Effects of Banhabaekchulcheonma-Tang on Brain Injury and Cognitive Function Impairment Caused by Bilateral Common Carotid Artery Stenosis in a Mouse Model.

Vascular dementia (VD) is the second most prevalent dementia type, with no drugs approved for its treatment. Here, the effects of Banhabaekchulcheonma-Tang (BBCT) on ischemic brain injury and cognitive function impairment were investigated in a bilateral carotid artery stenosis (BCAS) mouse model. Mice were divided into sham-operated, BCAS control, L-BBCT (40 ml/kg), and H-BBCT (80 ml/kg) groups. BBCT's effects were characterized using the Y-maze test, novel object recognition test (NORT), immunofluorescence staining, RNA sequencing, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses. The NORT revealed cognitive function improvement in the H-BBCT group, while the Y-maze test revealed no significant difference among the four groups. The CD68+ microglia and GFAP+ astrocyte numbers were reduced in the H-BBCT group. Furthermore, H-BBCT treatment restored the dysregulation of gene expression caused by BCAS. The major BBCT targets were predicted to be cell division cycle protein 20 (CDC20), Epidermal growth factor (EGF), and tumor necrosis factor receptor-associated factor 1 (TRAF1). BBCT regulates the neuroactive ligand-receptor interaction and neuropeptide signaling pathways, as predicted by KEGG and GO analyses, respectively. BBCT significantly improved cognitive impairment in a BCAS mouse model by inhibiting microglial and astrocyte activation and regulating the expression of CDC20, EGF, TRAF1, and key proteins in the neuroactive ligand-receptor interaction and neuropeptide signaling pathways.

Chuanzhitongluo capsule improves cognitive impairment in mice with chronic cerebral hypoperfusion via the cholinergic anti-inflammatory pathway.

Vascular cognitive impairment (VCI) has become a common disease-causing cognitive deficit in humans, second only to Alzheimer's Disease (AD). Chuanzhitongluo capsule (CZTL) is a Traditional Chinese Medicine (TCM) preparation known for its effective protection against cerebral ischemia. However, its potential to ameliorate VCI remains unclear. This study aimed to investigate the cognitive improvement effects of CZTL in a mouse model of VCI. Chronic cerebral hypoperfusion (CCH) was induced in mice by bilateral common carotid artery stenosis (BCAS) to simulate the pathological changes associated with VCI. Spatial learning and memory abilities were assessed using the Morris Water Maze (MWM). RNA sequencing (RNA-Seq) was employed to identify differentially expressed genes (DEGs) in the hippocampus. Levels of inflammatory factors were measured through enzyme-linked immunosorbent assay (ELISA), while immunofluorescence (IF) determined the expression intensity of target proteins. Western Blot (WB) confirmed the final action pathway. Results indicated that CZTL significantly improved the spatial learning and memory abilities of CCH mice, along with alterations in gene expression profiles in the hippocampus. It also reduced neuroinflammation in the hippocampus and upregulated the choline acetyltransferase (ChAT) and α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR), which are in synaptic plasticity and neuronal development. Moreover, CZTL inhibited the NF-κB signaling pathway. In conclusion, CZTL may alleviate neuroinflammation induced by CCH and improve cognitive impairment in CCH mice by regulating the cholinergic anti-inflammatory pathway (CAIP) involving ChAT/α7nAChR/NF-κB.

Antithrombotic regimen in emergent carotid stenting for acute ischemic stroke due to tandem occlusion: a meta-analysis of aggregate data.

