Culprit Carotid Research Articles

Non-invasive in vivo thrombus imaging in patients with ischaemic stroke or transient ischaemic attack

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Life Molecular Imaging provide reagents for GP1 production free of charge. Background and Purpose 18F-GP1 is a novel positron-emitting radiotracer that has high and specific binding affinity for the activated glycoprotein IIb/IIIa receptor, a key receptor in platelet activation and thrombus formation. Preliminary studies 18F-GP1 demonstrated excellent in vivo binding properties which enabled detection of intravascular thrombosis in a range of conditions including coronary thrombosis, left ventricular thrombus, pulmonary thromboembolism, and deep vein thrombosis. In a pilot proof-of-concept study, we aimed to determine its potential clinical application in establishing the role and origin of thrombus in stroke . Methods Autoradiography of 18F-GP1 uptake was performed on post-mortem samples of infarcted brain tissue following an acute ischaemic stroke and from control brain tissue without stroke. Eleven patients with recent ischaemic stroke (n=9) or transient ischaemic attack (n=2) underwent 18F-GP1 positron emission tomography and computed tomography angiography at median of 11 (absolute range 2–21) days from symptom onset. 18F-GP1 uptake (quantified by maximum target-to-background ratio, TBRmax) was assessed in the carotid arteries and brain. Results Ex vivo autoradiography of post-mortem infarcted brain tissue showed focal uptake corresponding to intraluminal thrombus within the culprit vessel and downstream microvasculature. There was also evidence of lower diffuse uptake within some of the infarcted brain tissue reflecting microthrombi within regions of reperfusion haemorrhage. In vivo 18F-GP1 uptake was identified in 9 of 11 patients: 3 in the carotid arteries only, 3 in the brain only and 3 in both the brain and carotid arteries. In those with carotid uptake, 3 participants had >50% stenosis and 3 had non-stenotic disease. One case had bilateral stenotic disease (>70%) but only the culprit carotid artery demonstrated 18F-GP1 uptake. The average uptake was higher in the culprit (median TBRmax 1.55 [interquartile range 1.26–1.82]) compared with the contralateral non-culprit carotid artery (TBRmax 1.22 [1.19–1.6]). In those with brain 18F-GP1 uptake (TBRmax 6.45 [4.89–7.65]), areas of acute infarction on computed tomography correlated with brain 18F-GP1 uptake in 6 cases. There was no brain 18F-GP1 uptake in the 7 cases without CT-defined acute cerebral infarction. Conclusions 18F-GP1 positron emission tomography and computed tomography angiography is a novel non-invasive method of identifying in vivo cerebrovascular thrombosis which holds major promise in understanding the role and origin of thrombosis in stroke.

18F-NaF PET/MRI for Detection of Carotid Atheroma in Acute Neurovascular Syndrome.

Background MRI and fluorine 18-labeled sodium fluoride (18F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed. Purpose To evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome. Materials and Methods In this prospective observational cohort study (October 2017 to January 2020), participants underwent 18F-NaF PET/MRI. An experienced clinician determined the culprit carotid artery based on symptoms and record review. 18F-NaF uptake was quantified using standardized uptake values and tissue-to-background ratios. Statistical significance was assessed with the Welch, χ2, Wilcoxon, or Fisher test. Multivariable models were used to evaluate the relationship between the imaging markers and the culprit versus nonculprit vessel. Results A total of 110 participants were evaluated (mean age, 68 years ± 10 [SD]; 70 men and 40 women). Of the 110, 34 (32%) had prior cerebrovascular disease, and 26 (24%) presented with amaurosis fugax, 54 (49%) with transient ischemic attack, and 30 (27%) with stroke. Compared with nonculprit carotids, culprit carotids had greater stenoses (≥50% stenosis: 30% vs 15% [P = .02]; ≥70% stenosis: 25% vs 4.5% [P < .001]) and had increased prevalence of MRI-derived adverse plaque features, including intraplaque hemorrhage (42% vs 23%; P = .004), necrotic core (36% vs 18%; P = .004), thrombus (7.3% vs 0%; P = .01), ulceration (18% vs 3.6%; P = .001), and higher 18F-NaF uptake (maximum tissue-to-background ratio, 1.38 [IQR, 1.12-1.82] vs 1.26 [IQR, 0.99-1.66], respectively; P = .04). Higher 18F-NaF uptake was positively associated with necrosis, intraplaque hemorrhage, ulceration, and calcification and inversely associated with fibrosis (P = .04 to P < .001). In multivariable analysis, carotid stenosis at or over 70% (odds ratio, 5.72 [95% CI: 2.2, 18]) and MRI-derived adverse plaque characteristics (odds ratio, 2.16 [95% CI: 1.2, 3.9]) were both associated with the culprit versus nonculprit carotid vessel. Conclusion Fluorine 18-labeled sodium fluoride PET/MRI characteristics were associated with the culprit carotid vessel in study participants with acute neurovascular syndrome. Clinical trial registration no. NCT03215550 and NCT03215563 © RSNA, 2022 Online supplemental material is available for this article.

