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

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.

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Abstract WP40: “Good” Angiographic Collateral Circulation Correlates With Lower Dwi Infarct Volumes In Acute Ischemic Stroke

Stroke ◽

10.1161/str.44.suppl_1.awp40 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Esteban Cheng-Ching ◽

Dolora Wisco ◽

Shumei Man ◽

Ferdinand Hui ◽

Gabor Toth ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Symptom Onset ◽

Collateral Circulation ◽

Infarct Volume ◽

Artery Occlusion ◽

Grading System ◽

Large Artery ◽

Anterior Circulation ◽

Vessel Occlusion

Background and purpose Large artery occlusion leads to ischemic stroke which volume is influenced by time from symptom onset. This effect is modulated by several factors, including the presence and degree of collateral circulation. We analyze the correlation between a standard angiographic collateral grading system and DWI infarct volumes. Methods We reviewed a prospectively collected retrospective database of ischemic stroke patients admitted between august of 2006 and december of 2011. We included patients with anterior circulation acute ischemic stroke presenting within 8 hours from symptom onset with large vessel occlusion, who underwent pre-treatment MRI and endovascular therapy. DWI infarct volumes were measured by region of interest. ASITN collateral grading system was used and grouped into “good collaterals” for grades 3 and 4, and “poor collaterals” for grades 0, 1 and 2. JMP statistical software was utilized. Results 152 patients (71 (46.7%) male, mean age: 68±15 years;) were included in the initial analysis. We identified 49 patients who had angiographic collateral circulation grading. Seven patients had ASITN collateral grade 0 with mean infarct volume of 27.6 cc, 25 had collateral grade of 1 with mean infarct volume of 27.9 cc, 10 had collateral grade of 2 with mean infarct volume of 23.4 cc, 5 had collateral grade of 3 with mean infarct volume of 6.3 cc, and 2 had collateral grade of 4 with mean infarct volume of 14.6 cc. Forty two patients had “poor collaterals” with a mean infarct volume of 26.8 cc. Seven patients had “good collaterals” with mean infarct volume of 8.7 cc. When comparing the infarct volumes between these two groups, the difference was statistically significant (p=0.017). Conclusions In anterior circulation acute ischemic stroke, “good” angiographic collateral circulation defined as ASITN grading system of 3 or 4, correlates with lower infarct volumes on presentation.

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Endovascular Acute Ischemic Stroke Treatment with FlowGate Balloon Guide Catheter: A Single-Center Observational Study of FlowGate Balloon Guide Catheter Use

Interventional Neurology ◽

10.1159/000488601 ◽

2018 ◽

Vol 7 (6) ◽

pp. 327-333 ◽

Cited By ~ 3

Author(s):

Mohamed S. Teleb

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Mechanical Thrombectomy ◽

Standard Of Care ◽

Vessel Occlusion ◽

Stroke Treatment ◽

Guide Catheter ◽

Stent Retrievers ◽

Number Of Passes ◽

Single Center Observational Study

Background: Treatment of large vessel occlusion acute ischemic stroke with mechanical thrombectomy has become the standard of care after recent clinical trials. However, the degree of recanalization with stent retrievers remains very important in overall outcomes. We sought to review the utility of a new balloon guide catheter (BGC) in improving the degree of recanalization in conjunction with mechanical thrombectomy. Methods: The medical records of a prospectively collected endovascular ischemic stroke database were reviewed. All consecutive strokes when a FlowGate BGC was used with a thrombectomy stent retriever were identified. Use of a FlowGate BGC, number of passes, final Thrombolysis in Cerebral Infarction (TICI) score, trackability, and use of adjunct devices were all collected and analyzed. Results: Use of a FlowGate BGC resulted in 64% (33/52) first-pass effect (FPE) of TICI 2b/3, and specifically 46% (24/52) TICI 3 FPE (true FPE). A total of 52/62 (84%) of thrombectomy cases were treated with BGCs. In the remaining 10, the BGC was not inflated or used due to the clot not being visualized or the lesions being distal and BGC use thus not deemed appropriate. Adjunct use of an aspiration catheter was seen in 12% (6/52) of cases. The overall success with FlowGate BGCs with one or more passes of TICI 2b/3 was 94% (49/52). Trackability was achieved in 92% (57/62) of cases. Conclusions: Use of the FlowGate BGC as an adjunct to mechanical thrombectomy was associated with good FPE and an overall recanalization of TICI 2b/3 of 94%.

