Publications
185 results found
Zhang G, Harput S, Toulemonde M, et al., 2019, Acoustic wave sparsely-activated localization microscopy (AWSALM): in vivo fast ultrasound super-resolution imaging using nanodroplets, IEEE International Ultrasonics Symposium (IUS), Publisher: IEEE, Pages: 1930-1933, ISSN: 1948-5719
Current localization-based super-resolution ultrasound imaging requires a low concentration of flowing microbubbles to visualize microvasculature beyond the diffraction limit and acquisition is slow. Nanodroplets offer a promising solution as they can be sparsely activated and deactivated on-demand. In this study, acoustic wave sparsely-activated localization microscopy (AWSALM) using activation and deactivation of nanodroplets, an acoustic counterpart of photo-activated localization microscopy (PALM) which is less dependent on agent concentration and the presence of flow, is demonstrated for super-resolution imaging in deep tissues in vivo. An in vivo super-resolution image of a rabbit kidney is obtained in 1.1 seconds using AWSALM, where micro-vessels with apparent sizes far below the half-wavelength of 220 μm were visualized. This preliminary result demonstrates the feasibility of applying AWSALM for in vivo super-resolution imaging.
Wen Y, Ahmad F, Mohri Z, et al., 2019, Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice, Atherosclerosis, Vol: 291, Pages: 9-18, ISSN: 0021-9150
BACKGROUND AND AIMS: We have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice. METHODS: LDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170 nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19-22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured. RESULTS: Confocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine. CONCLUSIONS: These results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease.
Zhu J, Lin S, Leow CH, et al., 2019, High Frame Rate Contrast-Enhanced Ultrasound Imaging for Slow Lymphatic Flow: Influence of Ultrasound Pressure and Flow Rate on Bubble Disruption and Image Persistence, Ultrasound in Medicine and Biology, Vol: 45, Pages: 2456-2470, ISSN: 0301-5629
Contrast enhanced ultrasound (CEUS) utilising microbubbles shows great potential for visualising lymphatic vessels and identifying sentinel lymph nodes (SLN) which is valuable for axillary staging in breast cancer patients. However, current CEUS imaging techniques have limitations that affect the accurate visualisation and tracking of lymphatic vessels and SLN. (1) Tissue artefacts and bubble disruption can reduce the image contrast. (2) Limited spatial and temporal resolution diminishes the amount of information that can be captured by CEUS. (3) The slow lymph flow makes Doppler based approaches less effective. This work evaluates on a lymphatic vessel phantom the use of high frame-rate (HFR) CEUS for the detection of lymphatic vessels where flow is slow. Specifically the work particularly investigates the impact of key factors in lymphatic imaging, including ultrasound pressure and flow velocity as well as probe motion during vessel tracking, on bubble disruption and image contrast. A trail was also conducted to apply HFR CEUS imaging on vasculature in a rabbit popliteal lymph node (LN). Our results show that (1) HFR imaging and SVD filtering can significantly reduce tissue artefacts in the phantom; (2) the slow flow rate within the phantom makes image contrast and signal persistence more susceptible to changes in ultrasound amplitude/MI, and an MI value can be chosen to reach a compromise between images contrast and bubble disruption under slow flow condition; (3) probe motion significantly decreases image contrast of the vessel, which can be improved by applying motion correction prior to SVD filtering; (4) the optical observation of the impact of ultrasound pressure in HFR CEUS further confirm the importance of optimising ultrasound amplitude MI; (5) Vessels inside rabbit LN with blood flow less than 3 mm/s are clearly visualised.