BACKGROUND: The periprocedural antithrombotic regimen might affect the risk-benefit profile of emergent carotid artery stenting (eCAS) in patients with acute ischemic stroke (AIS) due to tandem lesions, especially after intravenous thrombolysis. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of antithrombotics following eCAS. METHODS: We followed PRISMA guidelines and searched MEDLINE, Embase, and Scopus from January 1, 2004 to November 30, 2022 for studies evaluating eCAS in tandem occlusion. The primary endpoint was 90-day good functional outcome. Secondary outcomes were symptomatic intracerebral hemorrhage, in-stent thrombosis, delayed stent thrombosis, and successful recanalization. Meta-analysis of proportions and meta-analysis of odds ratios were implemented. RESULTS: 34 studies with 1658 patients were included. We found that the use of no antiplatelets (noAPT), single antiplatelet (SAPT), dual antiplatelets (DAPT), or glycoprotein IIb/IIIa inhibitors (GPI) yielded similar rates of good functional outcomes, with a marginal benefit of GPI over SAPT (OR 1.88, 95% CI 1.05 to 3.35, Pheterogeneity=0.31). Sensitivity analysis and meta-regression excluded a significant impact of intravenous thrombolysis and Alberta Stroke Program Early CT Score (ASPECTS). We observed no increase in symptomatic intracerebral hemorrhage (sICH) with DAPT or GPI compared with noAPT or SAPT. We also found similar rates of delayed stent thrombosis across groups, with acute in-stent thrombosis showing marginal, non-significant benefits from GPI and DAPT over SAPT and noAPT. CONCLUSIONS: In AIS due to tandem occlusion, the periprocedural antithrombotic regimen of eCAS seems to have a marginal effect on good functional outcome. Overall, high intensity antithrombotic therapy may provide a marginal benefit on good functional outcome and carotid stent patency without a significant increase in risk of sICH.

Inflammation, anti-inflammatory agents, and the role of colchicine in carotid artery stenosis.

Cardiovascular disease is a major cause of morbidity and mortality worldwide. In the last few years, the role of inflammation and inflammatory modulatory medications is investigated for the optimal treatment of coronary artery disease. It can be hypothesized that since inflammation is also involved in carotid artery stenosis development and progression, the same class of medication could be useful. Our objective with this review is to present the available evidence, published studies and promising ongoing trials on the role of anti-inflammatory medications - with a special emphasis on the most commonly used drug of this class: colchicine - in patients with carotid artery stenosis.

Edaravone dexborneol ameliorates cognitive impairment by regulating the NF-κB pathway through AHR and promoting microglial polarization towards the M2 phenotype in mice with bilateral carotid artery stenosis (BCAS).

Cerebral small vessel disease (CSVD) is one of the most important causes of stroke and vascular dementia, so exploring effective treatment modalities for CSVD is warranted. This study aimed to explore the anti-inflammatory effects of Edaravone dexborneol (C.EDA) in a CSVD model. Mice with CSVD showed distinct cognitive decline, as assessed by the Morris water maze (MWM). Pathological staining verified leakage across the blood‒brain barrier (BBB), microglial proliferation, neuronal loss and demyelination. Western blot analysis demonstrated that M1 microglia dominated prophase and released proinflammatory molecules; the aryl hydrocarbon receptor (AHR) was found to participate in modulating nuclear factor-kappa B (NF-κB) signalling activation through tumour necrosis factor receptor-associated factor-6 (TRAF6). C.EDA treatment resulted in the polarization of microglia from the M1 to the M2 phenotype. Mice sequentially treated with C.EDA exhibited a significant improvement in cognitive function; expression of the anti-inflammatory cytokines and modulatory proteins AHR and TRAF6 was upregulated, while the levels of pNF-κBp65 and pIΚBα were downregulated. C.EDA promoted microglial activation towards the M2 phenotype by upregulating AHR expression, which prevented TRAF6 ubiquitination, promoted NF-κB RelA/p65 protein degradation and inhibited subsequent NF-κB phosphorylation. Mechanistically, the anti-inflammatory effect of C.EDA alleviated neuronal loss and myelin damage, while at the functional level, C.EDA improved cognitive function and thus showed good application prospects.

Pharmacological interventions for asymptomatic carotid stenosis.