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Enhancing performance of a computed tomography perfusion software for improved prediction of final infarct volume in acute ischemic stroke patients

The Neuroradiology Journal ◽

10.1177/1971400920988668 ◽

2021 ◽

pp. 197140092098866

Author(s):

Ryan A Rava ◽

Kenneth V Snyder ◽

Maxim Mokin ◽

Muhammad Waqas ◽

Alexander R Podgorsak ◽

...

Keyword(s):

Computed Tomography ◽

Ischemic Stroke ◽

Conservative Treatment ◽

Acute Ischemic Stroke ◽

Mechanical Thrombectomy ◽

Infarct Volume ◽

Correlation Coefficients ◽

Intravenous Thrombolysis ◽

Vessel Occlusion ◽

Computed Tomography Perfusion

Computed tomography perfusion (CTP) is crucial for acute ischemic stroke (AIS) patient diagnosis. To improve infarct prediction, enhanced image processing and automated parameter selection have been implemented in Vital Images’ new CTP+ software. We compared CTP+ with its previous version, commercially available software (RAPID and Sphere), and follow-up diffusion-weighted imaging (DWI). Data from 191 AIS patients between March 2019 and January 2020 was retrospectively collected and allocated into endovascular intervention ( n = 81) and conservative treatment ( n = 110) cohorts. Intervention patients were treated for large vessel occlusion, underwent mechanical thrombectomy, and achieved successful reperfusion of thrombolysis in cerebral infarction 2b/2c/3. Conservative treatment patients suffered large or small vessel occlusion and did not receive intravenous thrombolysis or mechanical thrombectomy. Infarct and penumbra were assessed using intervention and conservative treatment patients, respectively. Infarct and penumbra volumes were segmented from CTP+ and compared with 24-h DWI along with RAPID, Sphere, and Vitrea. Mean infarct differences (95% confidence intervals) and Spearman correlation coefficients (SCCs) between DWI and each CTP software product for intervention patients are: CTP+ = (5.8 ± 5.9 ml, 0.62), RAPID = (10.0 ± 5.2 ml, 0.73), Sphere = (3.0 ± 6.0 ml, 0.56), Vitrea = (7.2 ± 4.9 ml, 0.66). For conservative treatment patients, mean infarct differences and SCCs are: CTP+ = (–8.0 ± 5.4 ml, 0.64), RAPID = (–25.6 ± 11.5 ml, 0.60), Sphere = (–25.6 ± 8.0 ml, 0.66), Vitrea = (1.3 ± 4.0 ml, 0.72). CTP+ performed similarly to RAPID and Sphere in addition to its semi-automated predecessor, Vitrea, when assessing intervention patient infarct volumes. For conservative treatment patients, CTP+ outperformed RAPID and Sphere in assessing penumbra. Semi-automated Vitrea remains the most accurate in assessing penumbra, but CTP+ provides an improved workflow from its predecessor.

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Implications of the use of mechanical thrombectomy on outcome in large vessel occlusion following the 2015 landmark trials

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2020-015903 ◽

2020 ◽

Vol 13 (1) ◽

pp. 4-7

Author(s):

Okkes Kuybu ◽

Vijayakumar Javalkar ◽

Abdallah Amireh ◽

Arshpreet Kaur ◽

Roger E Kelley ◽

...

Keyword(s):

Ischemic Stroke ◽

Hospital Mortality ◽

Acute Ischemic Stroke ◽

Mechanical Thrombectomy ◽

Intravenous Thrombolysis ◽

Binary Logistic Regression ◽

Standard Of Care ◽

Vessel Occlusion ◽

Stroke Treatment ◽

Before And After

BackgroundThe effectiveness of mechanical thrombectomy (MT) was demonstrated in five landmark trials published in2015.Mechanical thrombectomy is now standard of care for acute ischemic stroke and has been growing in popularity after publication of landmark trials.ObjectiveTo analyze outcomes and trends of the use of MT and intravenous thrombolysis (IVT) in patients with acute ischemic stroke in US hospitals before and after publication of these trials.MethodsPatients discharged with a diagnosis of ischemic stroke between 2012 to 2017 were diagnosed using ICD codes from the National Inpatient Sample. Thereafter, patients given acute stroke treatment were identified using the corresponding procedure codes for IVT and MT. The primary clinical outcomes of in-hospital mortality and disability were then compared between two time periods: 2012–2014 (pre-landmark trials) and 2015–2017 (post-landmark trials). Binary logistic regression and Χ2 tests were used for statistical analysis.ResultsA total of 57 675 patients (median age 68.9 years (range 18-90), 50.1% female) were identified with acute procedures. Of these patients, 57.6% were from the post-landmark trials time period. Despite an increased number of cases, the rate of IVT decreased from 84.3% to 75.9% and the rate of IVT+MT decreased from 7.1% to 6.3%. After publication of the pivotal trials in 2015, the rates of MT increased from 8.7% to 17.8%. Significant reductions of in-hospital mortality (7.1% vs 8.7%, p<0.001) and disability (64% vs 66.2%, p<0.001) were noted.ConclusionThe analysis showed a significant increase in the proportion of patients receiving MT after 2015. This has translated into reduction of in-hospital mortality and improvement in disability.