Feasibility of ex vivo fluorescence imaging of angiogenesis in (non-) culprit human carotid atherosclerotic plaques using bevacizumab-800CW

Vascular endothelial growth factor-A (VEGF-A) is assumed to play a crucial role in the development and rupture of vulnerable plaques in the atherosclerotic process. We used a VEGF-A targeted fluorescent antibody (bevacizumab-IRDye800CW [bevacizumab-800CW]) to image and visualize the distribution of VEGF-A in (non-)culprit carotid plaques ex vivo. Freshly endarterectomized human plaques (n = 15) were incubated in bevacizumab-800CW ex vivo. Subsequent NIRF imaging showed a more intense fluorescent signal in the culprit plaques (n = 11) than in the non-culprit plaques (n = 3). A plaque received from an asymptomatic patient showed pathologic features similar to the culprit plaques. Cross-correlation with VEGF-A immunohistochemistry showed co-localization of VEGF-A over-expression in 91% of the fluorescent culprit plaques, while no VEGF-A expression was found in the non-culprit plaques (p < 0.0001). VEGF-A expression was co-localized with CD34, a marker for angiogenesis (p < 0.001). Ex vivo near-infrared fluorescence (NIRF) imaging by incubation with bevacizumab-800CW shows promise for visualizing VEGF-A overexpression in culprit atherosclerotic plaques in vivo.

Radiomics applied to carotid CT angiograms can identify significant differences between culprit and non-culprit lesions in patients with stroke and transient ischaemic attack

Abstract Background Carotid artery atherosclerosis is an important cause of ischaemic stroke. In oncology, textural analysis (“radiomics”) of computed tomography (CT) images can predict the metastatic potential and prognosis of several types of malignant tumours. We investigated whether this quantitative approach could be applied in carotid artery disease. Purpose (1) To evaluate the feasibility of computed tomography angiography (CTA) texture analysis in differentiating symptomatic from asymptomatic patients. (2) To investigate whether CTA carotid texture analysis can identify culprit lesions in patients with stroke and transient ischaemic attack (TIA). Methods Carotid CTAs of consented research subjects were included in the study. Symptomatic patients had confirmed carotid artery-related ischaemic stroke or TIA in the 7 days before CTA imaging. Asymptomatic (ASX) patients had no prior stroke/TIA. Both TexRAD, a research texture analysis software, and PyRadiomics, a Python package for radiomics studies, were used to extract 99 first-order and higher-order texture features from regions-of-interest (ROI) drawn around the outer wall of the carotid artery. Single-slice analysis compared the carotid bifurcations of symptomatic and asymptomatic patients, and of culprit (CC) and non-culprit (NC) arteries in symptomatic patients. Multi-slice analysis was conducted using a 3D volume defined by ROIs drawn on 14 consecutive CT slices of 3mm thickness, covering 3cm of carotid artery. The Mann-Whitney U test was used for inter-subject comparisons (ASX vs CC; ASX vs NC) and the Wilcoxon signed-rank test was used for intra-subject comparisons (CC vs NC). A p value &amp;lt;0.0005 was deemed statistically significant after Bonferroni correction for multiple comparisons. Non-normally distributed variables are reported as median (interquartile range). Results The dataset comprised 82 carotid arteries from 41 symptomatic patients (41 culprit; 41 non-culprit) and 50 carotid arteries from 25 asymptomatic patients. Single-slice analysis revealed greater homogeneity in asymptomatic carotids versus symptomatic culprit carotids (Uniformity: ASX 0.11 (0.05); CC 0.08 (0.05), p&amp;lt;0.0005) and non-culprit carotids (NC 0.08 (0.18), p&amp;lt;0.0005). In multi-slice analysis, culprit and non-culprit carotid arteries displayed greater heterogeneity than asymptomatic carotids (GLSZM zone entropy: CC 6.57 (0.59); NC 6.76 (0.65); ASX 6.21 (0.32), p&amp;lt;0.0005). Multi-slice analysis of symptomatic culprit versus non-culprit carotids revealed greater heterogeneity in culprit carotids than non-culprit carotids (GLRLM run entropy CC 6.57 (0.59); NC 5.05 (0.70), p&amp;lt;0.0001). Conclusion Textural analysis of carotid CTAs reveal significant differences between symptomatic and asymptomatic patients and between culprit and non-culprit carotid arteries within symptomatic patients. This approach could be used to identify patients at high risk of further stroke for aggressive medical therapy and surveillance. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): EPVL is undertaking a PhD funded by the Cambridge School of Clinical Medicine and the Medical Research Council's Doctoral Training Partnership

