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

Calcifications in atherosclerotic plaques and impact on plaque biomechanics

The catastrophic mechanical rupture of an atherosclerotic plaque is the underlying cause of the majority of cardiovascular events. The infestation of vascular calcification in the plaques creates a mechanically complex tissue composite. Local stress concentrations and plaque tissue strength properties are the governing parameters required to predict plaque ruptures. Advanced imaging techniques have permitted insight into fundamental mechanisms driving the initiating inflammatory-driven vascular calcification of the diseased intima at the (sub-) micron scale and up to the macroscale. Clinical studies have potentiated the biomechanical relevance of calcification through the derivation of links between local plaque rupture and specific macrocalcification geometrical features. The clinical implications of the data presented in this review indicate that the combination of imaging, experimental testing, and computational modelling efforts are crucial to predict the rupture risk for atherosclerotic plaques. Specialised experimental tests and mo

The influence of constitutive law choice used to characterise atherosclerotic tissue material properties on computing stress values in human carotid plaques.

Calculating high stress concentration within carotid atherosclerotic plaques has been shown to be complementary to anatomical features in assessing vulnerability. Reliability of stress calculation may depend on the constitutive laws/strain energy density functions (SEDFs) used to characterize tissue material properties. Different SEDFs, including neo-Hookean, one-/two-term Ogden, Yeoh, 5-parameter Mooney-Rivlin, Demiray and modified Mooney-Rivlin, have been used to describe atherosclerotic tissue behavior. However, the capacity of SEDFs to fit experimental data and the difference in the stress calculation remains unexplored. In this study, seven SEDFs were used to fit the stress-stretch data points of media, fibrous cap, lipid and intraplaque hemorrhage/thrombus obtained from 21 human carotid plaques. Semi-analytic solution, 2D structure-only and 3D fully coupled fluid-structure interaction (FSI) analyses were used to quantify stress using different SEDFs and the related material stability examined. Results show that, except for neo-Hookean, all other six SEDFs fitted the experimental points well, with vessel stress distribution in the circumferential and radial directions being similar. 2D structural-only analysis was successful for all seven SEDFs, but 3D FSI were only possible with neo-Hookean, Demiray and modified Mooney-Rivlin models. Stresses calculated using Demiray and modified Mooney-Rivlin models were nearly identical. Further analyses indicated that the energy contours of one-/two-term Ogden and 5-parameter Mooney-Rivlin models were not strictly convex and the material stability indictors under homogeneous deformations were not always positive. In conclusion, considering the capacity in characterizing material properties and stabilities, Demiray and modified Mooney-Rivlin SEDF appear practical choices for mechanical analyses to predict the critical mechanical conditions within carotid atherosclerotic plaques.This research is supported by BHF PG/11/74/29100, HRUK RG2638/14/16, the NIHR Cambridge Biomedical Research Centre, and National Natural Science Foundation of China (81170291).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.jbiomech.2015.09.02

Novel ultrasound features for the identification of the vulnerable carotid plaque

