scholarly journals Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke

2020 ◽  
Vol 40 (9) ◽  
pp. 1806-1822 ◽  
Author(s):  
Hua Zhang ◽  
Wojciech Rzechorzek ◽  
Amir Aghajanian ◽  
James E Faber
Keyword(s):  
Ischemic Stroke ◽  
De Novo ◽  
Infarct Volume ◽  
First Report ◽  
Oxygen Levels ◽  
No Formation ◽  
Mca Occlusion ◽  
Dose Dependent ◽  
Inspired Oxygen ◽  
Collateral Formation

Pial collaterals provide protection in stroke. Evidence suggests their formation late during gestation (collaterogenesis) is driven by reduced oxygen levels in the cerebral watersheds. The purpose of this study was to determine if collaterogenesis can be re-activated in the adult to induce formation of additional collaterals (“neo-collateral formation”, NCF). Mice were gradually acclimated to reduced inspired oxygen (FIO2) and maintained at 12, 10, 8.5 or 7% for two-to-eight weeks. Hypoxemia induced “dose”-dependent NCF and remodeling of native collaterals, and decreased infarct volume after permanent MCA occlusion. In contrast, no formation occurred of addition collateral-like intra-tree anastomoses, PComs, or branches within the MCA tree. Hypoxic NCF, remodeling and infarct protection were durable, i.e. retained for at least six weeks after return to normoxia. Hypoxia increased expression of Hif2α, Vegfa, Rabep2, Angpt2, Tie2 and Cxcr4. Neo-collateral formation was abolished in mice lacking Rabep2, a novel gene involved in VEGFA→Flk1 signaling and required for formation of collaterals during development, and inhibited by knockdown of Vegfa, Flk1 and Cxcr4. Rabep2-dependent NCF was also induced by permanent MCA occlusion. This is the first report that hypoxia induces new pial collaterals to form. Hypoxia- and occlusion-induced neo-collateral formation provide models to study collaterogenesis in the adult.

Abstract T P68: Outcome of Cervical Internal Carotid Artery Occlusions After Intravenous Thrombolysis in Acute Ischemic Stroke Patients With Tandem Occlusions

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Héctor Avellón-Liaño ◽  
Ana I Calleja ◽  
Elisa Cortijo ◽  
Pablo García-Bermejo ◽  
Luis López-Mesonero ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Carotid Artery ◽  
Internal Carotid Artery ◽  
Acute Ischemic Stroke ◽  
Internal Carotid ◽  
Infarct Volume ◽  
Lower Mortality ◽  
Carotid Revascularization ◽  
Mca Occlusion ◽  
Tandem Occlusion

Background and Objective: Acute ischemic stroke (AIS) associated with tandem extracranial internal carotid artery (EICA) - middle cerebral artery (MCA) occlusion is burdened with a poor clinical outcome. The recanalization rate of extracranial ICA occlusion after i.v. thrombolysis and its prognostic significance in this group of patients remain largely unknown. Methods: Retrospective analysis of a prospectively collected database including consecutive AIS patients treated with i.v. thrombolysis. All patients underwent urgent assessment of extracranial and intracranial large arteries with either computed tomography angiography (CTA) or echo-Doppler ultrasound to document an acute EICA-MCA tandem occlusion prior to thrombolysis. EICA was monitored by control carotid ultrasound and/or CTA in order to detect transition from occlusion to relevant stenosis. Outcome variables: carotid revascularization, in-hospital mortality, Rankin 0-2 at three months, and infarct volume. Results: From January 2008 to December 2013, 606 AIS patients received i.v. thrombolysis, of whom 53 (9%) had a documented EICA-MCA tandem occlusion. Four of them died within first 24 hours and EICA could not be monitored. Occluded EICA evolved towards a severe stenosis in 14/49 (29%) after thrombolysis. Angiographic confirmation was obtained in 11 of them, who underwent carotid endarterectomy. EICA recanalization was more frequent among active smokers and was associated with carotid revascularization (79% vs. 0%, p<0.001), lower mortality (0% vs. 26%, p=0.03) and a smaller infarct volume (27 vs. 89 cc, p=0.04). Conclusion: Around 30% of AIS patients with tandem EICA-MCA occlusion treated with i.v. thrombolysis experience transition from initially occluded to severely stenosed EICA that can be rescued for revascularization. This evolution is associated with a lower mortality and smaller infarct volume.

