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

Imaging of the Vulnerable Atherosclerotic Plaque. Pre-Clinical Evaluation of PET Tracers for Vascular Inflammation

Atherosclerosis is a vascular inflammatory disease causing coronary artery disease, myocardial infarct and stroke, the leading causes of death in Finland and in many other countries. The development of atherosclerotic plaques starts already in childhood and is an ongoing process throughout life. Rupture of a plaque and the following occlusion of the vessel is the main reason for myocardial infarct and stroke, but despite extensive research, the prediction of rupture remains a major clinical problem. Inflammation is considered a key factor in the vulnerability of plaques to rupture. Measuring the inflammation in plaques non-invasively is one potential approach for identification of vulnerable plaques. The aim of this study was to evaluate tracers for positron emission tomography (PET) imaging of vascular inflammation. The studies were performed with a mouse model of atherosclerosis by using ex vivo biodistribution, autoradiography and in vivo PET and computed tomography (CT). Several tracers for inflammation activity were tested and compared with the morphology of the plaques. Inflammation in the atherosclerotic plaques was evaluated as expression of active macrophages. Systematic analysis revealed that the uptake of 18F-FDG and 11C-choline, tracers for metabolic activity in inflammatory cells, was more prominent in the atherosclerotic plaques than in the surrounding healthy vessel wall. The tracer for αvβ3 integrin, 18Fgalacto- RGD, was also found to have high potential for imaging inflammation in the plaques. While 11C-PK11195, a tracer targeted to receptors in active macrophages, was shown to accumulate in active plaques, the target-to-background ratio was not found to be ideal for in vivo imaging purposes. In conclusion, tracers for the imaging of inflammation in atherosclerotic plaques can be tested in experimental pre-clinical settings to select potential imaging agents for further clinical testing. 18F-FDG, 18F-galacto-RGD and 11C-choline choline have good properties, and further studies to clarify their applicability for atherosclerosis imaging in humans are warranted.Siirretty Doriast

Molecular Imaging

The present book gives an exceptional overview of molecular imaging. Practical approach represents the red thread through the whole book, covering at the same time detailed background information that goes very deep into molecular as well as cellular level. Ideas how molecular imaging will develop in the near future present a special delicacy. This should be of special interest as the contributors are members of leading research groups from all over the world

Advanced imaging to detect disease burden, activity and progression in coronary artery disease and aortic valve disease