Background: The identification of the vulnerable carotid plaque is of paramount importance in order to prevent the significant stroke-related mortality and morbidity. Currently the clinical decision-making around this condition is based on the traditional ultrasound evaluation of the degree of stenosis. However, there is emerging evidence supporting that this is not sufficient for all patients. Aim of this thesis: The evaluation of novel carotid plaque features for the characterisation of plaque composition, volume and motion using 2 and 3 dimensional ultrasound technology. The ultimate goal is to identify novel sensitive imaging markers for carotid plaque characterisation and stroke-risk stratification. Methods: The Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study was a large prospective multicentre trial that was recently completed. A post-hoc analysis of the sonographic and clinical data from this study was performed in order to evaluate the effectiveness of novel ultrasound texture features, such as second order statics, on stroke-risk prediction. In addition, the change of specific texture features and degree of stenosis during the ACSRS follow-up time (8 years) and their importance for stroke prediction was evaluated. In order to assess the potential of 3D ultrasound carotid imaging we also developed a special methodology using a 3D broadband, linear array probe and the Q-lab software. This methodology was then applied in a clinical, cross-sectional study of patients with symptomatic and asymptomatic carotid disease. Finally we developed a carotid plaque motion analysis methodology that we tested on a feasibility study. Results: The post-hoc analysis of more than 1, 000 patients from the ACSRS database showed that there are novel ultrasound features of plaque homogeneity that can contribute to plaque characterisation and improve stroke-risk prediction. Similarly our results suggest that the change of degree of stenosis or plaque’s composition through time might have significant predictive value when combined with the above novel features. The study in 3D ultrasound prospectively assessed more than 80 people with symptomatic and asymptomatic carotid disease with both 2 and 3D carotid ultrasound without, though, revealing any significant benefit from the use of 3D imaging in terms of stroke-risk prediction. Finally, our feasibility study on plaque motion analysis showed that it is possible to objectively characterise plaque motion, using ultrasound and dedicated software without complicated reconstructions. Conclusion: The use of novel 2D ultrasound texture features in combination with traditional ones can improve the stroke-risk stratification. 3D ultrasound is a promising new approach, however, the current technology does not appear to offer a significant benefit in comparison to cheaper traditional 2D ultrasound for carotid plaque evaluation. Further research is warranted on this issue.Open Acces

Morphometric and Mechanical Analyses of Calcifications and Fibrous Plaque Tissue in Carotid Arteries for Plaque Rupture Risk Assessment

Objective: Atherosclerotic plaque rupture in carotid arteries is a major source of cerebrovascular events. Calcifications are highly prevalent in carotid plaques, but their role in plaque rupture remains poorly understood. This work studied the morphometric features of calcifications in carotid plaques and their effect on the stress distribution in the fibrous plaque tissue at the calcification interface, as a potential source of plaque rupture and clinical events. Methods: A comprehensive morphometric analysis of 65 histology cross-sections from 16 carotid plaques was performed to identify the morphology (size and shape) and location of plaque calcifications, and the fibrous-tissue fiber organization around them. Calcification-specific finite element models were constructed to examine the fibrous plaque tissue stresses at the calcification interface. Statistical correlation analysis was performed to elucidate the impact of calcification morphology and fibrous tissue organization on interface stresses. Results: Hundred-seventy-one calcifications were identified on the histology cross-sections, which showed great variation in morphology. Four distinct patterns of fiber organization in the plaque tissue were observed around the calcification. They were termed as attached, pushed-aside, encircling and random patterns. The stress analyses showed that calcifications are correlated with high interface stresses, which might be comparable to or even above the plaque strength. The stress levels depended on the calcification morphology and fiber organization. Thicker calcification with a circumferential slender shape, located close to the lumen were correlated most prominently to high interface stresses. Conclusion: Depending on its morphology and the fiber organization around it, a calcification in an atherosclerotic plaque can act as a stress riser and cause high interface stresses. Significance: This study demonstrated the potential of calcifications in atherosclerotic plaques to cause elevated stresses in plaque tissue and provided a biomechanical explanation for the histopathological findings of calcification-associated plaque rupture

Improving stroke risk prediction and individualised treatment in carotid atherosclerosis