scholarly journals Hemorrhage Rates and Outcomes When Using up to 100 mg Intra-Arterial t-PA for Thrombolysis in Acute Ischemic Stroke

2010 ◽  
Vol 16 (3) ◽  
pp. 297-305 ◽  
Author(s):  
G.A. Christoforidis ◽  
A.P. Slivka ◽  
C. Karakasis ◽  
Y. Mohammad ◽  
B. Avutu ◽  
...  
Keyword(s):  
Platelet Count ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Infarct Volume ◽  
Multivariate Logistic Regression Analysis ◽  
Single Center Experience ◽  
Radiographic Outcomes ◽  
Hospital Deaths ◽  
Hemorrhage Volume ◽  
Collateral Formation

This work presents a unique single center experience with intra-arterial delivery of tissue plasminogen activator (t-PA) doses as high as 100mg for thrombolysis. Hemorrhage volumes, hemorrhage rates, clinical outcomes and radiographic outcomes were assessed. Prospectively collected angiographic, clinical and laboratory information on 67 consecutive patients with acute ischemic stroke involving either the m1 segment of the middle cerebral artery, the intracranial internal carotid artery or the basilar artery were retrospectively analyzed. Patients who received more than 50 mg t-PA were compared with those patients receiving 50 mg or less. Outcome measures included: symptomatic hemorrhage, significant hemorrhage volume (greater than 25 ml), hemorrhage rate, change in National Institutes of Health stroke scale score at 24 hours and at hospital discharge, modified Rankin score at 90 days, in-hospital deaths, death within 90 days, reperfusion rate, and infarct volume. Multivariate logistic regression analysis demonstrated that t-PA dose over 50 mg was associated with higher rates of hemorrhage and larger hemorrhages. Poor pial collateral formation, poor reperfusion (less than 50% of the territory involved), and platelet count below 200 K/μL influenced hemorrhage. Limiting t-PA dose to 100mg rather than 50mg improved documented reperfusion rates from 37% to 61%. Restricting intra-arterial t-PA administration to 100mg rather than 50mg, is associated with higher overall reperfusion rates and improves overall outcomes, however, the hemorrhage rate is also elevated. Poor pial collateral formation and platelet count less than 200 K/μL may be reasons to curtail the use of higher t-PA dose to reduce hemorrhage rate.

scholarly journals Three-dimensional cultured mesenchymal stem cells enhance repair of ischemic stroke through inhibition of microglia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuejiao Li ◽  
Yankai Dong ◽  
Ye Ran ◽  
Yanan Zhang ◽  
Boyao Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ischemic Stroke ◽  
Proinflammatory Cytokines ◽  
Infarct Volume ◽  
Brain Lesion ◽  
Three Dimensional ◽  
Artery Occlusion ◽  
Rna Seq ◽  
The Brain

Abstract Background We show previously that three-dimensional (3D) spheroid cultured mesenchymal stem cells (MSCs) exhibit reduced cell size thus devoid of lung entrapment following intravenous (IV) infusion. In this study, we determined the therapeutic effect of 3D-cultured MSCs on ischemic stroke and investigated the mechanisms involved. Methods Rats underwent middle cerebral artery occlusion (MCAO) and reperfusion. 1 × 106 of 3D- or 2D-cultured MSCs, which were pre-labeled with GFP, were injected through the tail vain three and seven days after MCAO. Two days after infusion, MSC engraftment into the ischemic brain tissues was assessed by histological analysis for GFP-expressing cells, and infarct volume was determined by MRI. Microglia in the lesion were sorted and subjected to gene expressional analysis by RNA-seq. Results We found that infusion of 3D-cultured MSCs significantly reduced the infarct volume of the brain with increased engraftment of the cells into the ischemic tissue, compared to 2D-cultured MSCs. Accordingly, in the brain lesion of 3D MSC-treated animals, there were significantly reduced numbers of amoeboid microglia and decreased levels of proinflammatory cytokines, indicating attenuated activation of the microglia. RNA-seq of microglia derived from the lesions suggested that 3D-cultured MSCs decreased the response of microglia to the ischemic insult. Interestingly, we observed a decreased expression of mincle, a damage-associated molecular patterns (DAMPs) receptor, which induces the production of proinflammatory cytokines, suggestive of a potential mechanism in 3D MSC-mediated enhanced repair to ischemic stroke. Conclusions Our data indicate that 3D-cultured MSCs exhibit enhanced repair to ischemic stroke, probably through a suppression to ischemia-induced microglial activation.