Contrast CT classification of asymptomatic and symptomatic carotids in stroke and transient ischaemic attack with deep learning and interpretability

Abstract Background Convolutional neural networks (CNNs), part of deep learning, are used widely for computer vision tasks and in some medical domains, such as mammography interpretation. The application of deep learning to carotid artery imaging is scarce. We investigated the ability of deep learning to correctly classify contrast CT images of the carotid arteries without the need for prior feature selection. Purpose (1) To assess the ability of deep learning to differentiate symptomatic patients (had prior stroke or transient ischaemic attack [TIA]) from asymptomatic patients (no prior stroke/TIA) using contrast CT scans alone. (2) To investigate whether deep learning can further discriminate between culprit and non-culprit carotid arteries in symptomatic patients. (3) To assess the interpretability of the deep learning models. Methods Carotid contrast CT scans of consented research subjects were included in the study. Symptomatic patients had confirmed carotid artery-related ischaemic stroke or TIA in the 7 days before CT imaging, and asymptomatic patients had no prior cerebrovascular events. The dataset comprised 1148 axial symptomatic slices (covering a 3cm area of each carotid artery in 41 patients; 41 culprit and 41 non-culprit carotids) and 700 asymptomatic slices (from the bilateral carotid arteries of 25 patients). The dataset was split such that 75% was used for training and 25% for testing. A 30x30 bounding box was used to create patches of the carotid arteries from these axial slices for use as input to the CNN, a modified VGG16 architecture initialised with ImageNet weights to leverage transfer learning (the application of a model trained in one domain to a different domain) implemented in Python. Data augmentation was applied to the training set and the model was trained for 100 epochs using a cyclic learning rate, the RMSProp optimizer and binary cross-entropy loss. Class activation heatmaps were generated using the GradCAM method to highlight the areas of the image that were most important to the model for making its classification decision. Results The deep learning model was 92% accurate in correctly identifying carotid arteries from symptomatic patients versus those from asymptomatic patients. Discriminating between culprit versus non-culprit carotid arteries in symptomatic patients alone was 71% accurate. The class activation heatmaps demonstrated how the model learnt to localise the carotid artery within the image patch, and to ignore the arterial lumen when making its classification decision. Conclusions Deep learning can be used to differentiate between symptomatic and asymptomatic carotid CT scans from stroke/TIA subjects without the need for prior feature engineering. The model learns to identify relevant features in the image that predict the patients' symptom state. If further validated, this approach could be used to identify high-risk patients for intensive medical therapy. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): EPVL is undertaking a PhD funded by the Cambridge School of Clinical Medicine and the Medical Research Council's Doctoral Training Partnership

Dual-Tracer Positron-Emission Tomography for Identification of Culprit Carotid Plaques and Pathophysiology In Vivo.

