PIV-based Investigation of Hemodynamic Factors in Diseased Carotid Artery Bifurcations with Varying Plaque Geometries

Ischemic stroke is often a consequence of complications due to clot formation (i.e. thrombosis) at the site of an atherosclerotic plaque developed in the internal carotid artery. Hemodynamic factors, such as shear-stress forces and flow disturbances, can facilitate the key mechanisms of thrombosis. Atherosclerotic plaques can differ in the severity of stenosis (narrowing), in eccentricity (symmetry), as well as inclusion of ulceration (wall roughness). Therefore, in terms of clinical significance, it is important to investigate how the local hemodynamics of the carotid artery is mediated by the geometry of plaque. Knowledge of thrombosis-associated hemodynamics may provide a basis to introduce advanced clinical diagnostic indices that reflect the increased probability of thrombosis and thus assist with better estimation of stroke risk, which is otherwise primarily assessed based on the degree of narrowing of the lumen. A stereoscopic particle image velocimetry (stereo-PIV) system was configured to obtain instantaneous full-field velocity measurements in life-sized carotid artery models. Extraction of the central-plane and volumetric features of the flow revealed the complexity of the stenotic carotid flow, which increased with increasing stenosis severity and changed with the symmetry of the plaque. Evaluation of the energy content of two models of the stenosed carotid bifurcation provided insight on the expected level of flow instabilities with potential clinical implications. Studies in a comprehensive family of eight models ranging from disease-free to severely stenosed (30%, 50%, 70% diameter reduction) and with two types of plaque symmetry (concentric or eccentric), as well as a single ulcerated stenosed model, clearly demonstrated the significance of plaque geometry in marked alteration of the levels and patterns of downstream flow disturbances and shear stress. Plaque eccentricity and ulceration resulted in enhanced flow disturbances. In addition, shear-stress patterns in those models with eccentric stenosis were suggestive of increased thrombosis potential at the post-stenotic recirculation zone compared to their concentric counterpart plaques

Tissue Doppler imaging of carotid plaque wall motion: a pilot study

BACKGROUND: Studies suggest the physical and mechanical properties of vessel walls and plaque may be of clinical value in the diagnosis and treatment of cardiovascular atherosclerotic disease. The purpose of this pilot study was to investigate the potential clinical application of ultrasound Tissue Doppler Imaging (TDI) of Arterial Wall Motion (AWM) and to quantify simple wall motion indices in normal and diseased carotid arteries. METHODS: 224 normal and diseased carotid arteries (0–100% stenoses) were imaged in 126 patients (age 25–88 years, mean 68 ± 11). Longitudinal sections of the carotid bifurcation were imaged using a Philips HDI5000 scanner and L12-5 probe under optimized TDI settings. Temporal and spatial AWMs were analyzed to evaluate the vessel wall displacements and spatial gradients at peak systole averaged over 5 cardiac cycles. RESULTS: AWM data were successfully extracted in 91% of cases. Within the carotid bifurcation/plaque region, the maximum wall dilation at peak systole ranged from -100 to 750 microns, mean 335 ± 138 microns. Maximum wall dilation spatial gradients ranged 0–0.49, mean 0.14 ± 0.08. The AWM parameters showed a wide variation and had poor correlation with stenoses severity. Case studies illustrated a variety of pertinent qualitative and quantitative wall motion features related to the biophysics of arterial disease. CONCLUSION: Our clinical experience, using a challenging but realistic imaging protocol, suggests the use of simple quantitative AWM measures may have limitations due to high variability. Despite this, pertinent features of AWM in normal and diseased arteries demonstrate the potential clinical benefit of the biomechanical information provided by TDI

Computer assisted analysis of contrast enhanced ultrasound images for quantification in vascular diseases