scholarly journals Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA

2021 ◽  
pp. 0271678X2199298
Author(s):  
Chao Li ◽  
Chunyang Wang ◽  
Yi Zhang ◽  
Owais K Alsrouji ◽  
Alex B Chebl ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Mechanical Thrombectomy ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Therapeutic Effects ◽  
Vessel Occlusion ◽  
Healthy Human ◽  
Stroke Treatment

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.

Abstract WP47: Reperfusion Following Ischemic Stroke is Associated with Reduced Brain Edema

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hannah J Irvine ◽  
Thomas W Battey ◽  
Ann-Christin Ostwaldt ◽  
Bruce C Campbell ◽  
Stephen M Davis ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Edema ◽  
Infarct Volume ◽  
Brain Magnetic Resonance Imaging ◽  
Lesion Volume ◽  
Stroke Patients ◽  
Early Reperfusion ◽  
Echoplanar Imaging ◽  
Swelling Volume

Introduction: Revascularization is a robust therapy for acute ischemic stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. In stroke patients, early reperfusion consistently reduces infarct volume and improves long-term functional outcome, but there is little clinical data available regarding reperfusion edema. We sought to elucidate the relationship between reperfusion and brain edema in a patient cohort of moderate to severe stroke. Methods: Seventy-one patients enrolled in the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) with serial brain magnetic resonance imaging and perfusion-weighted imaging (PWI) were analyzed. Reperfusion percentage was calculated based on the difference in PWI lesion volume at baseline and follow-up (day 3-5). Midline shift (MLS) was measured on the day 3-5 fluid attenuated inversion recovery (FLAIR) sequence. Swelling volume and infarct growth volume were assessed using region-of-interest analysis on the baseline and follow-up DWI scans based on our prior methods. Results: Greater percentage of reperfusion was associated with less MLS (Spearman ρ = -0.46; P <0.0001) and reduced swelling volume (Spearman ρ = -0.56; P <0.0001). In multivariate analysis, reperfusion was an independent predictor of less MLS ( P <0.006) and decreased swelling volume ( P <0.0054), after adjusting for age, baseline NIHSS, admission blood glucose, baseline DWI volume, and IV tPA treatment. Conclusions: Reperfusion is associated with reduced brain edema as measured by MLS and swelling volume. While our data do not exclude the possibility of reperfusion edema in certain circumstances, in stroke patients, reperfusion following acute stroke is predominantly linked to less brain swelling.

Penumbra Consumption Rates Based on Time-to-Maximum Delay and Reperfusion Status: A Post Hoc Analysis of the DEFUSE 3 Trial

Stroke ◽  
2021 ◽  
Author(s):  
Shadi Yaghi ◽  
Eytan Raz ◽  
Seena Dehkharghani ◽  
Howard Riina ◽  
Ryan McTaggart ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Interquartile Range ◽  
Large Vessel ◽  
Large Vessel Occlusion ◽  
Vessel Occlusion ◽  
Endovascular Thrombectomy ◽  
Post Hoc Analysis ◽  
Consumption Rates ◽  
Post Hoc

Background and Purpose: In patients with acute large vessel occlusion, the natural history of penumbral tissue based on perfusion time-to-maximum (T max ) delay is not well established in relation to late-window endovascular thrombectomy. In this study, we sought to evaluate penumbra consumption rates for T max delays in patients with large vessel occlusion evaluated between 6 and 16 hours from last known normal. Methods: This is a post hoc analysis of the DEFUSE 3 trial (The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke), which included patients with an acute ischemic stroke due to anterior circulation occlusion within 6 to 16 hours of last known normal. The primary outcome is percentage penumbra consumption, defined as (24-hour magnetic resonance imaging infarct volume–baseline core infarct volume)/(T max 6 or 10 s volume–baseline core volume). We stratified the cohort into 4 categories based on treatment modality and Thrombolysis in Cerebral Infarction (TICI score; untreated, TICI 0-2a, TICI 2b, and TICI3) and calculated penumbral consumption rates in each category. Results: We included 141 patients, among whom 68 were untreated. In the untreated versus TICI 3 patients, a median (interquartile range) of 53.7% (21.2%–87.7%) versus 5.3% (1.1%–14.6%) of penumbral tissue was consumed based on T max >6 s ( P <0.001). In the same comparison for T max >10 s, we saw a difference of 165.4% (interquartile range, 56.1%–479.8%) versus 25.7% (interquartile range, 3.2%–72.1%; P <0.001). Significant differences were not demonstrated between untreated and TICI 0-2a patients for penumbral consumption based on T max >6 s ( P =0.52) or T max >10 s ( P =0.92). Conclusions: Among extended window endovascular thrombectomy patients, T max >10-s mismatch volume may comprise large volumes of salvageable tissue, whereas nearly half the T max >6-s mismatch volume may remain viable in untreated patients at 24 hours.