Background: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. Currently, this risk estimation is based on measurements of stenosis and neurological symptoms, which determines the therapy of either medical treatment with or without carotid endarterectomy. The efficacy of this therapy is low and higher accuracy of diagnosis and therapy is warranted. Imaging of carotid plaque morphology using software for visualisation of plaque components may improve assessment of plaque phenotype and stroke risk. These studies aimed firstly to investigate if, and if yes, how, the carotid plaque morphology with image analysis of CTA associated with on-going biology in the corresponding specimen. Secondly, if risk stratification in clinical risk scores can be linked to the aforementioned associations. Finally, if the on-going biological processes can be specifically predicted out of the CTA imaging analysis. Methods: Plaque features were analysed in pre-operative CTA with dedicated software. In study I and II, the plaques were stratified according to quantified high and low of each feature, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry was performed to evaluate the findings in plaques. In study III, patient phenotype, according to clinical stroke risk scores of CAR and ABCD2 stratified the cohorts of high vs low scores which were subsequently profiled with microarrays, followed by bioinformatic analyses and correlation analyses of plaque morphology in CTA. In study IV, the microarray transcriptomes were individually coupled to morphological data from the CTA analysis, developing models with machine intelligence to predict the gene expression from a CTA image. The models were then tested in unseen patients. Results: In study I, stabilising markers and processes related to SMCs and ECM organisation were associated with highly calcified plaques, while inflammatory and lipid related processes were repressed. PRG4, a novel marker for atherosclerosis, was identified as the most up-regulated gene in highly calcified plaques. Study II showed that carotid lesions with large lipid rich necrotic core, intraplaque haemorrhage or plaque burden were characterized by molecular signatures coupled with inflammation and extracellular matrix degradation, typically linked with instability. Symptomatology associated with large lipid rich necrotic core and plaque burden. Cross-validated prediction model for symptoms, showed that plaque morphology by CTA alone was superior to stenosis degree. Study III revealed that a high clinical risk score in CAR and ABCD2, reflect a plaque phenotype linked to immune response and coagulation, where the novel ABCB5, was one of the most up-regulated genes. The high risk scores correlated with the plaque components matrix and calcification but no positive association with stenosis degree. Study IV resulted in 414 robustly predicted transcripts from the CTA image analysis, of which pathway analysis showed biological processes associated with typical pathophysiology of atherosclerosis and plaque instability. The model testing demonstrated a good correlation between predicted and observed transcript expression levels and pathway analysis revealed a unique dominant mechanism for each individual. Conclusions: Biological processes in carotid plaques associated to vulnerability, can be linked to plaque morphology analysed with CTA image analysis. Patient phenotype classified with clinical risk scores associates to plaque phenotype and morphology in CTA. The biological processes in the atherosclerotic plaque can be predicted with plaque morphology CTA analysis in this small pilot study, providing a possibility to precision medicine after validation in larger scale studie

Complicated approaches towards complicated atherosclerotic plaques

Medical research is oriented to vascular events’ prevention, either by the inhibition of growth or by the early detection and stabilization of the vulnerable atherosclerotic plaques. Numerous studies have been published in literature, aiming to determine vulnerability,by means of associating traditional risk factors, epidemiological data or morphological characteristics of atheromatous plaque ,as these are provided by routine or highly specialized imaging techniques. All of these studies though, focus to only a few factors implicated in plaque instability. The largest part of the current atherosclerosis research is targeted to the attempt of modelling the systemic and the local events, leading in plaque vulnerability. Of particular interest is the role of molecular signaling pathways and of gene interactions. The experimental reproducing of atheromatous plaque formation, growth and destabilization remains challenging, because of the limitations that animal models present. An holistic approach of atherosclerotic plaque vulnerability , considering mechanical and flow parameters of the prone to disease arterial segments, the circulating molecules, the enzymatic systems and the cells contributing to plaque evolution, the dynamic transformation , function and degeneration of arterial wall components are reviewed in this study