Zhu J, Rowland E, Harput S, et al., 2019, 3D super-resolution ultrasound imaging of rabbit lymph node vasculature in vivo using microbubbles, Radiology, Vol: 291, Pages: 642-650, ISSN: 0033-8419
Background: Variations in lymph node (LN) microcirculation can be indicative of metastasis. Identifying and quantifying metastatic LNs remains essential for prognosis and treatment planning but a reliable non-invasive imaging technique is lacking. 3D super-resolution (SR) ultrasound has shown potential to noninvasively visualize microvascular networks in vivo.Purpose: To study the feasibility of 3D SR ultrasound imaging of rabbit lymph node (LN) microvascular structure and blood flow using microbubbles.Materials and Methods: In vivo studies were carried out to image popliteal LNs of two healthy male New Zealand White rabbits aged 6-8 weeks. 3D high frame rate contrast enhanced ultrasound was achieved by mechanically scanning a linear imaging probe. Individual microbubbles were identified, localized, and tracked to form 3D SR images and super-resolved velocity maps. Acoustic sub-aperture processing (ASAP)was used to improve image contrast and generateenhanced power Doppler (PD) and color Doppler (CD) images. Vessel size and blood flow velocity distributions were evaluated and assessed by Student’s paired t-test. Results:SR images revealed micro-vessels in the rabbitLN, with branches clearly resolved when separated by 30 μm, which is less than half of the acoustic wavelength and not resolvable by power or color Doppler. The apparent size distribution of most vessels in the SR images was below 80 μm and agrees with micro-CT data whereas most of those detected by Doppler techniques were larger than 80 μm. The blood flow velocity distribution indicated that most of the blood flow in the rabbit popliteal LN was at velocities lower than 5mm/s. Conclusion: 3D super-resolution ultrasound imaging using microbubbles allows non-invasive and non-ionizing visualization and quantification of rabbit lymph node microvascular structures and blood flow dynamics with resolution below the wave diffraction limit.
Warboys CM, Ghim M, Weinberg PD, 2019, Understanding mechanobiology in cultured endothelium: A review of the orbital shaker method, Atherosclerosis, Vol: 285, Pages: 170-177, ISSN: 0021-9150
A striking feature of atherosclerosis is its highly non-uniform distribution within the arterial tree. This has been attributed to variation in the haemodynamic wall shear stress (WSS) experienced by endothelial cells, but the WSS characteristics that are important and the mechanisms by which they lead to disease remain subjects of intensive investigation despite decades of research. In vivo evidence suggests that multidirectional WSS is highly atherogenic. This possibility is increasingly being studied by culturing endothelial cells in wells that are swirled on an orbital shaker. The method is simple and cost effective, has high throughput and permits chronic exposure, but interpretation of the results can be difficult because the fluid mechanics are complex; hitherto, their description has largely been restricted to the engineering literature. Here we review the findings of such studies, which indicate that putatively atherogenic flow characteristics occur at the centre of the well whilst atheroprotective ones occur towards the edge, and we describe simple mathematical methods for choosing experimental variables that avoid resonance, wave breaking and uncovering of the cells. We additionally summarise a large number of studies showing that endothelium cultured at the centre of the well expresses more pro-inflammatory and fewer homeostatic genes, has higher permeability, proliferation, apoptosis and senescence, and shows more endothelial-to-mesenchymal transition than endothelium at the edge. This simple method, when correctly interpreted, has the potential to greatly increase our understanding of the homeostatic and pathogenic mechanobiology of endothelial cells and may help identify new therapeutic targets in vascular disease.
Zhang G, Pang KT, Ghim M, et al., 2018, Investigation of Nanodroplet Adhesion to Endothelial Cells under Atheroprone Flow Conditions, IEEE International Ultrasonics Symposium (IUS), Publisher: IEEE, ISSN: 1948-5719
Zhou X, Leow CH, Rowland E, et al., 2018, 3D velocity and volume flow measurement in vivo using speckle decorrelation and 2D high frame rate contrast-enhanced ultrasound, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 65, Pages: 2233-2244, ISSN: 0885-3010
