Cohort profile: BIOVASC-late, a prospective multicentred study of imaging and blood biomarkers of carotid plaque inflammation and risk of late vascular recurrence after non-severe stroke in Ireland

PurposeInflammation is important in stroke. Anti-inflammatory therapy reduces vascular events in coronary patients. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) identifies plaque inflammation-related metabolism. However, long-term prospective cohort studies investigating the association between carotid plaque inflammation, identified on 18F-FDG PET and the risk of recurrent vascular events, have not yet been undertaken in patients with stroke.ParticipantsThe Biomarkers Imaging Vulnerable Atherosclerosis in Symptomatic Carotid disease (BIOVASC) study and Dublin Carotid Atherosclerosis Study (DUCASS) are two prospective multicentred observational cohort studies, employing near-identical methodologies, which recruited 285 patients between 2008 and 2016 with non-severe stroke/transient ischaemic attack and ipsilateral carotid stenosis (50%–99%). Patients underwent coregistered carotid 18F-FDG PET/CT angiography and phlebotomy for measurement of inflammatory cytokines. Plaque 18F-FDG-uptake is expressed as maximum standardised uptake value (SUVmax) and tissue-to-background ratio. The BIOVASC-Late study is a follow-up study (median 7 years) of patients recruited to the DUCASS/BIOVASC cohorts.Findings to dateWe have reported that 18F-FDG-uptake in atherosclerotic plaques of patients with symptomatic carotid stenosis predicts early recurrent stroke, independent of luminal narrowing. The incorporation of 18F-FDG plaque uptake into a clinical prediction model also improves discrimination of early recurrent stroke, when compared with risk stratification by luminal stenosis alone. However, the relationship between 18F-FDG-uptake and late vascular events has not been investigated to date.Future plansThe primary aim of BIOVASC-Late is to investigate the association between SUVmax in symptomatic ‘culprit’ carotid plaque (as a marker of systemic inflammatory atherosclerosis) and the composite outcome of any late major vascular event (recurrent ischaemic stroke, coronary event or vascular death). Secondary aims are to investigate associations between: (1) SUVmax in symptomatic plaque, and individual vascular endpoints (2) SUVmax in asymptomatic contralateral carotid plaque and SUVmax in ipsilateral symptomatic plaque (3) SUVmax in asymptomatic carotid plaque and major vascular events (4) inflammatory cytokines and vascular events.

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Abstract TMP119: Early Cerebral Ischemic Events in Symptomatic Carotid Stenosis are Related to Plaque Inflammation

Stroke ◽

10.1161/str.48.suppl_1.tmp119 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Prakash R Paliwal ◽

Arvind K Sinha ◽

Hock L Teoh ◽

James Hallinan ◽

Zhengdao Du ◽

...

Keyword(s):