Effect of microstructure on mechanical behaviour of arterial tissue

The total number of annual deaths caused by cardiovascular diseases (CVDs), aortic aneurysms (AAs) and aortic dissections (ADs) is more than from any other cause. Most CVDs are a result of atherosclerosis, in which a fibrous cap covered lipid-rich plaque is formed in the arteries. The fibrous cap can rupture, blocking the artery and limiting the flow of blood to vital organs. AAs and ADs manifest as localised dilatations of the aorta, while simultaneously weakening the aortic wall. In atherosclerosis, AAs and ADs disruptions of the fibrous network and incorporation of microstructural defects make the artery vulnerable to rupture. This dissertation is aimed at describing the relationship between microstructure and mechanical, including fracture behaviour of arterial tissue. Unnotched and notched mechanical tests were performed on tissue samples from aneurysm-affected aortas. Mechanical parameters of ultimate material strength and extreme extensibility were measured, showing arterial layer and direction dependent differences in both unnotched and notched test. Similar differences were observed in fracture parameters of J-integral and crack tip curvature at failure. Interestingly, aneurysmal tissues were found to be notch-insensitive as the notched samples did not fail at a low stretch level. Histopathological analysis was performed on the mechanically tested tissues to investigate the influence of collagen, elastin, macrophage and glycosaminoglycan (GAG) contents, as well as collagen fibre dispersion on the mechanical and fracture behaviours. Both collagen and GAGs were associated with tissue strength, while higher GAG deposition was found to result in larger local collagen fibre dispersion in media and adventitia layers, but not in the intima. Stress-stretch behaviour of healthy, aneurysmal and atherosclerotic tissues were characterised with the modified Mooney-Rivlin constitutive material model. Curve fitting was used to compute the corresponding values of the model constants for each tissue type. Fitted material constants were found to differ amongst distinct types of tissue, while histological analyses showed that material constants were associated with waviness and dispersion of collagen fibres. To study the stretch driven microstructural reorganisations of the fibrous network, tensile tests with unnotched and notched tissue strips from porcine carotid arteries were performed while imaging with multiphoton microscopy. In general, fibres rotated towards the direction of stretch, where in notched samples, fibres rearranged themselves to redistribute loads away from the notch tip. Finally, a complete microstructural component based finite element model of the arterial tissue was developed, which consisted of the collagen fibres and the other structural entities such as elastin and GAGs. The collagen fibres were modelled as discrete entities within the model, where all the other structural entities were modelled in the form of ground matrix. The developed model was used to study the influence of distinct microstructural parameters on the mechanical behaviour of arterial tissues.Engineering and Physical Sciences Research Counci

Development of a novel uncovered stent system for the management of complex aortic aneurysms

Endovascular aortic repair (EVAR) is a minimally invasive alternative to open surgery for the treatment of aortic aneurysms (AA). However, standard EVAR is not applicable to complex AA with involvement of vital branches, which could be occluded by the endograft. As an emerging technique, the concept of multiple overlapping uncovered stents (MOUS) have been proposed to manage complex lesions. MOUS was used to modulate the flow pattern inside the aneurysm sac, and promote the thrombus formation followed by the aneurysm shrinkage. In this dissertation, we sought to investigate the mechanism of MOUS-induced flow modulation and key factors associated with the success of this novel technique: - The mechanical behaviour of AA was characterised by uniaxial material tests (Chapter 4). A Bayesian framework was proposed for material constants identification. They were found correlated to the microstructure of tissue fibre network and were capable in differentiating tissue types. - Solid-to-solid interaction and one-way fluid-solid interaction (FSI) analysis was performed based on patient-specific computer tomography angiography (Chapters 5&6). Structural stress concentrations were observed within the landing zones, which increased with the number of stents deployed. In the parameter studies (Chapter 6), the overall porosity was identified as the dominant factor of the flow-diverting outcome, while cross-stent structures of MOUS had limited influence. - The pathological effect of structural stress concentration induced by an implanted device was further studied in rabbit models (Chapter 7). The wall structural stress and fluid shear stress were obtained from FSI analysis based on magnetic resonance imaging (MRI), and correlated to plaque characteristics. Both high structural stress and low fluid shear stress were found correlated to plaque initialisation and increased inflammation. Overall, MOUS modulates the blood flow with robust performance under different overlapping patterns. Image-based biomechanical analysis can optimise MOUS design and can contribute to personalised pre-surgery planning.Shuo Wang was sponsored by China Scholarship Council (2014-2018)

Editor's Choice – European Society for Vascular Surgery (ESVS) 2023 Clinical Practice Guidelines on the Management of Atherosclerotic Carotid and Vertebral Artery Disease

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