Application of mask images of contrast-enhanced MR angiography to detect carotid intraplaque hemorrhage in patients with moderate to severe symptomatic and asymptomatic carotid stenosis.

PURPOSE: Carotid intraplaque hemorrhage (IPH) on MRI predicts stroke. Magnetization-prepared rapid acquisition gradient (MP-RAGE) is widely used to detect IPH. CE-MRA is used routinely to assess stenosis. Initial studies indicated that IPH can be identified on mask images of CE-MRA, while Time-of-Flight (TOF) images were reported to have high specificity but lower sensitivity. We investigated the diagnostic accuracy of detecting IPH on mask images of CE-MRA and TOF. METHODS: Thirty-six patients with ≥ 50% stenosis enrolled in the ongoing 2nd European Carotid Surgery Trial underwent carotid MRI. A 5-point quality score was used. Inter-observer agreement between two independent readers was determined. The sensitivity and specificity of IPH detection on mask MRA and TOF were calculated with MP-RAGE as a reference standard. RESULTS: Of the 36 patients included in the current analysis, 66/72 carotid arteries could be scored. The inter-observer agreements for identifying IPH on MP-RAGE, mask, and TOF were outstanding (κ: 0.93, 0.96, and 0.85). The image quality of mask (1.42 ± 0.66) and TOF (2.42 ± 0.66) was significantly lower than MP-RAGE (3.47 ± 0.61). When T1w images were used to delineate the outer carotid wall, very high specificities (>95%) of IPH detection on mask and TOF images were found, while the sensitivity was high for mask images (>81%) and poor for TOF (50-60%). Without these images, the specificity was still high (>97%), while the sensitivity reduced to 62-71%. CONCLUSION: Despite the lower image quality, routinely acquired mask images from CE-MRA, but not TOF, can be used as an alternative to MP-RAGE images to visualize IPH.

Leukocyte Count Predicts Carotid Artery Stenosis in Men with Ischemic Stroke: Sub Study of the Preventive Antibiotics in Stroke Study (PASS).

Background: Inflammation is important in the development of atherosclerosis. Research suggested sex-dependent differences for the value of inflammatory markers for risk stratification of stroke patients with internal carotid artery stenosis (ICAS). We investigated whether leukocytes and thrombocytes were associated with ≥50% ICAS in acute stroke and whether this was sex-dependent. Patients included in the Preventive Antibiotics in Stroke Study (PASS) were used. PASS is a randomized controlled trial that randomized between four days of preventive ceftriaxone intravenously or standard stroke care alone. It investigated whether ceftriaxone could improve functional outcome at three months after stroke. Methods: Patients included in PASS were evaluated for the predictive value of leukocytes and thrombocytes for ICAS. Ischemic stroke and TIA patients were selected out of PASS patients. Logistic regression analysis was performed adjusting for NIHSS and other covariates. Results: 2550 patients were included in PASS. 1413 of 2550 patients (55%) were evaluated in this sub study. Female patients showed a mean of 8.55 × 109/L for leukocytes and 259 × 109/L for thrombocytes. Men showed a mean of 8.29 × 109/L for leukocytes and 224 × 109/L for thrombocytes. Multivariate logistic regression analysis showed that leukocytes were independently associated with ICAS ≥ 50% in male patients (OR 1.094, p = 0.008), but not in female patients (OR 1.041, p = 0.360). Thrombocytes were not associated with ICAS. Conclusions: We conclude that blood leukocyte count independently predicts ICAS in men after acute stroke, but not in women. Clinical Trial unique identifier: ISRCTN66140176.

The 2nd European Carotid Surgery Trial (ECST-2): rationale and protocol for a randomised clinical trial comparing immediate revascularisation versus optimised medical therapy alone in patients with symptomatic and asymptomatic carotid stenosis at low to intermediate risk of stroke.

