Periprocedural intravenous heparin in patients with acute ischemic stroke treated with endovascular thrombectomy after intravenous thrombolysis.

OBJECTIVE: The benefit-to-risk ratio of periprocedural heparin in patients treated with endovascular thrombectomy (EVT) after intravenous thrombolysis (IVT) remains unclear. This study aimed to evaluate the potential effects of periprocedural heparin on clinical outcomes of EVT after IVT. METHODS: The authors retrospectively analyzed patients from multicenter studies treated with EVT after IVT in the anterior circulation. The endpoints were unfavorable outcome (defined as modified Rankin Scale score ≥ 3 at 90 days), 90-day mortality, symptomatic intracranial hemorrhage (SICH), successful recanalization, and early neurological deterioration. Patients were divided into two groups based on whether they were treated with heparin (heparin-treated group) or not (untreated group), and the efficacy and safety outcomes were compared using multivariable logistic regression models and propensity score-matching methods. RESULTS: Among the 322 included patients (mean age 67.4 years, 54.3% male), 32% of patients received periprocedural heparin. In multivariable analyses, the administration of periprocedural heparin was a significant predictor for unfavorable outcome (OR 2.821, 95% CI 1.15-7.326; p = 0.027), SICH (OR 24.925, 95% CI 2.363-780.262; p = 0.025), and early neurological deterioration (OR 5.344, 95% CI 1.299-28.040; p = 0.029). Regarding successful recanalization and death, no significant differences between the groups were found after propensity score matching. CONCLUSIONS: The results showed that periprocedural heparin is associated with an increased risk of unfavorable outcomes and SICH in patients treated with EVT after IVT. Further studies are warranted to evaluate the utility and safety of periprocedural heparin.

Trajectories of stroke severity and functional outcomes after endovascular treatment in ischemic stroke: A post hoc analysis of a randomized controlled trial.

BACKGROUND: The trajectory of early neurological changes in patients with acute ischemic stroke has been understudied. This study aimed to investigate the association between longitudinal trajectories of stroke severity and 90-day functional outcomes in patients with acute ischemic stroke receiving endovascular treatment. METHODS: We enrolled patients from a prospective, multicenter, randomized controlled trial. The stroke severity was assessed with the National Institute of Health Stroke Scale at the pre-procedure, 24 hours, and seven days after the procedure. Group-based trajectory modeling (GBTM) was used to identify trajectories of stroke severity. Multivariable logistic regression was performed to explore the association between stroke severity markers and 90-day functional outcomes. RESULTS: Of 218 enrolled patients, 127 (58.3%) had poor functional outcomes at 90 days. We identified three trajectories of stroke severity in the GBTM: stable symptom (38.1%), symptom deterioration (17.0%), and symptom improvement (44.9%). In multivariable analyses, trajectories of stroke severity were associated with an increased risk of poor functional outcomes (symptom improvement versus symptom deterioration: odds ratio, 0.007; 95% confidence interval, 0.001-0.040; P <0.001). Reclassification indexes revealed that trajectories of stroke severity would increase the predictive ability for poor functional outcomes at 90 days. CONCLUSION: After endovascular treatment, patients would follow one of three distinct trajectories of stroke severity. Symptom deterioration trajectory was associated with an increased risk of poor functional outcomes at 90 days. TRIAL REGISTRATION NUMBER: NCT04973332.