Being able to measure 3D flow velocity and volumetric flow rate effectively in the cardiovascular system is valuable but remains a significant challenge in both clinical practice and research. Currently there has not been an effective and practical solution to the measurement of volume flow using ultrasound imaging systems due to challenges in existing 3D imaging techniques and high system cost. In this study, a new technique for quantifying volumetric flow rate from the cross-sectional imaging plane of the blood vessel was developed by using speckle decorrelation, 2D high frame rate imaging with a standard 1D array transducer, microbubble contrast agents, and ultrasound imaging velocimetry (UIV). Through speckle decorrelation analysis of microbubble signals acquired with a very high frame rate and by using UIV to estimate the two in-plane flow velocity components, the third and out-of-plane velocity component can be obtained over time and integrated to estimate volume flow. The proposed technique was evaluated on a wall-less flow phantom in both steady and pulsatile flow. UIV in the longitudinal direction was conducted as a reference. The influences of frame rate, mechanical index, orientation of imaging plane, and compounding on velocity estimation were also studied. In addition, an in vivo trial on the abdominal aorta of a rabbit was conducted. The results show that the new system can estimate volume flow with an averaged error of 3.65±2.37% at a flow rate of 360 ml/min and a peak velocity of 0.45 m/s, and an error of 5.03±2.73% at a flow rate of 723 ml/min and a peak velocity of 0.8 m/s. The accuracy of the flow velocity and volumetric flow rate estimation directly depend on the imaging frame rate. With a frame rate of 6000 Hz, a velocity up to 0.8 m/s can be correctly estimated. A higher mechanical index (MI=0.42) is shown to produce greater errors (up to 21.78±0.49%, compared to 3.65±2.37% at MI=0.19). An in vivo trial, where velo
van Ooij P, Cibis M, Rowland EM, et al., 2018, Spatial correlations between MRI-derived wall shear stress and vessel wall thickness in the carotid bifurcation, European Radiology Experimental, Vol: 2, ISSN: 2509-9280
BACKGROUND: To explore the possibility of creating three-dimensional (3D) estimation models for patient-specific wall thickness (WT) maps using patient-specific and cohort-averaged WT, wall shear stress (WSS), and vessel diameter maps in asymptomatic atherosclerotic carotid bifurcations. METHODS: Twenty subjects (aged 75 ± 6 years [mean ± standard deviation], eight women) underwent a 1.5-T MRI examination. Non-gated 3D phase-contrast gradient-echo images and proton density-weighted echo-planar images were retrospectively assessed for WSS, diameter estimation, and WT measurements. Spearman's ρ and scatter plots were used to determine correlations between individual WT, WSS, and diameter maps. A bootstrapping technique was used to determine correlations between 3D cohort-averaged WT, WSS, and diameter maps. Linear regression between the cohort-averaged WT, WSS, and diameter maps was used to predict individual 3D WT. RESULTS: Spearman's ρ averaged over the subjects was - 0.24 ± 0.18 (p < 0.001) and 0.07 ± 0.28 (p = 0.413) for WT versus WSS and for WT versus diameter relations, respectively. Cohort-averaged ρ, averaged over 1000 bootstraps, was - 0.56 (95% confidence interval [- 0.74,- 0.38]) for WT versus WSS and 0.23 (95% confidence interval [- 0.06, 0.52]) for WT versus diameter. Scatter plots did not reveal relationships between individual WT and WSS or between WT and diameter data. Linear relationships between these parameters became apparent after averaging over the cohort. Spearman's ρ between the original and predicted WT maps was 0.21 ± 0.22 (p < 0.001). CONCLUSIONS: With a combination of bootstrapping and cohort-averaging methods, 3D WT maps can be predicted from the individual 3D WSS and diameter maps. The methodology may help to elucidate pathological p
Pang KT, Fhu CW, Ghim M, et al., 2018, LRG1 IS A NOVEL REGULATOR OF ENDOTHELIAL ACTIVATION AND IS SHEAR DEPENDENT: A POTENTIAL THERAPEUTIC TARGET?, 86th Congress of the European-Atherosclerosis-Society (EAS), Publisher: ELSEVIER IRELAND LTD, Pages: E37-E37, ISSN: 0021-9150
Ghim M, Pang K, Arshad M, et al., 2018, A novel method for segmenting growth of cells in sheared endothelial culture reveals the secretion of an anti-inflammatory mediator, Journal of Biological Engineering, Vol: 12, ISSN: 1754-1611
BackgroundEffects of shear stress on endothelium are important for the normal physiology of blood vessels and are implicated in the pathogenesis of atherosclerosis. They have been extensively studied in vitro. In one paradigm, endothelial cells are cultured in devices that produce spatially varying shear stress profiles, and the local profile is compared with the properties of cells at the same position. A flaw in this class of experiments is that cells exposed to a certain shear profile in one location may release mediators into the medium that alter the behaviour of cells at another location, experiencing different shear, thus obscuring or corrupting the true relation between shear and cell properties.MethodsSurface coating methods were developed for attaching cells only to some areas of culture-ware and preventing them from spreading into other regions even during prolonged culture.ResultsSegmenting the growth of cells had no effect on cell shape, alignment and number per unit area compared to culturing cells in the whole well, but there were differences in tumour-necrosis-factor-α (TNF-α)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and monocyte adherence to the monolayer.ConclusionsThe results are consistent with the release of a mediator from cells exposed to high-magnitude uniaxial shear stress that has anti-inflammatory effects on activated endothelium; the mediator may be of importance in atherogenesis. Hence the new methods revealed an important property that would not have been observed without growth segmentation, suggesting that they could find more widespread application.
