relevant findings for treating physicians. Lastly, a fully fluid-structure interaction (FSI) modelling over left coronary artery models with different bifurcation angles was conducted. The relationship between the mechanical force (first principle stress), the hemodynamic force (wall shear stress), and the bifurcation angle was analysed. In summary, this thesis developed a new downstream artery impedance model, and converted the numerical simulation results into clinical indicators, which can improve the current simulation accuracy and contribute more meaningful results to assist a better clinical diagnosis. A FSI simulation was performed over left coronary artery bifurcation models. The bifurcation angle influence on atherosclerosis progression was addressed. The left circumflex side bifurcation shoulder was found to be more vulnerable in developing atherosclerosis

The Numerical Study of Fluid-Solid Interactions for Modelling Blood Flow in Arteries

Atherosclerosis is a problem that affects millions of people worldwide. The causative factors that contribute to the formation of atherosclerotic lesions have been studied extensively. Haemodynamic factors are known to be important determinants. However, the precise role played by haemodynamics in the development and progression of vascular disease is incompletely understood and findings have sometimes been contradictory. At the same time much solid mechanics oriented work has been done with a specific focus on stress concentrations in the arterial wall in order to examine other possible factors. While great progress has been made in studies of both haemodynamics and vessel wall mechanics separately, it is apparent that the problem of blood flow in arteries is one of fluid-wall interaction, and this necessitates the incorporation of the wall mechanics into fluid dynamics. The combination of fluid/solid mechanics may lead to further insight into the mechanisms underlying the formation of atherosclerotic lesions by taking the dynamic interaction between the blood and vessel wall into account. In this study, a novel numerical algorithm for coupled solid/fluid problems was developed and applied to arterial flows. The coupled model involves the use of two commercial codes, CFX and ABAQUS. The hybrid nature (finite volume method for the fluid and finite element method for the solid) makes itself a highly efficient tool for modelling fluid/solid interactions. The method is able to predict the full, time-dependent wall behaviour, as well as the details of the flow field. Computer programs, originally developed to process clinically obtained MRI images, have been modified in order to provide geometrical data of in vivo human carotid bifurcations and to generate computational grids. New program routines were developed for the incorporation of wall movement required by the computer simulation, and integration of the fluid and solid mechanics codes for the coupled model. A comprehensive range of code validation exercises have been carried out to determine the reliability of the computer codes. Finally, the coupled model has been applied to the modelling of pulsatile flow in anatomically realistic compliant human carotid bifurcations. In vivo pressure and mass flow waveforms in the carotid arteries were obtained from the individual subjects using non-invasive techniques. The geometry of the computational models was reconstructed from magnetic resonance angiograms. Results have been validated against the in vivo MRI measurements obtained from the individuals scanned. High wall stress and low shear stress was found in those areas most prone to atherosclerosis. It is demonstrated that the presented coupled modelling scheme can be used as an efficient and reliable tool for detailed analysis of blood flow and vessel mechanics. In future, application of the coupled model in a large number of individual cases together with disease patterns may further elucidate the roles of haemodynamics and vessel wall mechanics in atherosclerosis

Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists

New updated edition first published with Cambridge University Press. This new edition includes 29 chapters on topics as diverse as pathophysiology of atherosclerosis, vascular haemodynamics, haemostasis, thrombophilia and post-amputation pain syndromes

Effect of antioxidants on the oxidation of low density lipoprotein at lysosomal pH

Oxidised forms of low-densitylipoprotein (LDL) are widely belived to beinvolved in the pathogenesis of atherogenesis,but large clinical trials have not shown protectionof cardiovascular diseaseby antioxidants. Recently, it has been shownthat LDL can be oxidised by iron in the lysosomes of macrophages. We hypothesised that antioxidants would protect LDL against oxidation less well at lysosomal pH than at pH 7.4.LDL was enriched with α-tocopherol by incubating plasma with α-tocopherol and isolating the LDL. This enrichment inhibited LDL oxidation by copper ions (Cu2+) at pH 7.4,but not at pH4.5, as shown by spectrophotometry at 234 nm to measure conjugated dienes and by HPLC to measure individual oxidised lipids. α-Tocopherol enrichment did not inhibit LDL oxidation by Fe3+ (2, 5 or 20 μM) at pH4.5 ,but inhibiteitby 5 or 20 μM Fe2+,but not 2 μM Fe2+. This might help to explain whyα-tocopherol did not inhibit cardiovascular diseases inthe large clinical trials. The antioxidant tempol and probucol inhibited the late phase of LDL oxidation by Fe2+and Cu2+at pH 4.5 more than the early phase, possibly because they were located mainly in the phospholipid monolayer of LDL, rather than in the cholesteryl ester of the LDL particle. There is a suggestion that lysosomal dysfunction plays an important role in atherosclerosis. Thelysosomal oxidation of LDL aggregated by sphingomelinaseresulted in the production of the advanced lipid peroxidation product (ceroid).α-Tocopherol enrichment of macrophagesdid notprotectthem against apoptosis induced by H2O2.The work presented here also demonstrated LDL oxidisedFe2+at pH 4.5, decreasedendothelium-dependent vasodilatationof rat aortic rings. This suggests that VIlysosomallyoxidised LDL released from dead cells in atherosclerotic lesionsmight damage the endothelium.Takentogather,these results suggest that inhibiting the oxidation of LDLin lysosomes might be a therapy of atherosclerosis