Angiography­based quantitative flow ratio for functional assessment of intracranial atherosclerotic disease.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS), an important cause of stroke, is associated with a considerable stroke recurrence rate despite optimal medical treatment. Further assessment of the functional significance of ICAS is urgently needed to enable individualised treatment and, thus, improve patient outcomes. AIMS: We aimed to evaluate the haemodynamic significance of ICAS using the quantitative flow ratio (QFR) technique and to develop a risk stratification model for ICAS patients. METHODS: Patients with moderate to severe stenosis of the middle cerebral artery, as shown on angiography, were retrospectively enrolled. For haemodynamic assessment, the Murray law-based QFR (µQFR) was performed on eligible patients. Multivariate logistic regression models composed of µQFR and other risk factors were developed and compared for the identification of symptomatic lesions. Based on the superior model, a nomogram was established and validated by calibration. RESULTS: Among 412 eligible patients, symptomatic lesions were found in 313 (76.0%) patients. The µQFR outperformed the degree of stenosis in discriminating culprit lesions (area under the curve [AUC]: 0.726 vs 0.631; DeLong test p-value=0.001), and the model incorporating µQFR and conventional risk factors also performed better than that containing conventional risk factors only (AUC: 0.850 vs 0.827; DeLong test p-value=0.034; continuous net reclassification index=0.620, integrated discrimination improvement=0.057; both p<0.001). The final nomogram showed good calibration (p for Hosmer-Lemeshow test=0.102) and discrimination (C-statistic 0.850, 95% confidence interval: 0.812-0.883). CONCLUSIONS: The µQFR was significantly associated with symptomatic ICAS and outperformed the angiographic stenosis severity. The final nomogram effectively discriminated symptomatic lesions and may provide a useful tool for risk stratification in ICAS patients.

Angiography-based hemodynamic features predict recurrent ischemic events after angioplasty and stenting of intracranial vertebrobasilar atherosclerotic stenosis.

OBJECTIVES: To assess the predictive value of hemodynamic features for stroke relapse in patients with intracranial vertebrobasilar atherosclerotic stenosis treated with percutaneous transluminal angioplasty and stenting (PTAS) using quantitative digital subtraction angiography (q-DSA). METHODS: In this retrospective longitudinal study, patients with intracranial vertebrobasilar atherosclerotic stenosis and who underwent PTAS treatment between January 2012 and May 2020 were enrolled. The q-DSA assessment was performed before and after PTAS. ROIs 1-4 were placed along the vertebral artery, proximal and distal basilar artery, and posterior cerebral artery; ROIs 5-8 were in 5 mm and 10 mm proximal and distal to the lesion, respectively. Relative time to peak (rTTP) was defined as the difference in TTP between ROIs. Cox regression analyses were performed to determine risk factors for recurrent stroke. RESULTS: A total of 137 patients (mean age, 62 years ± 10 [standard deviation], 83.2% males) were included, and 26 (19.0%) patients had stroke relapse during follow-up (median time of 42.6 months [interquartile range, 19.7-60.7]). Preprocedural rTTP4-1 (adjusted hazard ratio (HR) = 2.270; 95% CI 1.371-3.758; p = 0.001) and preprocedural rTTP8-5 (adjusted HR = 0.240; 95% CI 0.088-0.658; p = 0.006) were independently associated with the recurrent stroke. These hemodynamic parameters provided an incremental prognostic value for stroke relapse (AUC, 0.817 [0.704-0.931]; the net reclassification index, 0.431 [0.057-0.625]; and the integrated discrimination index, 0.140 [0.035-0.292]). CONCLUSIONS: In patients with intracranial vertebrobasilar atherosclerosis treated with PTAS, preprocedural prolonged TTP of the target vessel and shortened trans-stenotic TTP difference were associated with stroke relapse. Q-DSA-defined hemodynamic parameters provided incremental predictive value over conventional parameters for stroke recurrence. CLINICAL RELEVANCE STATEMENT: Quantitative DSA analysis enables intuitive observation and semi-quantitative evaluation of peri-therapeutic cerebral blood flow. More importantly, quantitative DSA-defined hemodynamic parameters have the potential for risk stratification of patients with intracranial atherosclerotic stenosis. KEY POINTS: Semi-quantitative angiography-based parameters can reflect pre- and postprocedural subtle changes in blood flow in patients with intracranial atherosclerotic stenosis. Although angioplasty procedures can significantly improve blood flow status, patients with more restricted baseline blood flow still show a higher risk of stroke recurrence. Angiography-based hemodynamic features possess prognostic value and can serve as clinical markers to assess stroke risk of patients with intracranial atherosclerotic stenosis.

Vascular endothelium deploys caveolin-1 to regulate oligodendrogenesis after chronic cerebral ischemia in mice.