Inflammation and microcalcification are interrelated processes contributing to atherosclerotic plaque vulnerability. Positron-emission tomography can quantify these processes in vivo. This study investigates (1) 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) uptake in culprit versus nonculprit carotid atheroma, (2) spatial distributions of uptake, and (3) how macrocalcification affects this relationship. Individuals with acute ischemic stroke with ipsilateral carotid stenosis of ≥50% underwent FDG-positron-emission tomography and NaF-positron-emission tomography. Tracer uptake was quantified using maximum tissue-to-background ratios (TBRmax) and macrocalcification quantified using Agatston scoring. In 26 individuals, median most diseased segment TBRmax (interquartile range) was higher in culprit than in nonculprit atheroma for both FDG (2.08 [0.52] versus 1.89 [0.40]; P<0.001) and NaF (2.68 [0.63] versus 2.39 [1.02]; P<0.001). However, whole vessel TBRmax was higher in culprit arteries for FDG (1.92 [0.41] versus 1.71 [0.31]; P<0.001) but not NaF (1.85 [0.28] versus 1.79 [0.60]; P=0.10). NaF uptake was concentrated at carotid bifurcations, while FDG was distributed evenly throughout arteries. Correlations between FDG and NaF TBRmax differed between bifurcations with low macrocalcification (rs=0.38; P<0.001) versus high macrocalcification (rs=0.59; P<0.001). This is the first study to demonstrate increased uptake of both FDG and NaF in culprit carotid plaques, with discrete distributions of pathophysiology influencing vulnerability in vivo. These findings have implications for our understanding of the natural history of the disease and for the clinical assessment and management of carotid atherosclerosis.

18F-sodium fluoride positron emission tomography assessed microcalcifications in culprit and non-culprit human carotid plaques

Background18F-NaF positron emission tomography (PET) targets microcalcifications. We compared in vitro microPET assessed 18F-NaF uptake between culprit and non-culprit human carotid plaques. Furthermore, we compared 18F-NaF uptake with calcification visualized on microcomputed tomography (microCT). MethodsCarotid plaques from stroke patients undergoing surgery were incubated in 18F-NaF and scanned using a microPET and a microCT scan. The average PET assessed 18F-NaF uptake was expressed as percentage of the incubation dose per gram (%Inc/g). 18F-NaF PET volume of interest (VOI) was compared with CT calcification VOI. Results23 carotid plaques (17 culprit, 6 non-culprit) were included. The average 18F-NaF uptake in culprit carotid plaques was comparable with the uptake in non-culprit carotid plaques (median 2.32 %Inc/g [IQR 1.98 to 2.81] vs. median 2.35 %Inc/g [IQR 1.77 to 3.00], P = 0.916). Only a median of 10% (IQR 4 to 25) of CT calcification VOI showed increased 18F-NaF uptake, while merely a median of 35% (IQR 6 to 42) of 18F-NaF PET VOI showed calcification on CT. Conclusions18F-NaF PET represents a different stage in the calcification process than CT. We observed a similar PET assessed 18F-NaF uptake and pattern in culprit and non-culprit plaques of high-risk patients, indicating that this method may be of more value in early atherosclerotic stenosis development.

Abstract TMP29: Non-invasive Identification of Culprit Carotid Atheroma Using Sodium Fluoride-positron Emission Tomography

Introduction: Microcalcification is a histopathological feature of atheroma at risk of rupture; so-called “vulnerable plaques.” Positron emission tomography (PET) using 18 F-sodium fluoride (NaF) has been used to detect microcalcification in ex vivo histology, though its use in vivo has been limited. We investigated the utility of NaF-PET to identify culprit carotid artery atheroma non-invasively in vivo in the setting of acute ischemic stroke. Methods: Symptomatic carotid artery stenosis of ≥50% was imaged using NaF-PET within 14 days of ipsilateral ischemic stroke. Symptomatic arteries were compared to contralateral asymptomatic carotid arteries. NaF dose was 125 MBq with 60 minute uptake on a GE Discovery 690 with 64 slice computed tomography. NaF uptake was measured using standardized uptake values for each artery’s single region of maximum uptake (SUVmax) and the mean of the three slices representing the most diseased segment (MDS-SUVmax). Arteries were compared using Wilcoxon signed-rank testing. Results: Fifty-two carotid arteries were analyzed: 26 symptomatic, 26 asymptomatic. Median SUVmax was higher in symptomatic than asymptomatic arteries: 2.16 (IQR 0.76) and 1.88 (IQR 0.94) respectively (p&lt;0.001). MDS-SUVmax was 2.04 (IQR 0.66) in symptomatic and 1.76 (IQR 0.83) in asymptomatic carotids (p&lt;0.001). Calcium scores did not differ between symptomatic and asymptomatic arteries (p=0.34). Conclusions: The ability to identify culprit carotid atheroma using NaF-PET in vivo represents an important advance in vascular imaging. This has important implications for understanding atherosclerosis pathophysiology, as well as potential clinical applications to identify and risk-stratify vulnerable carotid atheroma.