Abstract P538: A Detailed Analysis of Intracranial Hemorrhage After Endovascular Treatment in Acute Ischemic Stroke Due to Large Vessel Occlusion in the Escape-NA1 Trial

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Johanna Ospel ◽  
Michael D Hill ◽  
Nima Kashani ◽  
Arnuv Mayank ◽  
Nishita Singh ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Intracranial Hemorrhage ◽  
Intraventricular Hemorrhage ◽  
Infarct Volume ◽  
Prognostic Impact ◽  
Vessel Occlusion ◽  
Good Outcome

Purpose: We investigated the prevalence and prognostic impact on outcome of any intracranial hemorrhage, hemorrhage morphology, type and volume in acute ischemic stroke patients undergoing mechanical thrombectomy. Methods: Prevalence of intracranial hemorrhage, hemorrhage type, morphology and volume was determined on 24h follow-up imaging (non contrast head CT or gradient-echo/susceptibility-weighted MRI). Proportions of good outcome (mRS 0-2 at 90 days) were reported for patients with vs. without any intracranial hemorrhage. Multivariable logistic regression with adjustment for key minimization variables and total infarct volume was performed to obtain adjusted effect size estimates for hemorrhage type and volume on good outcome. Results: Hemorrhage on follow up-imaging was seen in 372/1097 (33.9%) patients, among them 126 (33.9%) with hemorrhagic infarction (HI) type 1, 108 (29.0%) with HI-2, 72 /19.4%) with parenchymal hematoma (PH) type 1, 37 (10.0) with PH2, 8 (2.2%) with remote PH and 21 (5.7%) with extra-parenchymal/intraventricular hemorrhage. Good outcomes were less often achieved by patients with hemorrhage on follow-up imaging (164/369 [44.4%] vs. 500/720 [69.4%]). Any type of intracranial hemorrhage was strongly associated with decreased chances of good outcome ( adj OR 0.62 [CI 95 0.44 - 0.87]). The effect of hemorrhage was driven by both PH hemorrhage sub-type [PH-1 ( adj OR 0.39 [CI 95 0.21 - 0.72]), PH-2 ( adj OR 0.15 [CI 95 0.05 - 0.50])] and extra-parenchymal/intraventricular hemorrhage ( adj OR 0.60 (0.20-1.78) Petechial hemorrhages (HI-1 and HI-2) were not associated with poorer outcomes. Hemorrhage volume ( adj OR 0.97 [CI 95 0.05 - 0.99] per ml increase) was significantly associated with decreased chances of good outcome. Conclusion: Presence of any hemorrhage on follow-up imaging was seen in one third of patients and strongly associated with decreased chances of good outcome.

Abstract P777: Statistical Modeling of Proteomic Signaling During Stroke in Patients Undergoing Thrombectomy

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sydney Claypoole ◽  
Jacqueline Frank ◽  
Madison Sands ◽  
Christopher J McLouth ◽  
Jill Roberts ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Statistical Modeling ◽  
Internal Control ◽  
Stepwise Regression ◽  
Infarct Volume ◽  
Tissue Samples ◽  
Bivariate Regression ◽  
Inflammatory Proteins ◽  
The Relationship ◽  
Proximity Extension Assay