BACKGROUND: Carotid endarterectomy is currently recommended for patients with recently symptomatic carotid stenosis ≥50%, based on randomised trials conducted 30 years ago. Several factors such as carotid plaque ulceration, age and associated comorbidities might influence the risk-benefit ratio of carotid revascularisation. A model developed in previous trials that calculates the future risk of stroke based on these features can be used to stratify patients into low, intermediate or high risk. Since the original trials, medical treatment has improved significantly. Our hypothesis is that patients with carotid stenosis ≥50% associated with a low to intermediate risk of stroke will not benefit from additional carotid revascularisation when treated with optimised medical therapy. We also hypothesise that prediction of future risk of stroke in individual patients with carotid stenosis can be improved using the results of magnetic resonance imaging (MRI) of the carotid plaque. METHODS: Patients are randomised between immediate revascularisation plus OMT versus OMT alone. Suitable patients are those with asymptomatic or symptomatic carotid stenosis ≥50% with an estimated 5-year risk of stroke of <20%, as calculated using the Carotid Artery Risk score. MRI of the brain at baseline and during follow-up will be used as a blinded measure to assess the incidence of silent infarction and haemorrhage, while carotid plaque MRI at baseline will be used to investigate the hypotheses that plaque characteristics determine future stroke risk and help identify a subgroup of patients that will benefit from revascularisation. An initial analysis will be conducted after recruitment of 320 patients with baseline MRI and a minimum of 2 years of follow-up, to provide data to inform the design and sample size for a continuation or re-launch of the study. The primary outcome measure of this initial analysis is the combined 2-year rate of any clinically manifest stroke, new cerebral infarct on MRI, myocardial infarction or periprocedural death. DISCUSSION: ECST-2 will provide new data on the efficacy of modern optimal medical therapy alone versus added carotid revascularisation in patients with carotid stenosis at low to intermediate risk of future stroke selected by individualised risk assessment. We anticipate that the results of baseline brain and carotid plaque MRI will provide data to improve the prediction of the risk of stroke and the effect of treatment in patients with carotid stenosis. TRIAL REGISTRATION: ISRCTN registry ISRCTN97744893 . Registered on 05 July 2012.

Association between plaque vulnerability and neutrophil extracellular traps (NETs) levels: The Plaque At RISK study.

Carotid atherosclerotic plaque rupture and its sequelae are among the leading causes of acute ischemic stroke. The risk of rupture and subsequent thrombosis is, among others, determined by vulnerable plaque characteristics and linked to activation of the immune system, in which neutrophil extracellular traps (NETs) potentially play a role. The aim of this study was to investigate how plaque vulnerability is associated with NETs levels. We included 182 patients from the Plaque At RISK (PARISK) study in whom carotid imaging was performed to measure plaque ulceration, fibrous cap integrity, intraplaque hemorrhage, lipid-rich necrotic core, calcifications and plaque volume. Principal component analysis generated a 'vulnerability index' comprising all plaque characteristics. Levels of the NETs marker myeloperoxidase-DNA complex were measured in patient plasma. The association between the vulnerability index and low or high NETs levels (dependent variable) was assessed by logistic regression. No significant association between the vulnerability index and NETs levels was detected in the total population (odds ratio 1.28, 95% confidence interval 0.90-1.83, p = 0.18). However, in the subgroup of patients naive to statins or antithrombotic medication prior to the index event, this association was statistically significant (odds ratio 2.08, 95% confidence interval 1.04-4.17, p = 0.04). Further analyses revealed that this positive association was mainly driven by intraplaque hemorrhage, lipid-rich necrotic core and ulceration. In conclusion, plaque vulnerability is positively associated with plasma levels of NETs, but only in patients naive to statins or antithrombotic medication prior to the index event.

Prevalence, predictors and outcome of carotid stenosis: a sub study in the Preventive Antibiotics in Stroke Study (PASS).

BACKGROUND: The prevalence of carotid artery stenosis (CAS) in acute ischaemic stroke (AIS) patients is historically reported at 15-20%, but an up-to-date estimate is lacking. We hypothesise it is lower than historically reported, due to better risk management to date. The study aims to study prevalence, predictors and survival of CAS in AIS patients. METHODS: We included patients with AIS from the Preventive Antibiotics in Stroke Study (PASS), a large Dutch randomized, multicentre, open-label phase III trial that included 2538 patients with acute stroke and randomised between standard care or preventive ceftriaxone. Patients with stroke in the anterior circulation that underwent diagnostic testing of the internal carotid artery (ICA) were eligible for this sub study and used in these secondary analyses. Logistic regression analyses were performed to identify predictors for CAS ≥ 50%. Additionally, an ordinal regression was performed to assess the association between presence of CAS at baseline and functional outcome at three months on the modified Rankin scale (mRS). RESULTS: 1480 patients with AIS were included; 277 had CAS (18.7%; 95%CI:17.7-19.7). Age, hypertension, smoking and male gender were found as best-fit predictors for presence of CAS. Significant shift in mRS score after 90 days for CAS ≥50% towards a higher mRS score with an OR of 1.66 (95% CI 1.30-2.10) was found. CONCLUSIONS: Current prevalence of CAS is 18.7%, which is higher than we expected. Gender, smoking and hypertension are important factors associated with CAS. Patients with CAS had a significantly higher mRs score after 90 days. TRIAL REGISTRATION: Unique identifier: ISRCTN66140176.