Stanziola A, Leow CH, Bazigou E, et al., 2018, ASAP: super-contrast vasculature imaging using coherence analysis and high frame- rate contrast enhanced ultrasound, IEEE Transactions on Medical Imaging, Vol: 37, Pages: 1847-1856, ISSN: 0278-0062
The very high frame rate afforded by ultrafast ultrasound, combined with microbubble contrast agents, opens new opportunities for imaging tissue microvasculature. However, new imaging paradigms are required to obtain superior image quality from the large amount of acquired data while allowing real-time implementation. In this paper, we report a technique - acoustic sub-aperture processing (ASAP) - capable of generating very high contrast/SNR images of macro- and microvessels, with similar computational complexity to classical Power Doppler (PD) imaging. In ASAP, the received data are split into sub- groups. The reconstructed data from each sub-group are temporally correlated over frames to generate the final image. As signals in sub-groups are correlated but the noise is not, this substantially reduces the noise floor compared to PD. Using a clinical imaging probe, the method is shown to visualize vessels down to 200μm with a SNR 10dB higher than PD, and to resolve microvascular flow/perfusion information in rabbit kidneys non-invasively in vivo at multiple centimeter depth. With careful filter design, the technique also allows estimation of flow direction and separation of fast flow from tissue perfusion. ASAP can readily be implemented into hardware/firmware for real-timing imaging, and can be applied to contrast enhanced and potentially non-contrast imaging and 3D imaging.
Toulemonde M, Zhang G, Riemer K, et al., 2018, Locally activated nanodroplets and high frame rate imaging for real-time flow visualization – preliminary in-vivo demonstration, BioMedEng18
Ahmad F, Yichuan W, Mohri Z, et al., 2018, CYSTEAMINE INHIBITS LYSOSOMAL OXIDATION OF LOW DENSITY LIPOPROTEIN IN HUMAN MACROPHAGES AND REDUCES ATHEROSCLEROSIS IN MICE, International Symposium on Atherosclerosis (ISA), Publisher: ELSEVIER IRELAND LTD, Pages: 122-123, ISSN: 1567-5688
Pang K, Fhu CW, Ghim M, et al., 2018, LRG1 is a novel regulator of endothelial activation and is shear dependent: a potential therapeutic target?, 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S13-S14, ISSN: 0008-6363
Alpresa P, Sherwin S, Weinberg P, et al., 2018, Orbitally shaken shallow fluid layers. I. Regime classification, PHYSICS OF FLUIDS, Vol: 30, ISSN: 1070-6631
Orbital shakers are simple devices that provide mixing, aeration, and shear stress at multiple scales and high throughput. For this reason, they are extensively used in a wide range of applications from protein production to bacterial biofilms and endothelial cell experiments. This study focuses on the behaviour of orbitally shaken shallow fluid layers in cylindrical containers. In order to investigate the behaviour over a wide range of different conditions, a significant number of numerical simulations are carried out under different configuration parameters. We demonstrate that potential theory—despite the relatively low Reynolds number of the system—describes the free-surface amplitude well and the velocity field reasonably well, except when the forcing frequency is close to a natural frequency and resonance occurs. By classifying the simulations into non-breaking, breaking, and breaking with part of the bottom uncovered, it is shown that the onset of wave breaking is well described by Δh/(2R) = 0.7Γ, where Δh is the free-surface amplitude, R is the container radius, and Γ is the container aspect ratio; Δh can be well approximated using the potential theory. This result is in agreement with standard wave breaking theories although the significant inertial forcing causes wave breaking at lower amplitudes.