Oligovascular coupling contributes to white matter vascular homeostasis. However, little is known about the effects of oligovascular interaction on oligodendrocyte precursor cell (OPC) changes in chronic cerebral ischemia. Here, using a mouse of bilateral carotid artery stenosis, we show a gradual accumulation of OPCs on vasculature with impaired oligodendrogenesis. Mechanistically, chronic ischemia induces a substantial loss of endothelial caveolin-1 (Cav-1), leading to vascular secretion of heat shock protein 90α (HSP90α). Endothelial-specific over-expression of Cav-1 or genetic knockdown of vascular HSP90α restores normal vascular-OPC interaction, promotes oligodendrogenesis and attenuates ischemic myelin damage. miR-3074(-1)-3p is identified as a direct inducer of Cav-1 reduction in mice and humans. Endothelial uptake of nanoparticle-antagomir improves myelin damage and cognitive deficits dependent on Cav-1. In summary, our findings demonstrate that vascular abnormality may compromise oligodendrogenesis and myelin regeneration through endothelial Cav-1, which may provide an intercellular mechanism in ischemic demyelination.

Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury.

BACKGROUND: Thrombo-inflammation is an important checkpoint that orchestrates infarct development in ischemic stroke. However, the underlying mechanism remains largely unknown. Here, we explored the role of endothelial Caveolin-1 (Cav-1) in cerebral thrombo-inflammation. METHODS: The correlation between serum Cav-1 level and clinical outcome was analyzed in acute ischemic stroke patients with successful recanalization. Genetic manipulations by endothelial-specific adeno-associated virus (AAV) and siRNA were applied to investigate the effects of Cav-1 in thrombo-inflammation in a transient middle cerebral artery occlusion (tMCAO) model. Thrombo-inflammation was analyzed by microthrombosis formation, myeloid cell infiltration, and endothelial expression of adhesion molecules as well as inflammatory factors. FINDINGS: Reduced circulating Cav-1, with the potential to predict microembolic signals, was more frequently detected in recanalized stroke patients without early neurological improvement. At 24 h after tMCAO, serum Cav-1 was consistently reduced in mice. Endothelial Cav-1 was decreased in the peri-infarct region. Cav-1-/- endothelium, with prominent barrier disruption, displayed extensive microthrombosis, accompanied by increased myeloid cell inflammatory infiltration after tMCAO. Specific enhanced expression of endothelial Cav-1 by AAV-Tie1-Cav-1 remarkably reduced infarct volume, attenuated vascular hyper-permeability and alleviated thrombo-inflammation in both wild-type and Cav-1-/- tMCAO mice. Transcriptome analysis after tMCAO further designated Rxrg as the most significantly changed molecule resulting from the knockdown of Cav-1. Supplementation of RXR-γ siRNA reversed AAV-Tie1-Cav-1-induced amelioration of thrombo-inflammation without affecting endothelial tight junction. INTERPRETATION: Endothelial Cav-1/RXR-γ may regulate infarct volume and neurological impairment, possibly through selectively controlling thrombo-inflammation coupling, in cerebral ischemia/reperfusion. FUNDING: This work was supported by National Natural Science Foundation of China.

Extracellular vesicles carrying proinflammatory factors may spread atherosclerosis to remote locations.

Most cells involved in atherosclerosis release extracellular vesicles (EVs), which can carry bioactive substances to downstream tissues via circulation. We hypothesized that EVs derived from atherosclerotic plaques could promote atherogenesis in remote locations, a mechanism that mimics the blood metastasis of cancer. Ldlr gene knockout (Ldlr KO) rats were fed on a high cholesterol diet and underwent partial carotid ligation to induce local atherosclerosis. EVs were separated from carotid artery tissues and downstream blood of carotid ligation by centrifugation. MiRNA sequencing and qPCR were then performed to detect miRNA differences in EVs from rats with and without induced carotid atherosclerosis. Biochemical analyses demonstrated that EVs derived from atherosclerosis could increase the expression of ICAM-1, VCAM-1, and E-selectin in endothelial cells in vitro. EVs derived from atherosclerosis contained a higher level of miR-23a-3p than those derived from controls. MiR-23a-3p could promote endothelial inflammation by targeting Dusp5 and maintaining ERK1/2 phosphorylation in vitro. Inhibiting EV release could attenuate atherogenesis and reduce macrophage infiltration in vivo. Intravenously administrating atherosclerotic plaque-derived EVs could induce intimal inflammation, arterial wall thickening and lumen narrowing in the carotids of Ldlr KO rats, while simultaneous injection of miR-23a-3p antagomir could reverse this reaction. The results suggested that EVs may transfer atherosclerosis to remote locations by carrying proinflammatory factors, particularly miR-23a-3p.

