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Introduction: Carotid atherosclerotic intraplaque hemorrhage (IPH) predicts stroke. Patients with a history of stroke are treated with antiplatelet agents to prevent secondary cardiovascular events. A positive association between previous antiplatelet use and IPH was reported in a cross-sectional analysis. We investigated the changes in IPH over 2 years in patients who recently started versus those with continued antiplatelet use. Methods: In the Plaque at Risk (PARISK) study, symptomatic patients with <70% ipsilateral carotid stenosis underwent carotid plaque magnetic resonance imaging (MRI) at the baseline and after 2 years to determine IPH presence and volume. Participants were categorized into new users (starting antiplatelet therapy following the index event) and continued users (previous use of antiplatelet therapy before the index event). The association between previous antiplatelet therapy and the presence of IPH at baseline MRI was investigated using multivariable logistic regression analysis. The IPH volume change over a period of 2 years, defined as the difference in volume between follow-up and baseline, was investigated in each group with a Wilcoxon signed-rank test. The IPH volume change was categorized as progression, regression, or no change. Using multivariable logistic regression, we investigated the association between new antiplatelet use and (1) newly developed ipsilateral or contralateral IPH and (2) IPH volume progression. Results: A total of 108 patients underwent carotid MRI at the baseline and follow-up. At the baseline, previous antiplatelet therapy was associated with any IPH (OR = 5.6, 95% CI: 1.3–23.1; p = 0.02). Ipsilateral IPH volume did not change significantly during the 2 years in patients who continued receiving antiplatelet agents (86.4 mm3 [18.2–235.9] vs. 59.3 mm3 [11.4–260.3]; p = 0.6) nor in the new antiplatelet users (n = 31) (61.5 mm3 [0.0–166.9] vs. 27.7 mm3 [9.5–106.4]; p = 0.4). Similar results of a nonsignificant change in contralateral IPH volume during those 2 years were observed in both groups (p > 0.05). No significant associations were found between new antiplatelet use and newly developed IPH at 2 years (odds ratio [OR] = 1.0, 95% CI: 0.1–7.4) or the progression of IPH (ipsilateral: OR = 2.4, 95% CI: 0.3–19.1; contralateral: OR = 0.3, 95% CI: 0.01–8.5). Conclusion: Although the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, the new onset of antiplatelet therapy after transient ischemic attack/stroke was not associated with the newly developed IPH or progression of IPH volume over the subsequent 2 years. Plain Language Summary: Carotid artery narrowing due to an atherosclerotic plaque is responsible for around 20% of stroke. Intraplaque hemorrhage (IPH) predicts stroke. Antiplatelet agents are often given to patients who have had a stroke to prevent further cardiovascular events. A previous study found an association between previous antiplatelet use and IPH at a specific point in time. In this study, researchers investigated whether starting antiplatelet therapy after a stroke or continuing to use antiplatelets had any effect on IPH over a 2-year period. The study included patients with <70% carotid narrowing who had a carotid plaque MRI at the baseline and after 2 years to determine the presence and volume of IPH. Patients were categorized into new users (starting antiplatelet therapy following the stroke) and continued users (already using antiplatelet therapy before the stroke). The presence and the volume change of IPH over 2 years were investigated in each group. The study found that IPH was more present at the baseline when patients used antiplatelet agents before the stroke. However, new antiplatelet use after the stroke did not lead to new IPH or an increase in IPH volume over the subsequent 2 years. There were no significant associations between the new antiplatelet use and newly developed IPH or IPH volume progression. Therefore, while the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, starting antiplatelet therapy after a stroke did not increase the risk of new IPH or progression of IPH volume over the subsequent 2 years. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications Intracranial atherosclerosis is one of the most common causes of ischaemic stroke. However, there is a substantial knowledge gap on the development of intracranial atherosclerosis. Intracranial arteries are characterized by an upregulation of tight junctions between endothelial cells, which control endothelial permeability. We investigated the role of N6‐methyladenosine (m6A), a common RNA modification, on endothelial integrity, focusing on the pro‐atherogenic microRNA miR‐494‐3p and tight junction proteins TJP1 and PECAM1.We assessed the m6A landscape, along with the expression of miR‐494‐3p, TJP1 and PECAM1 in postmortem human vertebral arteries (VA), internal carotid arteries (ICA), and middle cerebral arteries (MCA) with various stages of intimal thickening and plaque formation. The interactions between m6A‐modified miR‐494‐3p mimics, TJP1 and PECAM1, were investigated in vitro using primary human (brain) endothelial cells.Increased m6A expression was observed in the luminal lining of atherosclerosis‐affected VAs, accompanied by reduced TJP1 and PECAM1, but not VE‐cadherin, expression. Colocalization of m6A and miR‐494‐3p in the luminal lining of VA plaques was confirmed, indicating m6A methylation of miR‐494‐3p in intracranial atherosclerosis. Moreover, site‐specific m6A‐modification of miR‐494‐3p led to repression specifically of TJP1 protein expression at cell–cell junctions of brain microvascular endothelial cells, while unmodified miR‐494‐3p showed no effect.This study highlights increasing m6A levels during intracranial atherogenesis. Increases in m6A‐miR‐494‐3p contribute to the observed decreased TJP1 expression in endothelial cell–cell junctions. This is likely to have a negative effect on endothelial integrity and may thus accelerate intracranial atherosclerosis progression. [ABSTRACT FROM AUTHOR]

Background: Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making., Objectives: The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging., Methods: The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score., Results: During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78)., Conclusions: IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025)., Competing Interests: Funding Support and Disclosures This work was supported by the Dutch Heart Foundation (grant number DHF2008-T094) and was performed within the framework of the Center for Translational Molecular Medicine, project PARISK (Plaque At RISK; grant number 01C-202). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)