Alpresa P, Sherwin S, Weinberg P, et al., 2018, Orbitally shaken shallow fluid layers. II. An improved wall shear stress model, Physics of Fluids, Vol: 30, ISSN: 1070-6631
A new model for the analytical prediction of wall shear stress distributions at the base of orbitally shaken shallow fluid layers is developed. This model is a generalisation of the classical extended Stokes solution and will be referred to as the potential theory-Stokes model. The model is validated using a large set of numerical simulations covering a wide range of flow regimes representative of those used in laboratory experiments. It is demonstrated that the model is in much better agreement with the simulation data than the classical Stokes solution, improving the prediction in 63% of the studied cases. The central assumption of the model—which is to link the wall shear stress with the surface velocity—is shown to hold remarkably well over all regimes covered.
Ghim M, Alpresa P, Yang S, et al., 2017, Visualization of three pathways for macromolecule transport across cultured endothelium and their modification by flow., AJP - Heart and Circulatory Physiology, Vol: 313, Pages: H959-H973, ISSN: 1522-1539
Transport of macromolecules across vascular endothelium and its modification by fluid mechanical forces are important for normal tissue function and in the development of atherosclerosis. However, the routes by which macromolecules cross endothelium, the hemodynamic stresses that maintain endothelial physiology or trigger arterial disease, and the dependence of transendothelial transport on hemodynamic stresses are controversial. Here we visualised pathways for macromolecule transport and determined the effect on these pathways of different types of flow. Endothelial monolayers were cultured under static conditions or on an orbital shaker producing different flow profiles in different parts of the wells. Fluorescent tracers that bound to the substrate after crossing the endothelium were used to identify transport pathways. Maps of tracer distribution were compared with numerical simulations of flow to determine effects of different shear stress metrics on permeability. Albumin-sized tracers dominantly crossed the cultured endothelium via junctions between neighbouring cells, high-density-lipoprotein-sized tracers crossed at tricelluar junctions whilst low-density-lipoprotein-sized tracers crossed through cells. Cells aligned close to the angle that minimised shear stresses across their long axis. The rate of paracellular transport under flow correlated with the magnitude of these minimised transverse stresses, whereas transport across cells was uniformly reduced by all types of flow. These results contradict the long-standing two-pore theory of solute transport across microvessel walls and the consensus view that endothelial cells align with the mean shear vector. They suggest that endothelial cells minimise transverse shear, supporting its postulated pro-atherogenic role. Preliminary data show that similar tracer techniques are practicable in vivo.
Weinberg PD, Hernandez ADR, Brown R, 2017, Engineering solutions for cancer, CONVERGENT SCIENCE PHYSICAL ONCOLOGY, Vol: 3, ISSN: 2057-1739
Fraser KH, Poelma C, Zhou B, et al., 2017, Ultrasound imaging velocimetry with interleaved images for improved pulsatile arterial flow measurements: a new correction method, experimental and in vivo validation, Journal of the Royal Society Interface, Vol: 14, ISSN: 1742-5662
Blood velocity measurements are important in physiological science and clinical diagnosis. Doppler ultrasound is the most commonly used method but can only measure one velocity component. Ultrasound imaging velocimetry (UIV) is a promising technique capable of measuring two velocity components; however, there is a limit on the maximum velocity that can be measured with conventional hardware which results from the way images are acquired by sweeping the ultrasound beam across the field of view. Interleaved UIV is an extension of UIV in which two image frames are acquired concurrently, allowing the effective interframe separation time to be reduced and therefore increasing the maximum velocity that can be measured. The sweeping of the ultrasound beam across the image results in a systematic error which must be corrected: in this work, we derived and implemented a new velocity correction method which accounts for acceleration of the scatterers. We then, for the first time, assessed the performance of interleaved UIV for measuring pulsatile arterial velocities by measuring flows in phantoms and in vivo and comparing the results with spectral Doppler ultrasound and transit-time flow probe data. The velocity and flow rate in the phantom agreed within 5–10% of peak velocity, and 2–9% of peak flow, respectively, and in vivo the velocity difference was 9% of peak velocity. The maximum velocity measured was 1.8 m s−1, the highest velocity reported with UIV. This will allow flows in diseased arteries to be investigated and so has the potential to increase diagnostic accuracy and enable new vascular research.