Optical Coherence Tomography Evaluation of Carotid Artery Stenosis and Stenting in Patients With Previous Cervical Radiotherapy.

Objectives: Cervical radiotherapy can lead to accelerated carotid artery stenosis, increased incidence of stroke, and a higher rate of in-stent restenosis in irradiated patients. Our objective was to reveal the morphological characteristics of radiation-induced carotid stenosis (RICS) and the stent-vessel interactions in patients with previous cervical radiotherapy by optical coherence tomography (OCT). Materials and Methods: Between November 2017 and March 2019, five patients with a history of cervical radiotherapy were diagnosed with severe carotid artery stenosis and underwent carotid artery stenting (CAS). OCT was conducted before and immediately after the carotid stent implantation. Two patients received OCT evaluation of carotid stenting at 6- or 13-month follow-up. Results: The tumor types indicating cervical radiotherapy were nasopharyngeal carcinoma (n = 3), cervical esophageal carcinoma (n = 1), and cervical lymphoma (n = 1). The median interval from the radiotherapy to the diagnosis of RICS was 8 years (range 4-36 years). Lesion characteristics of RICS were detected with heterogeneous signal-rich tissue, dissection, and advanced atherosclerosis upon OCT evaluation. Post-interventional OCT revealed 18.2-57.1% tissue protrusion and 3.3-13.8% stent strut malapposition. Follow-up OCT detected homogeneous signal-rich neointima and signal-poor regions around stent struts. In the patient with high rates of tissue protrusion and stent strut malapposition, the 6-month neointima burden reached 48.9% and microvessels were detected. Conclusion: The morphological features of RICS were heterogeneous, including heterogeneous signal-rich tissue, dissection, and advanced atherosclerosis. Stenting was successful in all 5 patients with severe RICS. One patient, with high rates of tissue protrusion and stent strut malapposition immediately after stenting, received in-stent neointimal hyperplasia at a 6-month follow-up.

Astrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice.

Ischemic stroke can cause secondary myelin damage in the white matter distal to the primary injury site. The contribution of astrocytes during secondary demyelination and the underlying mechanisms are unclear. Here, using a mouse of distal middle cerebral artery occlusion, we show that lipocalin-2 (LCN2), enriched in reactive astrocytes, expression increases in nonischemic areas of the corpus callosum upon injury. LCN2-expressing astrocytes acquire a phagocytic phenotype and are able to uptake myelin. Myelin removal is impaired in Lcn2-/- astrocytes. Inducing re-expression of truncated LCN2(Δ2-20) in astrocytes restores phagocytosis and leads to progressive demyelination in Lcn2-/- mice. Co-immunoprecipitation experiments show that LCN2 binds to low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Knockdown of Lrp1 reduces LCN2-induced myelin engulfment by astrocytes and reduces demyelination. Altogether, our findings suggest that LCN2/LRP1 regulates astrocyte-mediated myelin phagocytosis in a mouse model of ischemic stroke.

Functional Assessment of Cerebral Artery Stenosis by Angiography-Based Quantitative Flow Ratio: A Pilot Study.