BACKGROUND: Carotid artery stenosis is narrowing of the carotid arteries. Asymptomatic carotid stenosis is when this narrowing occurs in people without a history or symptoms of this disease. It is caused by atherosclerosis; that is, the build-up of fats, cholesterol, and other substances in and on the artery walls. Atherosclerosis is more likely to occur in people with several risk factors, such as diabetes, hypertension, hyperlipidaemia, and smoking. As this damage can develop without symptoms, the first symptom can be a fatal or disabling stroke, known as ischaemic stroke. Carotid stenosis leading to ischaemic stroke is most common in men older than 70 years. Ischaemic stroke is a worldwide public health problem. OBJECTIVES: To assess the effects of pharmacological interventions for the treatment of asymptomatic carotid stenosis in preventing neurological impairment, ipsilateral major or disabling stroke, death, major bleeding, and other outcomes. SEARCH METHODS: We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, two other databases, and three trials registers from their inception to 9 August 2022. We also checked the reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs), irrespective of publication status and language, comparing a pharmacological intervention to placebo, no treatment, or another pharmacological intervention for asymptomatic carotid stenosis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Two review authors independently extracted the data and assessed the risk of bias of the trials. A third author resolved disagreements when necessary. We assessed the evidence certainty for key outcomes using GRADE. MAIN RESULTS: We included 34 RCTs with 11,571 participants. Data for meta-analysis were available from only 22 studies with 6887 participants. The mean follow-up period was 2.5 years. None of the 34 included studies assessed neurological impairment and quality of life. Antiplatelet agent (acetylsalicylic acid) versus placebo Acetylsalicylic acid (1 study, 372 participants) may result in little to no difference in ipsilateral major or disabling stroke (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.47 to 2.47), stroke-related mortality (RR 1.40, 95% CI 0.54 to 3.59), progression of carotid stenosis (RR 1.16, 95% CI 0.79 to 1.71), and adverse events (RR 0.81, 95% CI 0.41 to 1.59), compared to placebo (all low-certainty evidence). The effect of acetylsalicylic acid on major bleeding is very uncertain (RR 0.98, 95% CI 0.06 to 15.53; very low-certainty evidence). The study did not measure neurological impairment or quality of life. Antihypertensive agents (metoprolol and chlorthalidone) versus placebo The antihypertensive agent, metoprolol, may result in no difference in ipsilateral major or disabling stroke (RR 0.14, 95% CI 0.02 to1.16; 1 study, 793 participants) and stroke-related mortality (RR 0.57, 95% CI 0.17 to 1.94; 1 study, 793 participants) compared to placebo (both low-certainty evidence). However, chlorthalidone may slow the progression of carotid stenosis (RR 0.45, 95% CI 0.23 to 0.91; 1 study, 129 participants; low-certainty evidence) compared to placebo. Neither study measured neurological impairment, major bleeding, adverse events, or quality of life. Anticoagulant agent (warfarin) versus placebo The evidence is very uncertain about the effects of warfarin (1 study, 919 participants) on major bleeding (RR 1.19, 95% CI 0.97 to 1.46; very low-certainty evidence), but it may reduce adverse events (RR 0.89, 95% CI 0.81 to 0.99; low-certainty evidence) compared to placebo. The study did not measure neurological impairment, ipsilateral major or disabling stroke, stroke-related mortality, progression of carotid stenosis, or quality of life. Lipid-lowering agents (atorvastatin, fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin) versus placebo or no treatment Lipid-lowering agents may result in little to no difference in ipsilateral major or disabling stroke (atorvastatin, lovastatin, pravastatin, and rosuvastatin; RR 0.36, 95% CI 0.09 to 1.53; 5 studies, 2235 participants) stroke-related mortality (lovastatin and pravastatin; RR 0.25, 95% CI 0.03 to 2.29; 2 studies, 1366 participants), and adverse events (fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin; RR 0.76, 95% CI 0.53 to1.10; 7 studies, 3726 participants) compared to placebo or no treatment (all low-certainty evidence). The studies did not measure neurological impairment, major bleeding, progression of carotid stenosis, or quality of life. AUTHORS' CONCLUSIONS: Although there is no high-certainty evidence to support pharmacological intervention, this does not mean that pharmacological treatments are ineffective in preventing ischaemic cerebral events, morbidity, and mortality. High-quality RCTs are needed to better inform the best medical treatment that may reduce the burden of carotid stenosis. In the interim, clinicians will have to use other sources of information.

Metformin attenuates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion.

Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.

Ebselen alleviates white matter lesions and improves cognitive deficits by attenuating oxidative stress via Keap1/Nrf2 pathway in chronic cerebral hypoperfusion mice.