Contrast enhanced ultrasound (CEUS) with microbubble contrast agents has shown great potential in imaging microvasculature, quantifying perfusion and hence detecting vascular diseases. However, most existing perfusion quantification methods based on image intensity, and are susceptible to confounding factors such as attenuation artefacts. Improving reproducibility is also a key challenge to clinical translation. Therefore, this thesis aims at developing attenuation correction and quantification techniques in CEUS with applications for detection and quantification of microvascular flow / perfusion. Firstly, a technique for automatic correction of attenuation effects in vascular imaging was developed and validated on a tissue mimicking phantom. The application of this technique to studying contrast enhancement of carotid adventitial vasa vasorum as a biomarker of radiation-induced atherosclerosis was demonstrated. The results showed great potential in reducing attenuation artefact and improve quantification in CEUS of carotid arteries. Furthermore, contrast intensity was shown to significantly increase in irradiated carotid arteries and could be a useful imaging biomarker for radiation-induced atherosclerosis. Secondly, a robust and automated tool for quantification of microbubble identification in CEUS image sequences using a temporal and spatial analysis was developed and validated on a flow phantom. The application of this technique to evaluate human musculoskeletal microcirculation with contrast enhanced ultrasound was demonstrated. The results showed an excellent accuracy and repeatability in quantifying active vascular density. It has great potential for clinical translation in the assessment of lower limb perfusion. Finally, a new bubble activity identification and quantification technique based on differential intensity projection in CEUS was developed and demonstrated with an in-vivo study, and applied to the quantification of intraplaque neovascularisation in an irradiated carotid artery of patients who were previously treated for head and neck cancer. The results showed a significantly more specific identification of bubble signals and had good agreement between the differential intensity-based technique and clinical visual assessment. This technique has potential to assist clinicians to diagnose and monitor intraplque neovascularisation.Open Acces

Carotid Ultrasound for Stroke Prediction

Introduction: The aims of this thesis were to identify if carotid endarterectomy was cost-effective and affordable in the United Kingdom and secondly to explore the potential of contrast enhanced ultrasound and plaque texture analysis for risk stratification in asymptomatic patients with carotid atherosclerosis. Methods: A cost-utility analysis based on results from the Asymptomatic Carotid Surgery Trial was performed using a Markov transition state model. Three cross-sectional studies of symptomatic and asymptomatic individuals with 50-99% carotid stenosis were performed for late phase and dynamic phase contrast enhanced ultrasound, followed by plaque texture analysis. Results: There was a high probability of surgical endarterectomy lying under the £20-30, 000 per quality adjusted life year National Institute for Health and Clinical Excellence acceptability threshold in the United Kingdom. In men under 75 years of age, the cost per quality adjusted life year gained was lower and in women there was improved effectiveness with reduced long-term costs. Late phase contrast enhanced ultrasound imaging of carotid atherosclerosis suffered from a tissue suppression artefact which limited its ability to image microbubble retention. Quantification of plaque perfusion using low mechanical index imaging demonstrated a pseudoenhancement phenomenon from non-linear propagation, which artificially increased far wall intensity, again limiting its use for quantification of plaque perfusion. Semi-quantitative grading of plaque perfusion revealed no significant difference in generalised plaque perfusion between symptomatic and asymptomatic individuals, however detection of ulceration using dynamic contrast enhanced ultrasound showed a trend towards an association with symptomatic status. Type II plaque showed a significant independent association with symptomatic status. Conclusion: Carotid endarterectomy is likely to be cost-effective in those under 75 years of age, particularly women. However, without further selection, the upfront costs and high number needed to treat with endarterectomy limit its potential as a large scale strategy. Improvements in non-linear pulse sequencing are required before quantitative contrast enhanced ultrasound can reliably be used for functional imaging of carotid atherosclerosis. Qualitative assessment of plaque perfusion is unlikely to gain widespread use due to its high subjectivity. However assessment of plaque type and to a lesser extent imaging of ulceration using contrast enhanced ultrasound are promising and reproducible imaging biomarkers for further study. Validation of these markers with histology and then prospective study of individuals with these plaque phenotypes is proposed. In the future individuals with a recent transient ischaemic attack and moderate (50-69%) stenosis may prove to be an ideal group for risk stratification