BACKGROUND: Increasing attention has been paid to the hemodynamic evaluation of cerebral arterial stenosis. We aimed to demonstrate the performance of angiography-based quantitative flow ratio (QFR) to assess hemodynamic alterations caused by luminal stenoses, using invasive fractional pressure ratios (FPRs) as a reference standard. METHODS: Between March 2013 and December 2019, 29 patients undergoing the pressure gradient measurement of cerebral atherosclerosis were retrospectively enrolled. Wire-based FPR was defined by the arterial pressure distal to the stenotic lesion (Pd) to proximal (Pa) pressure ratios (Pd/Pa). FPR < 0.70 or FPR < 0.75 was assumed as hemodynamically significant stenosis. The new method of computing QFR from a single angiographic view, i.e., the Murray law-based QFR, was applied to the interrogated vessel. An artificial intelligence algorithm was developed to realize the automatic delineation of vascular contour. RESULTS: Fractional pressure ratio and QFR were assessed in 38 vessels from 29 patients. Excellent correlation and agreement were observed between QFR and FPR [r = 0.879, P < 0.001; mean difference (bias): -0.006, 95% limits of agreement: -0.198 to 0.209, respectively). Intra-observer and inter-observer reliability in QFR were excellent (intra-class correlation coefficients, 0.996 and 0.973, respectively). For predicting FPR < 0.70, the area under the receiver-operating characteristic curves (AUC) of QFR was 0.946 (95% CI, 0.820 to 0.993%). The sensitivity and specificity of QFR < 0.70 for identifying FPR < 0.70 was 88.9% (95% CI, 65.3 to 98.6%) and 85.0% (95% CI, 62.1 to 96.8%). For predicting FPR < 0.75, QFR showed similar performance with an AUC equal to 0.926. CONCLUSION: Computational QFR from a single angiographic view achieved comparable results to the wire-based FPR. The excellent diagnostic performance and repeatability empower QFR with high feasibility in the functional assessment of cerebral arterial stenosis.

Motor Network Reorganization After Repetitive Transcranial Magnetic Stimulation in Early Stroke Patients: A Resting State fMRI Study.

OBJECTIVE: To compare the effects of high-frequency (10 Hz) versus low-frequency (1 Hz) repetitive Transcranial Magnetic Stimulation (rTMS) on motor recovery and functional reorganization of the cortical motor network during the early phase of stroke. METHODS: Forty-six hospitalized, first-ever ischemic stroke patients in early stage (within two weeks) with upper limb motor deficits were recruited. They were randomly allocated to three groups with 10 Hz ipsilesional rTMS, 1 Hz contralesional rTMS, and sham rTMS of five daily session. All patients underwent motor function (Upper Extremity Fugl-Meyer), neurophysiological and resting-state  functional Magnetic Resonance Imaging (fMRI) (rs-fMRI) assessments before and after rTMS intervention. Motor recovery (△Fugl-Meyer Assessment) was defined as motor function changes before and after rTMS intervention. Motor function assessment was reevaluated at time point of three month follow-up. RESULTS: The two real rTMS groups manifested greater motor improvements than the sham group. The effect sustained for at least 3 months after the end of the treatment sessions. Compared with the sham group, 10 Hz ipsilesional rTMS group presented increased resting-state functional connectivity (FC) between ipsilesional primary motor cortex (M1) and contralesional M1 (P = .007), whereas 1 Hz contralesional rTMS group presented increased FC between contralesional M1 and ipsilesional supplementary motor area (P = .010), which were positively correlated with motor recovery (P < .05). CONCLUSION: Beneficial effect of rTMS on motor recovery might be underlaid by increased FC between stimulating site and the remote motor areas, highlighting the motor network reorganization mechanism of rTMS in early post-stroke phase.

Ferroptosis and traumatic brain injury.

Traumatic brain injury (TBI) is a worldwide health problem contributing to significant economic burden. TBI is difficult to treat partly due to incomplete understanding of pathophysiology. Ferroptosis is a type of iron-dependent programmed cell death which has gained increasing attention due to its possible role in TBI. Current studies have demonstrated that ferroptosis is related to the pathology of TBI, and inhibition of ferroptosis may improve long term outcomes of TBI. Therefore, clarification of the exact association between ferroptosis and traumatic brain injury is necessary and may provide new targets for treatment. This review describes (1) the ferroptosis pathways following traumatic brain injury, (2) the role of ferroptosis during the chronic phase of traumatic brain injury, and (3) potential therapies targeting the ferroptosis pathways.