Oxidative stress is crucial in cerebral white matter lesions (WMLs) induced by chronic cerebral hypoperfusion. Therefore, ameliorating oxidative damage is considered to be a beneficial strategy for the treatment of WMLs. Ebselen (EbSe), a small lipid organoselenium compound, its lipid peroxidation activity is mediated through the glutathione peroxidase-mimetic properties. This study aimed to investigate the role of EbSe in WMLs after bilateral common carotid artery stenosis (BCAS). The BCAS model can moderately reduce cerebral blood flow, and mimics white matter damage caused by chronic cerebral hypoperfusion or small vessel disease. Laser Speckle Contrast Imaging (LSCI) was used to monitor the cerebral blood flow of mice. The spatial learning and memory were tested by using the eight-arm maze. LFB staining was used to detect demyelination. The expression of MBP, GFAP and Iba1 was assayed by immunofluorescence. The demyelination was assessed by Transmission Electron Microscope (TEM). The activities of MDA, SOD and GSH-Px were detected by assay kits. The mRNA levels of SOD, GSH-Px and HO-1 was detected by realtime PCR. The activation of the Nrf2/ARE pathway and the expression of SOD, GSH-Px and HO-1was assessed by Western blot. EbSe ameliorated cognitive deficits and white matter lesions induced by bilateral common carotid artery stenosis (BCAS). The expression of GFAP and Iba1 was decreased in the corpus callosum of BCAS mice after EbSe treatment. Moreover, EbSe alleviated the level of MDA by elevating the expression and mRNA of SOD, GSH-Px and HO-1 in BCAS mice. Furthermore, EbSe promoted the dissociation of the Keap1/Nrf2 complex, resulting in the accumulation of Nrf2 in the nucleus. This study demonstrates a favorable effect of EbSe on cognitive impairment in a chronic cerebral hypoperfusion model, and the improvement of EbSe's antioxidant property is mediated by Keap1/Nrf2 pathway.

Potential Biomarkers and Therapeutic Targets: Inflammation and Oxidative Stress in Left Carotid Artery Stenosis with Coronary Artery Disease.

INTRODUCTION: Patients with left carotid artery atherosclerotic stenosis have an increased ischemic stroke risk. Left carotid stenosis, the most common cause of the transient ischemic attack, is related to a higher risk of acute stroke. Left carotid artery stenosis is also associated with cerebral artery infarction. The significant coronary stenosis promotes ST-segment elevation myocardial infarctions. The severe coronary stenosis plays an important role in development and progression of myocardial infarction. However, the dynamic changes of circulating oxidative stress and inflammatory markers in the carotid stenosis combined with coronary artery stenosis are not clear, and it also remains unknown whether mark of oxidative stress and inflammation are potential therapeutic targets for carotid stenosis combined with coronary artery stenosis. AIM: This study aims to explore the effects of oxidative stress combined with an inflammatory response on left carotid artery stenosis with coronary artery disease in patients. METHODS: We, therefore, tested the hypothesis that levels of markers of oxidative stress and inflammation are associated with coexistent severe carotid and coronary artery stenosis in patients. We measured the circulating levels of malondialdehyde (MDA), oxidized low-density lipoprotein (OX-LDL), homocysteine (Hcy), F2- isoprostanes (F2-IsoPs), tumor necrosis factor-alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), prostaglandin E2 (PG-E2) and interferon-gamma (IFN-γ) in patients with combined carotid and coronary artery severe stenosis. We also assessed the relationships among oxidative stress, inflammation, and severe stenosis of the carotid with a coronary artery in patients. RESULTS: Levels of MDA, OX-LDL, Hcy, F2-IsoPs, TNF-α, hs-CRP, PG-E2, and IFN-γ were remarkably increased (P < 0.001) in patients with combined carotid and coronary artery severe stenosis. High levels of oxidative stress and inflammation may be related to severe stenosis of the carotid with coronary arteries in patients. CONCLUSION: Our observations indicated that measurements of oxidative stress and inflammatory markers may be valuable for the assessment of the degree of carotid with coronary artery stenosis. The biomarkers of oxidative stress and inflammatory response may become therapeutic targets for carotid artery stenosis with coronary artery stenosis in patients.

[Study of the effect of Unifuzol on cognitive impairment and damage to the hippocampus and cerebral cortex during course administration to rats with bilateral stenosis of the common carotid arteries, causing chronic circulatory failure]. / Vliyanie preparata Unifuzol na sostoyanie kognitivnykh funktsii v usloviyakh eksperimental'nogo khronicheskogo narusheniya mozgovogo krovoobrashcheniya.