Chooi KY, Comerford A, Sherwin SJ, et al., 2017, Noradrenaline has opposing effects on the hydraulic conductance of arterial intima and media., Journal of Biomechanics, Vol: 54, Pages: 4-10, ISSN: 1873-2380
The uptake of circulating macromolecules by the arterial intima is thought to be a key step in atherogenesis. Such transport is dominantly advective, so elucidating the mechanisms of water transport is important. The relation between vasoactive agents and water transport in the arterial wall is incompletely understood. Here we applied our recently-developed combination of computational and experimental methods to investigate the effects of noradrenaline (NA) on hydraulic conductance of the wall (Lp), medial extracellular matrix volume fraction (ϕ(ECM)) and medial permeability (K1(1)) in the rat abdominal aorta. Experimentally, we found that physiological NA concentrations were sufficient to induce SMC contraction and produced significant decreases in Lp and increases in ϕ(ECM). Simulation results based on 3D confocal images of the extracellular volume showed a corresponding increase in K1(1), attributed to the opening of the ECM. Conversion of permeabilities to layer-specific resistances revealed that although the total wall resistance increased, medial resistance decreased, suggesting an increase in intimal resistance upon application of NA.
Mohamied Y, Sherwin SJ, Weinberg PD, 2016, Understanding the fluid mechanics behind transverse wall shear stress, Journal of Biomechanics, Vol: 50, Pages: 102-109, ISSN: 1873-2380
The patchy distribution of atherosclerosis within arteries is widely attributed to local variation in haemodynamic wall shear stress (WSS). A recently-introduced metric, the transverse wall shear stress (transWSS), which is the average over the cardiac cycle of WSS components perpendicular to the temporal mean WSS vector, correlates particularly well with the pattern of lesions around aortic branch ostia. Here we use numerical methods to investigate the nature of the arterial flows captured by transWSS and the sensitivity of transWSS to inflow waveform and aortic geometry. TransWSS developed chiefly in the acceleration, peak systolic and deceleration phases of the cardiac cycle; the reverse flow phase was too short, and WSS in diastole was too low, for these periods to have a significant influence. Most of the spatial variation in transWSS arose from variation in the angle by which instantaneous WSS vectors deviated from the mean WSS vector rather than from variation in the magnitude of the vectors. The pattern of transWSS was insensitive to inflow waveform; only unphysiologically high Womersley numbers produced substantial changes. However, transWSS was sensitive to changes in geometry. The curvature of the arch and proximal descending aorta were responsible for the principal features, the non-planar nature of the aorta produced asymmetries in the location and position of streaks of high transWSS, and taper determined the persistence of the streaks down the aorta. These results reflect the importance of the fluctuating strength of Dean vortices in generating transWSS.
Chooi KY, Comerford A, Sherwin SJ, et al., 2016, Intimal and medial contributions to the hydraulic resistance of the arterial wall at different pressures: a combined computational and experimental study, Journal of the Royal Society Interface, Vol: 11, ISSN: 1742-5689
The hydraulic resistances of the intima and media determine water flux and the advection of macromolecules into and across the arterial wall. Despite several experimental and computational studies, however, these trans- port processes and their dependence on transmural pressure remain incompletely understood. Here we use a combination of experimental and computational methods to ascertain how the hydraulic permeability of the rat abdominal aorta depends on these two layers and how it is affected by structural rearrangement of the media under pressure. Ex vivo experiments determined the conductance of the whole wall, the thickness of the media, and the geometry of medial smooth muscle cells and extracellular matrix. Numerical methods were used to compute water flux through the media. Intimal values were obtained by subtraction. A mechanism was iden- tified that modulates pressure-induced changes in medial transport properties: compaction of the extracellular matrix leading to spatial reorganisation of smooth muscle cells. This is summarised in an empirical constitutive law for permeability and volumetric strain. This led to the physiologically interesting observation that, as a consequence of the changes in medial microstructure, the relative contributions of the intima and media to the hydraulic resistance of the wall depend on the applied pressure; medial resistance dominated at pressures above ∼93mmHg in this vessel.