Introduction: The previously published Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683) utilizes mechanical thrombectomy to obtain tissue samples for banking. Peripheral blood proximal to the clot and intracranial blood distal from the clot were isolated. Proteomic and statistical analyses revealed normalized (intracranial-systemic) CCL19 expression was a predictor of infarct volume. Statistical modeling analyses were used determine the CCL19-associated proteomic signaling network occurring during ischemic stroke relating to infarct volume. Methods: Arterial intracranial and systemic blood samples underwent analysis for inflammatory proteins using Proximity Extension Assay (PEA) via Olink (Olink Proteomics, Boston, MA). Systemic expression was used as an internal control to normalize expression in the intracranial blood. Bivariate regression was used to examine the relationship between the intracranial normalized CCL19 expression and infarct volume. A backwards stepwise regression was then used to determine a model of predictability of infarct volume by CCL19 and associated inflammatory proteins. Results: 25 subjects (>18 yrs) with a mean infarct volume of 8,172 ± 82,284 mm 3 and mean infarct time of 513 ± 246 minutes were included in this study. Their median age was 64 (24-91) and 10 (40%) were male. 16 subjects (64%) had hypertension, 15 (60%) had BMI > 25, and 6 (24%) had a previous stroke. The stepwise regression model shows normalized expression of 16 proteins correlated with an increase in infarct volume (p<0.005): CCL20, CXCL1, OSM, CD6, OSMR, TGF-alpha, TRANCE, CXCL10, LIF-R, CCL19, CDCP1, Flt3L, CCL23, CD244, TRAIL, NOTCH1. Conclusions: In our model, the expression of these proteins were consistently changed, though the directionality differed. LIF-R, NOTCH1, TRAIL, CD6, CCL23, TGF-alpha, and CCL20 were positively correlated, while the expressions of Flt3L, OSM, OSMR, TRANCE, CD244, CDCP1, CXCL1, CXCL10, and CCL19 were negatively correlated with infarct volume. This model depicts the proteomic signaling occurring during stroke in relationship to infarct volume, which reveals potential biomarkers and therapeutic targets for the early phase of ischemic stroke.

Abstract TP417: An Autoregulation-Derived Prediction Model for Midline Shift After Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Andrew Silverman ◽  
Anson Wang ◽  
Sreeja Kodali ◽  
Sumita Strander ◽  
Alexandra Kimmel ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Predictive Model ◽  
Infarct Volume ◽  
Classification Tree ◽  
Brain Mri ◽  
Projection Pursuit ◽  
Midline Shift ◽  
Vessel Occlusion ◽  
Patient Disposition ◽  
Hemodynamic Variables

Introduction: Identification of patients likely to develop midline shift (MLS) after large-vessel occlusion (LVO) stroke is essential for appropriate triage and patient disposition. Studies have identified clinical and radiographic predictors of MLS, but with limited accuracy. Using an innovative assessment of cerebral autoregulation, we sought to develop an accurate predictive model for MLS. Methods: We prospectively enrolled 73 patients with LVO stroke. Beat-by-beat cerebral blood flow (transcranial Doppler) and arterial pressure (arterial catheter or finger photoplethysmography) were recorded within 24 hours of the stroke, and a 24-hour brain MRI was obtained to determine infarct volume and MLS. Autoregulatory function was quantified from pressure-flow relation via projection pursuit regression (PPR), allowing for characterization of 5 hemodynamic markers (Figure 1A). We assessed the predictive relation of autoregulatory capacity and radiological and clinical variables to MLS using recursive classification tree models. Results: PPR successfully quantified autoregulatory function in 50/73 (68.5%) patients within 24 hours of LVO ischemic stroke (age 63.9±13.6, 66% F, NIHSS 15.8±6.7). Of these 50 patients, most (78%) underwent endovascular therapy. Thirteen (26%) experienced 24-h MLS; in these patients, infarct volumes were larger (140.2 vs. 48.6 mL, P<0.001 ), and ipsilateral (but not contralateral) falling slopes were steeper (1.1 vs. 0.7 cm·s -1 ·mmHg -1 , P=0.001 ). Among all clinical, demographic, and hemodynamic variables, only two (infarct volume, ipsilateral falling slope) significantly contributed to prediction of MLS (accuracy 94%; Figure 1B). Conclusions: This predictive model of MLS wields translatable potential for triaging level of care in patients suffering from LVO ischemic stroke, but further research, including optimization of the PPR algorithm as well as prospective use of the predictive model, is needed.

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