Incremental predictive value of carotid inflammation in acute ischemic stroke.

Microwave Radiometry (MWR) allows in vivo noninvasive assessment of internal temperature of tissues. The aim of the present study was to evaluate in patients with ischemic stroke and bilateral carotid plaques (1) whether ipsilateral carotid arteries exhibit higher temperature differences (ΔT), as assessed by MWR; (2) the predictive accuracy of MWR in symptomatic carotid artery identification. Consecutive patients with recent acute anterior circulation ischemic stroke because of large artery atherosclerosis were included in the study. Carotid arteries of all patients were evaluated by carotid ultrasound and MWR. In total, 50 patients were included in the study. Culprit carotid arteries had higher ΔT compared with nonculprit (0.93±0.58 versus 0.58±0.35°C; P<0.001). The addition of ΔT to a risk prediction model based only on ultrasound plaque characteristics increased its predictive accuracy significantly (c-statistic: 0.691 versus 0.768; Pdif=0.05). Culprit carotid arteries show higher thermal heterogeneity compared with nonculprit carotid arteries in patients with acute ischemic stroke and bilateral carotid plaques. MWR has incremental value in culprit carotid artery discrimination.

TCT-292 Identification of culprit carotid plaques in patients with ischemic stroke with a new noninvasive method

TCT-292 Identification of culprit carotid plaques in patients with ischemic stroke with a new noninvasive method

Snoring and Severity of Symptomatic and Asymptomatic Carotid Stenosis: A Population-Based Study

Obstructive sleep apnea has increasingly been linked to cardiovascular damage. More recently, the snoring component itself has been independently linked to the presence of carotid atheroma, via local arterial trauma. We aimed to identify whether a snoring history is a risk factor for carotid stenosis in individuals presenting with a TIA or ischemic stroke. Participants in the Oxford Vascular Study (OXVASC) were asked about their snoring history as part of an entry questionnaire. In 561 individuals with a recent TIA or stroke, who had both a complete snoring questionnaire and carotid imaging, the relationship between presence and severity of snoring and the degree of carotid artery stenosis in both the symptomatic (culprit) and asymptomatic (non-culprit) sides. Of 561 participants (287 male, mean/SD age = 73.3/11.0 years), 90 (16.0%) had ≥ 50% carotid stenosis, and 154 (27.5%) snored frequently (≥ 1-2 times/week). No significant associations were identified between frequency of self-reported snoring, and the degree of culprit and non-culprit carotid vessel stenosis, or plaque morphology. No significant association could be identified between a history of frequent snoring and the presence of carotid atheroma, degree of stenosis, or plaque type.

Carotid Plaque Inflammation Is Associated With Cerebral Microembolism in Patients With Recent Transient Ischemic Attack or Stroke

Cerebral infarcts distal to carotid stenoses are thought to be caused by emboli from inflamed, destabilized plaques. We hypothesized that microembolic signals (MES) on transcranial Doppler will be associated with carotid plaque inflammation on (18)F fluorodeoxyglucose positron-emission tomography (FDG PET) in recently symptomatic patients. Sixteen patients presenting with recent (47 ± 31 days) anterior circulation transient ischemic attack or minor stroke and 50% to 99% stenosis of the ipsilateral carotid bifurcation underwent FDG PET, high-resolution black-blood carotid MRI, and transcranial Doppler for detection of MES. Patients with potential cardiac sources of emboli or contralateral MES were excluded. Regions of interest defined on the coregistered MRI were used to measure FDG standardized uptake values (with Rousset partial volume correction) from the index and contralateral carotid plaques and artery. Ipsilateral MES were detected in 7 patients (MES+ group) and absent in 8 (MES- group). There was a significant difference in index-to-contralateral plaque standardized uptake value ratio between MES+ (median, 1.05; first to third quartile, 0.96 to 1.32) and MES- (median, 0.76; first to third quartile, 0.62 to 0.94) patients (P=0.005). The interval from symptom onset to PET and percent index carotid stenosis were not different between the 2 groups (P=0.68 and P=0.48, respectively). In this sample of recently symptomatic patients with carotid stenosis, an association was found between in vivo measures of plaque inflammation detected by FDG PET and the presence of transcranial Doppler MES. These findings strengthen the notion that embolic events distal to carotid stenoses are related to plaque inflammation, and FDG PET may be useful in the investigation of culprit carotid lesions.