Quantitative fat and R2* mapping in vivo to measure lipid-rich necrotic core and intraplaque hemorrhage in carotid atherosclerosis

Purpose: The aim of this work was to quantify the extent of lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) in atherosclerotic plaques. Methods: Patients scheduled for carotid endarterectomy underwent four-point Dixon and T1-weighted magnetic resonance imaging (MRI) at 3 Tesla. Fat and R2* maps were generated from the Dixon sequence at the acquired spatial resolution of 0.60 × 0.60 × 0.70 mm voxel size. MRI and three-dimensional (3D) histology volumes of plaques were registered. The registration matrix was applied to segmentations denoting LRNC and IPH in 3D histology to split plaque volumes in regions with and without LRNC and IPH. Results: Five patients were included. Regarding volumes of LRNC identified by 3D histology, the average fat fraction by MRI was significantly higher inside LRNC than outside: 12.64 ± 0.2737% versus 9.294 ± 0.1762% (mean ± standard error of the mean [SEM]; P < 0.001). The same was true for IPH identified by 3D histology, R2* inside versus outside IPH was: 71.81 ± 1.276 s−1 versus 56.94 ± 0.9095 s−1 (mean ± SEM; P < 0.001). There was a strong correlation between the cumulative fat and the volume of LRNC from 3D histology (R2 = 0.92) as well as between cumulative R2* and IPH (R2 = 0.94). Conclusion: Quantitative mapping of fat and R2* from Dixon MRI reliably quantifies the extent of LRNC and IPH

The determinants of intra-plaque neovascularisation: a study by contrast-enhanced carotid ultrasonography

Atherosclerosis is a chronic inflammatory disorder, initiated by arterial wall injury, mediated by well-recognised cardiovascular risk factors and culminating in formation of plaques, the patho-biological substrate that precedes events such as stroke and myocardial infarction. Intraplaque neovascularisation (IPN) is one of several defence mechanisms in response to atherosclerosis. With development of an atherosclerotic plaque within the intima, the distance between the deeper intimal layers and the luminal surface increases, producing hypoxia within the arterial wall. This stimulates release of pro-angiogenic factors that induces neoangiogenesis in an attempt to normalise oxygen tension. However, these neo-vessels are fragile, immature and leaky and thought to be the primary cause of intraplaque haemorrhage, now appreciated to be a key risk factor for plaque rupture. Therefore, the presence of IPN is now widely recognised as a precursor of the “vulnerable plaque”. Contrast-enhanced ultrasound (CEUS) is a non-invasive method of imaging carotid plaques and, as contrast bubbles travel wherever erythrocytes travel, they permit visualization of IPN. Prior research studies have demonstrated that CEUS can detect IPN with a high degree of accuracy (on comparison with histological plaque specimens) and have shown a relationship between extent of plaque neovessels and plaque echogenicity and between plaque neovascularization and prior cardiovascular events. However, CEUS is a relatively recently described imaging technique and there were a number of unanswered questions in this field, some of which formed the basis for study in this research Thesis. In this Thesis, research studies were conducted on human subjects using CEUS imaging to identify IPN and its determinants. The incidence and determinants of IPN in healthy asymptomatic individuals was unknown and was studied in subjects from the London Life Sciences Population (LOLIPOP) study, a large study exploring mechanisms for differences in cardiovascular disease (CVD) between South Asian and European White individuals. The study found that approximately half of all plaques contain IPN. The only variable associated with IPN presence in an adjusted analysis was Asian ethnicity. This finding potentially has significant implications as it may help explain, in part, the greater CVD burden observed in Asian populations. A study comparing visualization of the carotid tree during B-mode and CEUS imaging was also conducted. Both IMT visualization and plaque detection were significantly improved by CEUS, implying that CEUS is superior to B-mode imaging for detection of sub-clinical atherosclerosis. Radiotherapy (RT) damages arterial walls and promotes atherosclerosis. The carotid arteries frequently receive significant incidental doses of radiation during RT treatment of head and neck cancers. The effect of RT on plaque composition – specifically IPN – had not been studied and thus a collaborative cardio-oncological study was conducted to assess the effects of RT upon IPN in cancer survivors who had previously received RT. A significant association between RT and IPN was found which may provide insights into the mechanisms underlying the increased stroke risk amongst cancer survivors treated by RT. Finally, a collaboration with biophysicists was formed to develop and validate a novel algorithm for quantitative analysis of IPN. Patients clinically scheduled to undergo carotid endarterectomy were recruited and underwent CEUS imaging prior to surgery. This study did not achieve its principal aims due to challenges with patient recruitment, challenges in image quality and with the quantification software also. Future directions of study in this promising field have been addressed in the thesis summary.Open Acces