Cerebral Ischemia ◽

Carotid Stenosis ◽

Fdg Pet ◽

Carotid Plaque ◽

Stroke Recurrence ◽

Symptomatic Carotid ◽

Symptomatic Carotid Stenosis ◽

Plaque Inflammation ◽

Cerebral Ischemic ◽

Ischemic Events

Background and aims: Symptomatic carotid stenosis is associated with an increased risk of early stroke recurrence. Severity of the stenosis, current basis of revascularization, explains only the cerebral ischemic mechanism of regional hypoperfusion. Plaque inflammation, the initiating event for plaque rupture and thromboembolism (artery-to-artery embolism), is not evaluated routinely. Using 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET)/computed tomography (CT) and high resolution magnetic resonance imaging (HR-MRI), we investigated the role of plaque imaging and stroke recurrence in our cohort of stroke patients with recently symptomatic carotid stenosis. Methods: This ongoing prospective study included consecutive patients within 30-days of recent stroke and ipsilateral carotid stenosis (≥50%). FDG uptake was quantified as mean standardized uptake values (SUV, g/ml). The ratio of T1 hyperintensity of carotid plaque to the ipsilateral sternocleidomastoid muscle (SCM) was recorded on T1-weighted fat suppressed images. Patients were followed prospectively for stroke recurrence within 90-days. Embolic potential of carotid plaque is estimated by presence of spontaneous microembolic signals (MES) on extended transcranial Doppler monitoring of ipsilateral middle cerebral artery. Results: Of the 33 patients included in the study, 6 (18%) suffered from recurrent cerebral ischemic event in the same vascular territory within 90-days. Compared to patients without subsequent cerebral ischemic events, patients with recurrent cerebral ischemia showed higher mean T1 carotid-SCM ratio (2.49 versus 1.53; p<0.0001) and higher mean SUV value in the carotid plaque (3.52g/ml versus 1.51g/ml; p<0.0001). Higher T1 carotid-SCM ratio on HR-MRI (OR 4.249, 95%CI 1.818-5.18; p<0.0001), higher mean SUV on FDG-PET (OR 3.050, 95%CI 5.586-28.571; p=0.005) and MES on TCD (OR 2.186, 95%CI 1.652-47.619;p=0.037) were independent predictors of recurrent cerebral ischemia. Conclusions: FDG-PET/CT and HR-MRI imaging of carotid stenosis helps in identification of patients at higher risk of subsequent cerebral ischemic events and may aid in better therapeutic decision-making.

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Carotid Plaque Inflammation Imaged by PET and Prediction of Recurrent Stroke at 5 Years

Neurology ◽

10.1212/wnl.0000000000012909 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012909

Author(s):

John Joseph McCabe ◽

Pol Camps-Renom ◽

Nicola Giannotti ◽

Jonathan P. McNulty ◽

Sarah Coveney ◽

...

Keyword(s):

Ischaemic Stroke ◽

Pet Imaging ◽

Carotid Plaque ◽

Recurrent Stroke ◽

Carotid Revascularization ◽

Fdg Uptake ◽

Pet Ct ◽

Stenosis Severity ◽

Plaque Inflammation

Objective:To determine whether carotid plaque inflammation identified by 18F-fluorodeoxyglucose (18FDG)-PET is associated with late (5-year) recurrent stroke.Methods:We did an individual-participant data pooled analysis of three prospective studies with near-identical study methods. Eligible patients had recent non-severe (modified Rankin Score ≤3) ischaemic stroke/TIA and ipsilateral carotid stenosis (50-99%). Participants underwent carotid 18FDG-PET/CT angiography ≤14 days after recruitment. 18FDG uptake was expressed as maximum standardized uptake value (SUVmax) in the axial single hottest slice of symptomatic plaque. We calculated the previously-validated Symptomatic Carotid Atheroma Inflammation Lumen-stenosis (SCAIL) score, which incorporates a measure of stenosis severity and 18FDG uptake. The primary outcome was 5-year recurrent ipsilateral ischaemic stroke after PET imaging.Results:Of 183 eligible patients, 181 patients completed follow-up (98.9%). The median duration of follow-up was 4.9 years (interquartile range 3.3-6.4, cumulative follow-up period 901.8 patient-years). After PET imaging, 17 patients had a recurrent ipsilateral ischemic strokes at 5 years (recurrence rate 9.4%, 95% CI 5.6-14.6%). Baseline plaque SUVmax independently predicted 5-year ipsilateral recurrent stroke after adjustment for age, gender, carotid revascularization, stenosis severity, NIH Stroke Scale, and diabetes mellitus (adjusted HR 1.98; 95 % CI, 1.10-3.56, p=0.02, per 1g/mL increase SUVmax). On multivariable Cox regression, SCAIL score predicted 5-year ipsilateral stroke (adjusted HR 2.73 per 1-point increase; 95% CI 1.52-4.90, p=0.001).Conclusion:Plaque inflammation-related 18FDG uptake improved identification of 5-year recurrent ipsilateral ischaemic stroke. Addition of plaque inflammation to current selection strategies may target patients most likely to have late as well as early benefit from carotid revascularization.Classification of Evidence:This study provides Class I evidence that in individuals with recent ischemic stroke/TIA and ipsilateral carotid stenosis, carotid plaque inflammation-related 18FDG uptake on PET/CT angiography was associated with 5-year recurrent ipsilateral stroke.