Inhibition of miR-103-3p Preserves Neurovascular Integrity Through Caveolin-1 in Experimental Subarachnoid Hemorrhage.

Caveolin-1 (Cav-1) is a constitutive structural protein of caveolae in the plasma membrane. It plays an important role in maintaining blood brain barrier (BBB) integrity. In this study, we identified that miR-103-3p, a hypoxia-responsive miRNA, could interact with Cav-1. In endothelial cells, miR-103-3p mimic diminished the expression of Cav-1 and tight junction proteins, which were rescued by the inhibition of miR-103-3p. We found a substantial increase of miR-103-3p and decease of Cav-1 in the rat subarachnoid hemorrhage (SAH) model. Pre-SAH intracerebroventricularly injection of miR-103-3p antagomir relieved Cav-1 loss, sequentially reduced BBB permeability and improved neurological function. Finally, we demonstrated that the salutary effects of miR-103-3p antagomir were abolished in Cav-1 knock-out mice, suggesting that Cav-1 was required for the miR-103-3p inhibition-induced neurovascular protection. Taken together, our findings suggest that the inhibition of miR-103-3p could exert neuroprotective effects through preservation of Cav-1 and BBB integrity, making miR-103-3p a novel therapeutic target for SAH.

Recognition of Abnormal Chest Compression Depth Using One-Dimensional Convolutional Neural Networks.

When the displacement of an object is evaluated using sensor data, its movement back to the starting point can be used to correct the measurement error of the sensor. In medicine, the movements of chest compressions also involve a reciprocating movement back to the starting point. The traditional method of evaluating the effects of chest compression depth (CCD) is to use an acceleration sensor or gyroscope to obtain chest compression movement data; from these data, the displacement value can be calculated and the CCD effect evaluated. However, this evaluation procedure suffers from sensor errors and environmental interference, limiting its applicability. Our objective is to reduce the auxiliary computing devices employed for CCD effectiveness evaluation and improve the accuracy of the evaluation results. To this end, we propose a one-dimensional convolutional neural network (1D-CNN) classification method. First, we use the chest compression evaluation criterion to classify the pre-collected sensor signal data, from which the proposed 1D-CNN model learns classification features. After training, the model is used to classify and evaluate sensor signal data instead of distance measurements; this effectively avoids the influence of pressure occlusion and electromagnetic waves. We collect and label 937 valid CCD results from an emergency care simulator. In addition, the proposed 1D-CNN structure is experimentally evaluated and compared against other CNN models and support vector machines. The results show that after sufficient training, the proposed 1D-CNN model can recognize the CCD results with an accuracy rate of more than 95%. The execution time suggests that the model balances accuracy and hardware requirements and can be embedded in portable devices.

Aberrant oligodendroglial LDL receptor orchestrates demyelination in chronic cerebral ischemia.

Oligodendrocytes express low-density lipoprotein receptor (LDLR) to endocytose cholesterol for the maintenance of adulthood myelination. However, the potential role of LDLR in chronic cerebral ischemia-related demyelination remains unclear. We used bilateral carotid artery stenosis (BCAS) to induce sustained cerebral ischemia in mice. This hypoxic-ischemic injury caused a remarkable decrease in oligodendroglial LDLR, with impaired oligodendroglial differentiation and survival. Oligodendroglial cholesterol levels, however, remained unchanged. Mouse miR-344e-3p and the human homolog miR-410-3p, 2 miRNAs directly targeting Ldlr, were identified in experimental and clinical leukoaraiosis and were thus implicated in the LDLR reduction. Lentiviral delivery of LDLR ameliorated demyelination following chronic cerebral ischemia. By contrast, Ldlr-/- mice displayed inadequate myelination in the corpus callosum. Ldlr-/- oligodendrocyte progenitor cells (OPCs) exhibited reduced ability to differentiate and myelinate axons in vitro. Transplantation with Ldlr-/- OPCs could not rescue the BCAS-induced demyelination. Such LDLR-dependent myelin restoration might involve a physical interaction of the Asn-Pro-Val-Tyr (NPVY) motif with the phosphotyrosine binding domain of Shc, which subsequently activated the MEK/ERK pathway. Together, our findings demonstrate that the aberrant oligodendroglial LDLR in chronic cerebral ischemia impairs myelination through intracellular signal transduction. Preservation of oligodendroglial LDLR may provide a promising approach to treat ischemic demyelination.