Using a distance map and an active contour model to segment the carotid artery boundary from the lumen contour in proton density weighted magnetic resonance images

Segmentation methods have assumed an important role in image-based diagnosis of several cardiovascular diseases. Particularly, the segmentation of the boundary of the carotid artery is demanded in the detection and characterization of atherosclerosis and assessment of the disease progression. In this article, a fully automatic approach for the segmentation of the carotid artery boundary in Proton Density Weighted Magnetic Resonance Images is presented. The approach relies on the expansion of the lumen contour based on a distance map built using the gray-weighted distance relative to the center of the identified lumen region in the image under analysis. Then, a Snake model with a modified weighted external energy based on the combination of a balloon force along with a Gradient Vector Flow-based external energy is applied to the expanded contour towards the correct boundary of the carotid artery. The average values of the Dice coefficient, Polyline distance, mean contour distance and centroid distance found in the segmentation of 139 carotid arteries were 0.83 ± 0.11, 2.70 ± 1.69 pixels, 2.79 ± 1.89 pixels and 3.44 ± 2.82 pixels, respectively. The segmentation results of the proposed approach were also compared against the ones obtained by related approaches found in the literature, which confirmed the outstanding performance of the new approach. Additionally, the proposed weighted external energy for the Snake model was shown to be also robust to carotid arteries with large thickness and weak boundary image edges. (c) 202

Investigation of Flow Disturbances and Multi-Directional Wall Shear Stress in the Stenosed Carotid Artery Bifurcation Using Particle Image Velocimetry

Hemodynamics and shear forces are associated with pathological changes in the vascular wall and its function, resulting in the focal development of atherosclerosis. Flow complexities that develop in the presence of established plaques create environments favourable to thrombosis formation and potentially plaque rupture leading to stroke. The carotid artery bifurcation is a common site of atherosclerosis development. Recently, the multi-directional nature of shear stress acting on the endothelial layer has been highlighted as a risk factor for atherogenesis, emphasizing the need for accurate measurements of shear stress magnitude as well direction. In the absence of comprehensive patient specific datasets numerical simulations of hemodynamics are limited by modeling assumptions. The objective of this thesis was to investigate the relative contributions of various factors - including geometry, rheology, pulsatility, and compliance – towards the development of disturbed flow and multi-directional wall shear stress (WSS) parameters related to the development of atherosclerosis An experimental stereoscopic particle image velocimetry (PIV) system was used to measure instantaneous full-field velocity in idealized asymmetrically stenosed carotid artery bifurcation models, enabling the extraction of bulk flow features and turbulence intensity (TI). The velocity data was combined with wall location information segmented from micro computed tomography (CT) to obtain phase-averaged maps of WSS magnitude and direction. A comparison between Newtonian and non-Newtonian blood-analogue fluids demonstrated that the conventional Newtonian viscosity assumption underestimates WSS magnitude while overestimating TI. Studies incorporating varying waveform pulsatility demonstrated that the levels of TI and oscillatory shear index (OSI) depend on the waveform amplitude in addition to the degree of vessel constriction. Local compliance resulted in a dampening of disturbed flow due to volumetric capacity of the upstream vessel, however wall tracking had a negligible effect on WSS prediction. While the degree of stenosis severity was found to have a dominant effect on local hemodynamics, comparable relative differences in metrics of flow and WSS disturbances were found due to viscosity model, waveform pulsatility and local vessel compliance