INTRODUCTION: Coronary artery disease and aortic stenosis represent two important manifestations ofcardiovascular disease, a dominant cause of morbidity and mortality in the UK andworldwide. In recent years, advances in modern imaging techniques have transformedour understanding of the pathophysiology of these underlying disease states, enablingthe detailed characterisation of disease processes and the identification of a largenumber of potential therapeutic targets. To address the increasing burden ofcardiovascular disease, improved identification of patients at risk of diseaseprogression and future events is crucial. Application of advanced non-invasiveimaging will be instrumental in achieving this goal and could enable improvedtargeting of existing or novel therapies directed against these disease processes.The objective of this thesis was to investigate the ability of novel advanced noninvasiveimaging to quantify disease burden, to measure disease activity and to assessdisease progression in both coronary artery disease and aortic valve disease.METHODS AND RESULTS:•THE ASSOCIATION BETWEEN NON-INVASIVE FRACTIONAL FLOW RESERVE ANDPLAQUE BURDEN IN NON-OBSTRUCTIVE ATHEROSCLEROSIS - The association between nonobstructive atherosclerosis and non-invasive fractionalflow reserve derived from computed tomography (FFRCT) measured in distalcoronary vessels was investigated in 155 patients undergoing computed tomographycoronary angiography with greater than 25% coronary stenosis in at least oneepicardial vessel. Plaque analysis was performed on all vessels with between 25-70%stenosis using dedicated software (Autoplaque, Cedars Sinai Medical Center, LosAngeles, USA). Multiple plaque components including calcified plaque (CP) volume,non-calcified plaque (NCP) volume, low density plaque (LD-NCP) volume,remodelling index (RI) and contrast density difference (CDD) were quantified. Anabnormal distal vessel FFRCT (V-FFRCT) was defined as ≤0.75. Total plaque volume,calcified plaque volume, noncalcified plaque volume and low-density plaque volumewere higher in vessels with an abnormal V-FFRCT compared to those with a normalV-FFRCT (p1.25)correlated with change in calcium score at one year (Spearman’s Rho 0.37, p<0.0001).Participants with evidence of increased ¹⁸F-fluoride uptake at baseline demonstratedmore rapid progression of coronary calcification at one year (change in calcium score,97 [39-166] versus 35 [7-93] AU; p<0.0001). When individual coronary segments withincreased ¹⁸F-fluoride activity were compared to negative reference plaques in thesame participant, segments with increased ¹⁸F-fluoride uptake demonstratedprogressive calcification at one year (from 95 [30-209] AU to 148 [61-289] AU;p<0.001) whereas there was no change in calcium score for reference segments (from46 [16-113] to 49 [20-115] AU; p=0.329).• IMAGE OPTIMISATION AND MOTION CORRECTION OF CORONARY PET-CT: The effect of different PET reconstruction algorithms and application of cardiacmotion correction upon coronary 18F-fluoride PET activity was assessed in a cohort ofpatients with a recent diagnosis of Acute Coronary Syndrome (n=22). Image qualitywas assessed using Signal-to-Noise Ratio (SNR). An optimal balance between signalintensity and noise was achieved using 24 subsets, 4 iterations, point-spread-functionmodelling, time of flight and 5-mm post-filtering which provided the highest medianSNR. A novel cardiac motion correction method led to improved SNR of culprit plaques (24.5[19.9-31.5]) when compared to the standard method of using PET datafrom the diastolic cardiac phase only (15.7[12.4-18.1]; p<0.001). Further, motioncorrectionled to a greater SNR difference between culprit and reference lesions (10.9[6.3-12.6]) compared to diastolic (6.2 [3.6-10.3] p=0.001) and summed data (7.1 [4.8-11.6] p=0.001).• CT-AVC AND ECHOCARDIOGRAPHY IN THE PROGRESSION OF AORTIC STENOSIS: In a study of participants with aortic stenosis, the reproducibility of CT calcium scoringof the aortic valve as well as its ability to detect changes in disease severity over timewas assessed and compared with echocardiography, the current gold standard imagingtechnique in aortic stenosis. In a group of 15 participants who underwent repeat CTscanning within four weeks, quantification of aortic valve calcification by CT (CTAVC)was reproducible (limits of agreement -12 to 10%, ICC 0.99). Peak aortic jetvelocity was the most reproducible measure of aortic stenosis severity onechocardiography (limits of agreement -7 to 17%; ICC 0.96). In a second cohort ofpatients, progression of calcification on CT and haemodynamic progression byechocardiography was assessed and a ratio of annualised disease progression andmeasurement variability was generated and used to estimate numbers of patientsrequired to detect annualised changes in disease severity on both modalities. CT-AVCdemonstrated a favourable progression-to-variability ratio (Cohen’s d statistic 3.12)versus echocardiography (Cohen’s d statistic for peak velocity 0.71), suggesting fewerpatients would be required to detect changes in disease progression.• CARDIAC MOTION CORRECTION APPLIED TO PET-CT AND PET-MR OF THE AORTICVALVE: The application of cardiac motion correction was investigated in a group ofparticipants with aortic stenosis undergoing 18F-fluoride PET-CT (n=5) and PET-MR(n=1). When compared to the standard method of utilising PET data acquired duringthe diastolic phase only, the application of cardiac motion correction improved signalto noise ratio (48.8 vs 21.2; p<0.05) and tissue to background ratio (3.1 vs 2.5 p<0.05). CONCLUSIONS: The application of advanced non-invasive imaging techniques can provide novelmeasures of disease burden, activity and progression in both coronary atherosclerosisand aortic stenosis

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

Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy

nuclear medicine; diagnostic radiolog

Duplex ultrasound assessment of carotid arterial atherosclerotic disease : investigation of direct stenosis measurement methods and image analysis for vulnerable plaque identification

Purpose: Ultrasound assessment of carotid disease is currently based on stenosis haemodynamic effects. The accuracy of direct stenosis measurement remains unclear, while research on atherosclerosis suggests identification of other plaque characteristics beyond size. The aim of the study is to investigate whether direct stenosis measurement and plaque ultrasound image analysis could potentially be used for more accurate diagnostic investigation. Method and material: Eighty-seven patients with cardiovascular disease had a carotid duplex ultrasound scan and velocity and B-mode measurements data were recorded for direct diameter measurement evaluation. Forty patients were scanned for quantitative plaque analysis and association of several parameters with symptoms was investigated. Results: For the degree of stenosis, ECST method indicated greater agreement among direct measurement methods with velocity criteria, however in cases of mild stenosis difference was reported. ECST method measurements showed considerably better agreement with MRA stenosis calculations compared with other methods. Intima-media grey scale level was associated with plaque echogenicity but the correlation was not significant, however there was an association with blood cholesterol levels. Percentages of plaque area with grey scale value less than 35 and 40 showed good accuracy in identifying symptomatic patients. As far as fibrous cap is concerned, a thickness less than 300 μm was well correlated with symptomatic disease, however no association was noted for its echogenicity. Conclusion: ECST direct stenosis measurement method could potentially be used for better stenosis classification in cases with inconclusive haemodynamic estimations. Quantitative plaque analysis, such as fibrous cap thickness measurement and grey level analysis, shows promising results in association with symptomatic disease and particular plaque characteristics