Insulin enhances neointimal hyperplasia following arterial injury through the PI3K/Akt pathway in type 1 diabetic rats.

Although insulin is known to affect neointimal hyperplasia via distinct signaling pathways, how neointimal hyperplasia is affected in insulin­deficient type 1 diabetes remains unknown. The aim of the current study was to investigate two major signaling branches of insulin action regulating neointimal hyperplasia following arterial injury in type 1 diabetes with or without exogenous insulin administration. Rats were treated with vehicle (control group), streptozotocin (STZ) alone (STZ group; uncontrolled type 1 diabetes) or STZ followed by insulin (STZ + I group; controlled type 1 diabetes). Subsequently, a type 1 diabetic rat model of carotid artery balloon injury was established. Following this, the intima­to­media area ratios were examined for evidence of neointimal hyperplasia in the carotid arteries of the rats by performing hematoxylin­eosin staining. Furthermore, the protein expression of extracellular signal­regulated kinase (ERK), phosphorylated (p­) ERK, protein kinase B (Akt) and p­Akt in the carotid arteries of the rats was determined via immunoblotting. Moreover, an in vitro model of type 1 diabetes was induced by incubation of primary vascular smooth muscle cells (VSMCs) with glucose and/or insulin. Cellular proliferation and signaling protein expression levels in VSMCs were determined by measuring the incorporation of tritiated thymidine and performing immunoblotting, respectively. The results demonstrated that compared with that in control rats, neointimal hyperplasia and expression of p­Akt in uncontrolled type 1 diabetic rats were significantly decreased. This decrease was recovered in controlled type 1 diabetes with insulin therapy. Furthermore, the difference in the expression of p­ERK between groups was not significant. Additionally, the results of the cell experiments were consistent with those from the animal studies. In conclusion, the preferential signaling along the phosphatidylinositol 3­kinase/Akt pathway of insulin action in response to insulin restoration may contribute to neointimal hyperplasia. The present study provides a novel approach for the further treatment of neointimal hyperplasia in type 1 diabetes.

Superficial Calcification With Rotund Shape Is Associated With Carotid Plaque Rupture: An Optical Coherence Tomography Study.

Background: Plaque rupture is an important etiology for symptomatic carotid stenosis. The role of calcification in the plaque vulnerability has been controversial. We aimed to detect the geometric features of calcifications in carotid plaque and to examine its association with plaque rupture. Methods: Optical coherence tomography assessment of carotid plaque was performed in 88 patients. Calcification shape was evaluated through quantitative measurements of the long and short axis, area size, circumference, calcification arc, and longitudinal length. Calcification location was analyzed through the distance to the lumen. Furthermore, we developed idealized fluid-structure interaction models to investigate the association of calcification shape and plaque stress. Results: A total of 33 ruptured plaques and 30 non-ruptured plaques were recognized. Ruptured plaques had more multiple calcifications and protruded calcifications. The calcifications in the ruptured plaques displayed a remarkably lower long-axis/short-axis (L/S) ratio than in the non-ruptured plaques (p = 0.001). We classified calcification shape into crescentic calcification (L/S > 2.5) and rotund calcification (L/S ≤ 2.5). Rotund-shaped calcifications were more common in ruptured plaques than in non-ruptured plaques (p = 0.02). Superficial calcifications with minimal distance to the lumen ≤ 50 µm accounted for 79.4% of all calcifications in the ruptured plaques, and only 7.7% in the non-ruptured plaques (p < 0.001). Biomechanical analysis showed that the plaque with rotund-shaped calcification developed 7.91-fold higher von Mises stress than the plaque with crescentic calcification. Conclusions: Superficial calcifications and rotund-shaped calcifications are associated with carotid plaque rupture, suggesting that calcification location and shape may play a key role in plaque vulnerability.