Mahmoud MM, Kim HR, Xing R, et al., 2016, TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis, Circulation Research, Vol: 119, Pages: 450-462, ISSN: 0009-7330
Rationale: Blood flow–induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed during embryogenesis, but its role in EC responses to shear stress and focal atherosclerosis is unknown.Objective: To investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis and compare TWIST function in vascular development and disease.Methods and Results: The expression and function of TWIST1 was studied in EC in both developing vasculature and during the initiation of atherosclerosis. In zebrafish, twist was expressed in early embryonic vasculature where it promoted angiogenesis by inducing EC proliferation and migration. In adult porcine and murine arteries, TWIST1 was expressed preferentially at low shear stress regions as evidenced by quantitative polymerase chain reaction and en face staining. Moreover, studies of experimental murine carotid arteries and cultured EC revealed that TWIST1 was induced by low shear stress via a GATA4-dependent transcriptional mechanism. Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness.Conclusions: TWIST expression promotes developmental angiogenesis by inducing EC proliferation and migration. In addition to its role in development, TWIST is expressed preferentially at low shear stress regions of adult arteries where it promotes atherosclerosis by inducing EC proliferation and inflammation. Thus, pleiotropic functions of TWIST control vascular disease and development.
Chooi KY, Comerford A, Cremers SJ, et al., 2016, Role of endothelial permeability hotspots and endothelial mitosis in determining age-related patterns of macromolecule uptake by the rabbit aortic wall near branch points, Atherosclerosis, Vol: 250, Pages: 77-83, ISSN: 1879-1484
BACKGROUND AND AIMS: Transport of macromolecules between plasma and the arterial wall plays a key role in atherogenesis. Scattered hotspots of elevated endothelial permeability to macromolecules occur in the aorta; a fraction of them are associated with dividing cells. Hotspots occur particularly frequently downstream of branch points, where lesions develop in young rabbits and children. However, the pattern of lesions varies with age, and can be explained by similar variation in the pattern of macromolecule uptake. We investigated whether patterns of hotspots and mitosis also change with age. METHODS: Evans' Blue dye-labeled albumin was injected intravenously into immature or mature rabbits and its subsequent distribution in the aortic wall around intercostal branch ostia examined by confocal microscopy and automated image analysis. Mitosis was detected by immunofluorescence after adding 5-bromo-2-deoxiuridine to drinking water. RESULTS: Hotspots were most frequent downstream of branches in immature rabbits, but a novel distribution was observed in mature rabbits. Neither pattern was explained by mitosis. Hotspot uptake correlated spatially with the much greater non-hotspot uptake (p < 0.05), and the same pattern was seen when only the largest hotspots were considered. CONCLUSIONS: The pattern of hotspots changes with age. The data are consistent with there being a continuum of local permeabilities rather than two distinct mechanisms. The distribution of the dye, which binds to elastin and collagen, was similar to that of non-binding tracers and to lesions apart from a paucity at the lateral margins of branches that can be explained by lower levels of fibrous proteins in those regions.
Leow C, Tang M, Bazigou E, et al., 2015, Flow velocity mapping using contrast enhanced high-frame-rate plane wave ultrasound and image tracking: methods and initial in vitro and in vivo evaluation, Ultrasound in Medicine and Biology, Vol: 41, Pages: 2913-2925, ISSN: 0301-5629
Ultrasound imaging is the most widely used method for visualising and quantifying blood flow in medical practice, but existing techniques have various limitations in terms of imaging sensitivity, field of view, flow angle dependence, and imaging depth. In this study, we developed an ultrasound imaging velocimetry approach capable of visualising and quantifying dynamic flow, by combining high-frame-rate plane wave ultrasound imaging, microbubble contrast agents, pulse inversion contrast imaging and speckle image tracking algorithms. The system was initially evaluated in vitro on both straight and carotid-mimicking vessels with steady and pulsatile flows and in vivo in the rabbit aorta. Colour and spectral Doppler measurements were also made. Initial flow mapping results were compared with theoretical prediction and reference Doppler measurements and indicate the potential of the new system as a highly sensitive, accurate, angle-independent and full field-of-view velocity mapping tool capable of tracking and quantifying fast and dynamic flows.
Rowland EM, Mohamied Y, Chooi KY, et al., 2015, Comparison of Statistical Methods for Assessing Spatial Correlations Between Maps of Different Arterial Properties, Journal of Biomechanical Engineering-Transactions of the ASME, Vol: 137, ISSN: 0148-0731
Assessing the anatomical correlation of atherosclerosis with biomechanical localizing factors is hindered by spatial autocorrelation (SA), wherein neighboring arterial regions tend to have similar properties rather than being independent, and by the use of aggregated data, which artificially inflates correlation coefficients. Resampling data at lower resolution or reducing degrees-of-freedom in significance tests negated effects of SA but only in artificial situations where it occurred at a single length scale. Using Fourier or wavelet transforms to generate autocorrelation-preserving surrogate datasets, and thus to compute the null distribution, avoided this problem. Bootstrap methods additionally circumvented the errors caused by aggregating data. The bootstrap technique showed that wall shear stress (WSS) was significantly correlated with atherosclerotic lesion frequency and endothelial nuclear elongation, but not with the permeability of the arterial wall to albumin, in immature rabbits.