OBJECTIVE: To study the effect of Unifuzol (L-arginine sodium succinate) on cognitive impairment, cerebral blood flow, and damage to the tissues of the hippocampus and cerebral cortex during a 10-day course of administration to rats with chronic cerebral ischemia (CCI) caused by bilateral stenosis of the common carotid arteries (CCA). MATERIAL AND METHODS: The study was conducted on male rats with CCI caused by bilateral stenosis of the CCA by 60%. 40 days after surgery, rats received Unifusol (21, 42 and 84 ml/kg), nicergoline (10 mg/kg), citicoline (500 mg/kg) or placebo (0.9% NaCl) for 10 days. Next, cognitive impairments were assessed in the Morris Water Maze and the New Object Recognition (NOR) test, as well as the level of motor and exploratory activity in the Open Field test. The level of cerebral blood flow was determined immediately after the CCA stenosis and at the end of the experiment. Animals were euthanized in a CO2 incubator, after which the brain was removed and subjected to morphometric analysis. RESULTS: In animals that were modeled with CCA stenosis, pronounced behavioral and cognitive impairments occurred as a result of a decrease in blood flow in the vessels of the brain and subsequent changes in the tissues of the hippocampus and the cerebral cortex. Intravenous course administration of Unifuzol at doses of 42 and 84 ml/kg to animals with CCI was comparable in efficiency to nicergoline and citicoline, which was expressed in greater preservation of the cognitive abilities of animals in the Morris Water Maze and NOR tests. In the Open Field test, animals injected with Unifusol at doses of 42 and 84 ml/kg performed more acts of motor and exploratory activity than animals from the placebo group, and had a higher level of cerebral blood flow (compared to animals that were injected with citicoline). Based on the results of a morphological study, it was found that the most significant neuroprotective effect was provided by nicergoline and Unifuzol (at doses of 42 and 84 ml/kg). CONCLUSION: Unifuzol at a course of administration at doses of 42 and 84 ml/kg, comparable to the reference drugs nicergoline and citicoline, reduces the severity of psychoneurological deficit in animals with CCI, comparable to them improves the microcirculation of brain tissues, preventing damage to brain tissues.

Comparison of three antithrombotic strategies for emergent carotid stenting during stroke thrombectomy: a multicenter study.

BACKGROUND: Periprocedural antithrombotic treatment is a key determinant for the risk-benefit balance of emergent carotid artery stenting (eCAS) during stroke thrombectomy. We aimed to assess the safety and efficacy of three types of antithrombotic treatment. METHODS: Retrospective review of prospectively collected endovascular databases in four comprehensive stroke centers, including consecutive cases of eCAS for tandem lesion strokes between January 2019 and July 2021. During this period, each center prospectively applied one of three periprocedural protocols: (a) two centers administered aspirin (250 mg IV); (b) one center administered aspirin and heparin (bolus+24 hours infusion); and (c) one center applied an aggressive antiplatelet strategy consisting of aspirin and clopidogrel (loading doses), with added intravenous tirofiban if in-stent thrombosis was observed during thrombectomy. Dichotomized comparisons of outcomes were performed between aggressive versus non-aggressive strategy (aspirin±heparin) and aspirin+heparin versus aspirin-alone groups. RESULTS: Among 161 included patients, 62 received aspirin monotherapy, 38 aspirin+heparin, and 61 an aggressive treatment. Aggressive antiplatelet treatment was associated with an increased rate of excellent (modified Thrombolysis in Cerebral Infarction (mTICI) 2c-3) recanalization and reduced carotid stent thrombosis at day 1 (3.5% vs 16.3%), compared with non-aggressive strategy. There were no significant differences in hemorrhagic transformation or 90-day mortality. There was a tendency towards better clinical outcome with aggressive treatment, without reaching statistical significance. Addition of heparin to aspirin was not associated with an increased rate of carotid stent patency. CONCLUSIONS: Aggressive antiplatelet treatment was associated with improved intracranial recanalization and carotid stent patency, without safety concerns. These findings have implications for randomized trials and may be of utility for clinicians when making antithrombotic treatment choices.

Effects of Daehwang-Hwanglyoun-Sasim-Tang on brain injury and cognitive function in mice caused by bilateral common carotid artery stenosis.