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When to image carotid plaque inflammation with FDG PET/CT

Nuclear Medicine Communications ◽

10.1097/mnm.0b013e32833c365e ◽

2010 ◽

Vol 31 (9) ◽

pp. 773-779 ◽

Cited By ~ 16

Author(s):

Martin Graebe ◽

Lise Borgwardt ◽

Liselotte Højgaard ◽

Henrik Sillesen ◽

Andreas Kjaer

Keyword(s):

Fdg Pet ◽

Carotid Plaque ◽

Pet Ct ◽

Plaque Inflammation ◽

Fdg Pet Ct

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Carotid Plaque Inflammation Assessed by 18F-FDG PET/CT and Lp-PLA2 Is Higher in Symptomatic Patients

Angiology ◽

10.1177/0003319720965419 ◽

2020 ◽

pp. 000331972096541

Author(s):

Alicia Bueno ◽

Jose Ramon March ◽

Pilar Garcia ◽

Cristina Cañibano ◽

Antonio Ferruelo ◽

...

Keyword(s):

Carotid Stenosis ◽

Carotid Plaque ◽

Carotid Plaques ◽

Fdg Uptake ◽

Standardized Uptake Values ◽

Asymptomatic Patients ◽

Pet Ct ◽

Significant Difference ◽

Plaque Inflammation ◽

Artery Disease

Carotid plaque inflammation assessed by 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are higher in symptomatic patients. The aim of this study was to assess correlations between 18F-FDG uptake on PET scan of carotid artery plaques, plasma levels of Lp-PLA2, and cerebrovascular symptoms. The study included 45 consecutive patients (22 symptomatic, 23 asymptomatic) with >70% carotid stenosis. Patients were examined by hybrid PET/CT, and maximum standardized uptake values (SUVmax) were recorded. Blood samples were obtained, and plasma was stored at −80 °C for subsequent Lp-PLA2 analysis. Symptomatic and asymptomatic patients showed no significant difference in classical cardiovascular risk factors. Asymptomatic carotid stenosis patients more frequently had a history of coronary artery disease ( P = .025) and peripheral artery disease ( P = .012). The symptomatic group had higher 18F-FDG uptake in carotid plaques ( P < .001), higher plasma Lp-PLA2 ( P < .01), and higher high-sensitive C-reactive protein ( P = .022). 2-Deoxy-2-[18F]fluoro-D-glucose uptake on PET/CT and plasma Lp-PLA2 show a statistically significant association with the symptomatic status of carotid plaques.

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Carotid Plaque Inflammation Imaged by 18 F-Fluorodeoxyglucose Positron Emission Tomography and Risk of Early Recurrent Stroke

Stroke ◽

10.1161/strokeaha.119.025422 ◽

2019 ◽

Vol 50 (7) ◽

pp. 1766-1773 ◽

Cited By ~ 17

Author(s):

Peter J. Kelly ◽

Pol Camps-Renom ◽

Nicola Giannotti ◽

Joan Martí-Fàbregas ◽

Sean Murphy ◽

...

Keyword(s):

Positron Emission Tomography ◽

Carotid Plaque ◽

Recurrent Stroke ◽

Emission Tomography ◽

Fluorodeoxyglucose Positron Emission Tomography ◽

Positron Emission ◽

Plaque Inflammation ◽

Fluorodeoxyglucose Positron Emission

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Carotid Plaque Inflammation Assessed with 18F-FDG PET/CT is Higher in Symptomatic Compared with Asymptomatic Patients

International Journal of Stroke ◽

10.1111/ijs.12430 ◽

2015 ◽

Vol 10 (5) ◽

pp. 730-736 ◽

Cited By ~ 30

Author(s):

Karolina Skagen ◽

Kjersti Johnsrud ◽

Kristin Evensen ◽

Helge Scott ◽

Kirsten Krohg-Sørensen ◽

...