Bailey EL, Bazigou E, Sowinski PSJ, et al., 2015, Mass Transport Properties of the Rabbit Aortic Wall, PLOS ONE, Vol: 10, ISSN: 1932-6203
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Mohamied Y, Rowland EM, Bailey EL, et al., 2015, Change of direction in the biomechanics of atherosclerosis, Annals of Biomedical Engineering, Vol: 43, Pages: 16-25, ISSN: 0090-6964
The non-uniform distribution of atherosclerosis within the arterial system has been attributed to pro-atherogenic influences of low, oscillatory haemodynamic wall shear stress (WSS) on endothelial cells (EC). This theory is challenged by the changes in lesion location that occur with age in human and rabbit aortas. Furthermore, a number of point-wise comparisons of lesion prevalence and WSS have failed to support it. Here we investigate the hypothesis that multidirectional flow—characterized as the average magnitude of WSS components acting transversely to the mean vector (transWSS)—plays a key role. Maps of lesion prevalence around aortic branch ostia in immature and mature rabbits were compared with equivalent maps of time average WSS, the OSI (an index characterizing oscillatory flow) and transWSS, obtained from computational simulations; Spearman’s rank correlation coefficients were calculated for aggregated data and 95% confidence intervals were obtained by bootstrapping methods. Lesion prevalence correlated positively, strongly and significantly with transWSS at both ages. Correlations of lesion prevalence with the other shear metrics were not significant or were significantly lower than those obtained for transWSS. No correlation supported the low, oscillatory WSS theory. The data are consistent with the view that multidirectional near-wall flow is highly pro-atherogenic. Effects of multidirectional flow on EC, and methods for investigating them, are reviewed. The finding that oscillatory flow has pro-inflammatory effects when acting perpendicularly to the long axis of EC but anti-inflammatory effects when acting parallel to it may explain the stronger correlation of lesion prevalence with transWSS than with the OSI.
Mohri Z, Rowland EM, Clarke LA, et al., 2014, Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model, PLoS One, Vol: 9, ISSN: 1932-6203
Atherosclerosis may be triggered by an elevated net transport of lipid-carryingmacromolecules from plasma into the arterial wall. We hypothesised that whetherlesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and morefibrous depends on the degree of elevation of transport, with greater uptake leadingto the former. We further hypothesised that the degree of elevation can depend onhaemodynamic wall shear stress characteristics and nitric oxide synthesis. Placinga tapered cuff around the carotid artery of apolipoprotein E -/- mice modifiespatterns of shear stress and eNOS expression, and triggers lesion development atthe upstream and downstream cuff margins; upstream but not downstream lesionsresemble the TCFA. We measured wall uptake of a macromolecular tracer in thecarotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in theregions that develop lesions in hyperlipidaemic mice and was significantly moreelevated where plaques of the TCFA type develop. Computational simulations andeffects of reversing the cuff orientation indicated a role for solid as well as fluidmechanical stresses. Inhibiting NO synthesis abolished the difference in uptakebetween the upstream and downstream sites. The data support the hypothesis thatexcessively elevated wall uptake of plasma macromolecules initiates thedevelopment of the TCFA, suggest that such uptake can result from solid and fluidmechanical stresses, and are consistent with a role for NO synthesis. Modificationof wall transport properties might form the basis of novel methods for reducingplaque rupture.
Bazigou E, Bailey E, Sowinski P, et al., 2014, UNILATERAL NEPHRECTOMY AS A MODEL OF ALTERED BLOOD FLOW FOR THE STUDY OF ARTERIAL PERMEABILITY, Autumn Meeting of the British-Atherosclerosis-Society (BAS), Publisher: ELSEVIER IRELAND LTD, Pages: E4-E5, ISSN: 0021-9150
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