Among geriatric diseases, cerebrovascular disease ranks fourth according to the Causes of Death Statistics in 2019, Korea, and is the most common cause of acquired disorders in adults. Daehwang-Hwanglyoun-Sasim-Tang (DHST), a herbal prescription consisting of two herbal medicines, Rhei Rhizoma and Coptidis Rhizoma, has been reported to have anti-inflammatory, antioxidant, and anticancer effects. This study was conducted to confirm the anti-inflammatory mechanism of DHST treatment in ischemic brain injury and to confirm the role of DHST in cognitive function improvement. C57BL/6 male mice were randomly divided into four groups (sham operation, bilateral common carotid artery stenosis (BCAS) control, experimental group administered 5 mL/kg DHST, experimental group administered 50 mL/kg DHST), with each group containing five mice. After 1 week, DHST was orally administered for 4 weeks, 5 days a week, and then behavioral evaluation of learning and memory was performed. In addition, morphological changes in the neurons in the CA1 region of the hippocampus were observed. Inflammation-related factors were evaluated using western blot analysis. In the 50 mL/kg DHST (H-DHST) group, the expression of apoptosis-related proteins was reduced and neuronal damage was suppressed in the hippocampal CA1 region. However, cognitive improvement was observed in the H-DHST group that was attributable to anti-inflammatory and antiapoptotic pathways. In the 5 mL/kg DHST group, no significant effect was observed compared with the control group.

Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Multicenter Randomized Phase II Trial.

BACKGROUND: Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis. METHODS: International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up. RESULTS: Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88-1.53)/1.05 (95% CI, 0.78-1.42; P=0.629)/0.63 (95% CI, 0.43-0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21-0.99]; P=0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37-1.42]; P=0.343). CONCLUSIONS: Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01645306.

Incidence of Ischemic Stroke in Patients With Asymptomatic Severe Carotid Stenosis Without Surgical Intervention.

Importance: Optimal management of patients with asymptomatic severe carotid stenosis is uncertain, due to advances in medical care and a lack of contemporary data comparing medical and surgical treatment. Objective: To estimate stroke outcomes among patients with medically treated asymptomatic severe carotid stenosis who did not undergo surgical intervention. Design, Setting, and Participants: Retrospective cohort study that included 3737 adult participants with asymptomatic severe (70%-99%) carotid stenosis diagnosed between 2008 and 2012 and no prior intervention or ipsilateral neurologic event in the prior 6 months. Participants received follow-up through 2019, and all were members of an integrated US regional health system serving 4.5 million members. Exposures: Imaging diagnosis of asymptomatic carotid stenosis of 70% to 99%. Main Outcomes and Measures: Occurrence of ipsilateral carotid-related acute ischemic stroke. Censoring occurred with death, disenrollment, or ipsilateral intervention. Results: Among 94 822 patients with qualifying imaging studies, 4230 arteries in 3737 (mean age, 73.8 [SD 9.5 years]; 57.4% male) patients met selection criteria including 2539 arteries in 2314 patients who never received intervention. The mean follow-up in this cohort was 4.1 years (SD 3.6 years). Prior to any intervention, there were 133 ipsilateral strokes with a mean annual stroke rate of 0.9% (95% confidence interval [CI], 0.7%-1.2%). The Kaplan-Meier estimate of ipsilateral stroke by 5 years was 4.7% (95% CI, 3.9%-5.7%). Conclusions and Relevance: In a community-based cohort of patients with asymptomatic severe carotid stenosis who did not undergo surgical intervention, the estimated rate of ipsilateral carotid-related acute ischemic stroke was 4.7% over 5 years. These findings may inform decision-making regarding surgical and medical treatment for patients with asymptomatic severe carotid artery stenosis.

Clopidogrel Bolus is Inferior to Sustained Clopidogrel Pretreatment in Patients Undergoing Carotid Artery Stent Placement.