Keyword(s):

Fdg Pet ◽

Carotid Plaque ◽

Asymptomatic Patients ◽

Pet Ct ◽

Plaque Inflammation ◽

18F Fdg ◽

Fdg Pet Ct

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A Risk Score Including Carotid Plaque Inflammation and Stenosis Severity Improves Identification of Recurrent Stroke

Stroke ◽

10.1161/strokeaha.119.027268 ◽

2020 ◽

Vol 51 (3) ◽

pp. 838-845 ◽

Cited By ~ 8

Author(s):

Peter J. Kelly ◽

Pol Camps-Renom ◽

Nicola Giannotti ◽

Joan Martí-Fàbregas ◽

Jonathan P. McNulty ◽

...

Keyword(s):

Risk Score ◽

Carotid Plaque ◽

Recurrent Stroke ◽

Stenosis Severity ◽

Plaque Inflammation

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Dose-Dependent Association of Inflammatory Cytokines with Carotid Atherosclerosis in Transient Ischaemic Attack: Implications for Clinical Trials

Cerebrovascular Diseases ◽

10.1159/000517739 ◽

2021 ◽

pp. 1-10

Author(s):

Sarah Coveney ◽

John J. McCabe ◽

Sean Murphy ◽

Orina Belton ◽

Cleona Gray ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Transient Ischaemic Attack ◽

Carotid Atherosclerosis ◽

High Sensitivity ◽

Symptomatic Carotid ◽

Tnf Α ◽

Ischaemic Attack ◽

Plaque Inflammation ◽

Ifn Γ ◽

Dose Dependent

Introduction: The 5-year recurrence risk after ischaemic stroke and transient ischaemic attack (TIA) is 25–30%. Although inflammation may be a target for prevention trials, the contribution of plaque inflammation to acute cerebrovascular events remains unclear. We investigated the association of acute inflammatory cytokines and high-sensitivity C-reactive protein (CRP) with recently symptomatic carotid atherosclerosis in a prospective cohort study. Methods: Blood and Imaging markers of TIA BIO-TIA) is a multicentre prospective study of imaging and inflammatory markers in patients with TIA. Exclusion criteria were infection and other co-morbid illnesses associated with inflammation. CRP and serum cytokines (interleukin [IL]-6, IL-1β, IL-8, IL-10, IL-12, interferon-γ [IFN-γ] and tumour necrosis factor-α [TNF-α]) were measured. All patients had carotid imaging. Results: Two hundred and thirty-eight TIA cases and 64 controls (TIA mimics) were included. Forty-nine (20.6%) cases had symptomatic internal carotid artery stenosis. Pro-inflammatory cytokine levels increased in a dose-dependent manner across controls, TIA without carotid stenosis (CS), and TIA with CS (IL-1β, ptrend = 0.03; IL-6, ptrend < 0.0001; IL-8, ptrend = 0.01; interferon (IFN)-γ, ptrend = 0.005; TNF-α, ptrend = 0.003). Results were unchanged when DWI-positive cases were excluded. On multivariable linear regression, only age (p = 0.01) and CS (p = 0.04) independently predicted log-IL-6. On multivariable Cox regression, CRP was the only independent predictor of 90-day stroke recurrence (adjusted hazard ratio per 1-unit increase 1.03 [95% CI: 1.01–1.05], p = 0.003). Conclusion: Symptomatic carotid atherosclerosis was associated with elevated cytokines in TIA patients after controlling for other sources of inflammation. High-sensitivity CRP was associated with recurrent ischaemic stroke at 90 days. These findings implicate acute plaque inflammation in the pathogenesis of cerebral thromboembolism and support a rationale for randomized trials of anti-inflammatory therapy for stroke patients, who were excluded from coronary trials.

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