CD99 mediates neutrophil transmigration through the bEnd.3 monolayer via the induction of oxygen-glucose deprivation.

AIM/BACKGROUND: CD99 participate in neutrophil infiltration after inflammatory events; however, despite the important role of inflammation in ischemic stroke, the role of CD99 in ischemic stroke remains unclear. METHOD: In the present study, we detected the protein expression of CD99, ICAM-1, and CD31 (PECAM-1) in oxygen-glucose deprivation (OGD)-induced bEnd.3 cells and neutrophils and explored the influence of HIF-1α and IL-1ß on their expression. We also explored the role of CD99 in the OGD-induced transmigration of neutrophils. RESULTS: Our results showed that OGD induction upregulated CD99 in bEnd.3 cells and that this effect could be abolished by the preadministration of IL-1ß and was not mediated by HIF-1α. However, the activation of ICAM-1 by OGD remained activated with IL-1ß treatment. No significant influence of IL-1ß on OGD-induced CD31. Finally, we found a significant increase in infiltrated neutrophils after OGD induction compared with the control and OGD + anti-CD99 groups. CONCLUSION: Our results indicated that CD99 mediates neutrophil infiltration and transmigration via OGD induction and thus constitutes a potential therapeutic target for anti-inflammatory treatment after ischemic stroke.

Calcification in Atherosclerotic Plaque Vulnerability: Friend or Foe?

Calcification is a clinical marker of atherosclerosis. This review focuses on recent findings on the association between calcification and plaque vulnerability. Calcified plaques have traditionally been regarded as stable atheromas, those causing stenosis may be more stable than non-calcified plaques. With the advances in intravascular imaging technology, the detection of the calcification and its surrounding plaque components have evolved. Microcalcifications and spotty calcifications represent an active stage of vascular calcification correlated with inflammation, whereas the degree of plaque calcification is strongly inversely related to macrophage infiltration. Asymptomatic patients have a higher content of plaque calcification than that in symptomatic patients. The effect of calcification might be biphasic. Plaque rupture has been shown to correlate positively with the number of spotty calcifications, and inversely with the number of large calcifications. There may be certain stages of calcium deposition that may be more atherogenic. Moreover, superficial calcifications are independently associated with plaque rupture and intraplaque hemorrhage, which may be due to the concentrated and asymmetrical distribution of biological stress in plaques. Conclusively, calcification of differential amounts, sizes, shapes, and positions may play differential roles in plaque homeostasis. The surrounding environments around the calcification within plaques also have impacts on plaque homeostasis. The interactive effects of these important factors of calcifications and plaques still await further study.

Optical coherence tomography evaluation of vertebrobasilar artery stenosis: case series and literature review.

BACKGROUND: Intracranial vertebrobasilar artery stenosis is an important cause of ischemic stroke. With its high resolution, intravascular optical coherence tomography (OCT) provides detailed assessment of vessel wall features. It is widely applied to identify high-risk plaque in the cardiovascular system, but its use in the intracranial artery has been limited. OBJECTIVE: To explore, in this pilot study, the usefulness of OCT in imaging of the intracranial artery wall. METHODS: Between November 2017 and July 2018, four patients with severe intracranial vertebrobasilar artery stenosis were enrolled for preintervention OCT evaluation of the lesion artery. Stenosis was present in the basilar artery in one case and in the intracranial vertebral artery in three cases. RESULTS: OCT images of the lesions showed various features of plaque vulnerability, such as intraluminal thrombus, lipid-rich plaque with plaque rupture, thin fibrous cap, macrophage accumulations, and a mixed lesion with dissecting aneurysm. In view of the OCT findings, all patients received balloon angioplasty and stent implantation. CONCLUSIONS: These cases describe the successful implementation of OCT in intracranial vertebrobasilar artery stenosis. No side effects were seen during the OCT imaging. This technology may help in the diagnosis and treatment of cerebrovascular disease.