BACKGROUND: Clopidogrel bolus is an option used before carotid artery stent (CAS) placement when sustained clopidogrel pretreatment is not used. OBJECTIVE: To compare the effect of clopidogrel bolus (450 mg administered ≥4 hours) with sustained clopidogrel pretreatment (48 hours or greater) before CAS among patients recruited in the Carotid Revascularization Endarterectomy versus Stenting Trial. METHODS: We compared the rates of primary end point (either any stroke, myocardial infarction, or death during the periprocedural period or any ipsilateral stroke within 4 years) between patients who received clopidogrel bolus and those who received sustained clopidogrel pretreatment using Cox proportional hazards analysis after adjusting for age, sex, symptomatic status, and initial severity of stenosis (≥70% vs <70%) over 4 years. RESULTS: The rate of periprocedural stroke (7.3% vs 3.4%, P = .03) and primary end point (11.3% vs 5.9%, P = .02) was significantly higher among patients who received clopidogrel bolus. The risk of primary end point was significantly higher in patients who received clopidogrel bolus (hazards ratio 1.9, 95% CI 1.1-3.4, P = .02) after adjusting for potential confounders. The overall mean (±standard deviation) primary end point-free survival based on Kaplan-Meier analysis was 7.0 ± 0.2 years for patients who received clopidogrel bolus and 8.9 ± 0.1 years for those who received sustained clopidogrel pretreatment (log-rank test P = .011). CONCLUSION: Clopidogrel bolus was associated with higher rates of adverse outcomes compared with sustained clopidogrel pretreatment in patients who underwent CAS. Therefore, clopidogrel bolus may not be equivalent to sustained clopidogrel pretreatment.

Platelet Biomarkers in Patients with Atherosclerotic Extracranial Carotid Artery Stenosis: A Systematic Review.

OBJECTIVE: The aim was to enhance understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratifying patients with asymptomatic or symptomatic atherosclerotic carotid stenosis. DATA SOURCES: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. REVIEW METHODS: A systematic review collated data from 1975 to 2020 on ex vivo platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis. RESULTS: Forty-three studies met the inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥ 30% asymptomatic carotid stenosis (ACS) vs. controls, with one neutral study. Preliminary data from one study suggested that quantification of "coated platelets" in combination with stenosis severity may aid risk stratification in patients with ≥ 50% - 99% ACS. Platelets were excessively activated in patients with ≥ 30% symptomatic carotid stenosis (SCS) vs. controls (≥ 11 positive studies and one neutral study). Antiplatelet-High on Treatment Platelet Reactivity (HTPR), previously called "antiplatelet resistance", was observed in 23% - 57% of patients on aspirin, with clopidogrel-HTPR in 25% - 100% of patients with ≥ 50% - 99% ACS. Aspirin-HTPR was noted in 9.5% - 64% and clopidogrel-HTPR in 0 - 83% of patients with ≥ 50% SCS. However, the data do not currently support the use of ex vivo platelet function/reactivity testing to tailor antiplatelet therapy outside of a research setting. Platelets are excessively activated (n = 5), with increased platelet counts (n = 3) in recently symptomatic vs. asymptomatic patients, including those without micro-emboli on transcranial Doppler (TCD) monitoring (n = 2). Most available studies (n = 7) showed that platelets become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment. CONCLUSION: Platelets are excessively activated in patients with carotid stenosis vs. controls, in recently symptomatic vs. asymptomatic patients, and may become activated/hyper-reactive following carotid interventions despite commonly prescribed antiplatelet regimens. Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular imaging, and platelet biomarker data can facilitate optimised antiplatelet therapy in individual patients with carotid stenosis.

Rapid Regression of Carotid Artery Stenosis Shortly after Intensive Medical Therapy.

Carotid artery stenosis (CAS) is mainly caused by atherosclerosis. Intensive medical therapy is effective in preventing stroke in CAS. To date, there has been no published report of rapid regression of CAS. A woman with untreated hyperlipidemia visited our emergency room with left hemiparesis. She exhibited facial palsy, left hemiparesis, and dysarthria immediately after the visit. Brain magnetic resonance (MR) diffusion-weighted imaging confirmed acute infarction in the right middle cerebral artery (MCA) territory due to severe stenosis of the right internal carotid artery (ICA), which was revealed by MR angiography and carotid duplex ultrasonography. The patient started intensive statin therapy and dual antiplatelet agent therapy. Carotid artery stenting was not performed until hospitalization day 16 due to pleural effusion. On day 16, digital subtraction angiography was performed, and spontaneous regression of severe stenosis was observed. Only mild stenosis with ulcerative plaque was evident. The rapid CAS regression in this case may be caused by M2 macrophage polarization as a result of intensive statin therapy. This rapid regression may also result from reduced foam cell formation by statin and aspirin and thereby increased endogenous thrombolysis. Our patient demonstrated the efficacy of short-term intensive statin and aspirin therapy on atherosclerosis with untreated hyperlipidemia.