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Abstract P487: Cerebral Endothelial Cell-Derived Small Extracellular Vesicles Enhance Neurovascular Function and Neurological Recovery in Rat Ischemic Stroke

Stroke ◽

10.1161/str.52.suppl_1.p487 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Chao Li ◽

Chunyang Wang ◽

Yi Zhang ◽

Owais K Alsrouji ◽

Alex B Chebl ◽

...

Keyword(s):

Ischemic Stroke ◽

Therapeutic Effect ◽

Extracellular Vesicles ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Vessel Occlusion ◽

Western Blots ◽

Neurological Outcomes ◽

Transmission Electron

Background: Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) often leads to incomplete reperfusion. There is a compelling need to develop therapies to enhance the perfusion and to improve neurological outcomes. Methods: Using rat models of embolic middle cerebral artery occlusion (eMCAO) and transient MCAO (tMCAO), we investigated the effect of small extracellular vesicles (sEVs) derived from healthy rat cerebral endothelial cells (CECs) administered intravenously in combination with tPA (CECs/tPA) and as an acute intraarterial adjunct therapy with mechanical reperfusion on stroke outcomes. Recanalization, cerebral blood flow (CBF), and blood-brain barrier (BBB) permeability were analyzed. MicroRNAs (miRs) and proteins were analyzed in CECs harvested from ischemic rats by RT-PCR and Western blots. Transmission electron microscopy was employed to analyze the brain distribution of CEC-sEVs. The effect of sEVs derived from clots acquired from patients undergone thrombectomy was tested on human CEC permeability. Results: CEC-sEVs/tPA given 4h after eMCAO or CEC-sEVs given upon reperfusion after 2h tMCAO significantly reduced infarct volume by ~36% and ~43%, respectively, and robustly improved neurological outcomes compared with tPA or ischemia/reperfusion alone (n=10 rats/group). CEC-sEVs/tPA and upon reperfusion after eMCAO or tMCAO, resepectively, significantly increased recanalization of the occluded MCA, enhanced CBF and reduced BBB leakage. CEC-sEVs/tPA substantially reduced a network of microRNAs and proteins that mediate thrombosis, coagulation and inflammation in CECs. Moreover, CEC-sEVs intravenously administered crossed the BBB and were internalized by CECs cells, astrocytes, and neurons. Stroke patient-clot derived exosomes impaired human CEC permeability and upregulated pro-inflammatory and -coagulatant proteins, which were blocked by CEC-sEVs. Conclusion: CEC-sEVs have a therapeutic effect on acute ischemic stroke in rats by reducing neurovascular damage. Suppressing the network of pro-thrombotic, -coagulant and -inflammatory microRNAs and proteins in CECs by CEC-sEVs likely contributes to the therapeutic effect of CEC-sEVs.

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Mechanical Thrombectomy of COVID-19 positive acute ischemic stroke patient: a case report and call for preparedness

BMC Neurology ◽

10.1186/s12883-020-01930-x ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ossama Yassin Mansour ◽

Amer M. Malik ◽

Italo Linfante

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Health Care Providers ◽

Mechanical Thrombectomy ◽

Artery Occlusion ◽

Sudden Onset ◽

Care Providers ◽

Vessel Occlusion ◽

Nihss Score ◽

Acute Ischemic Stroke Patient

Abstract Background The novel coronavirus (COVID-19) global pandemic is associated with an increased incidence of acute ischemic stroke (AIS) secondary to large vessel occlusion (LVO). The treatment of these patients poses unique and significant challenges to health care providers requiring changes in existing protocols. Case presentation A 54-year-old COVID-19 positive patient developed sudden onset left hemiparesis secondary to an acute right middle cerebral artery occlusion (National Institutes of Health Stroke Scale (NIHSS) score = 11). Mechanical thrombectomy (MT) was performed under a new protocol specifically designed to maximize protective measures for the team involved in the care of the patient. Mechanical Thrombectomy was performed successfully under general anesthesia resulting in TICI 3 recanalization. With regards to time metrics, time from door to reperfusion was 60 mins. The 24-h NIHSS score decreased to 2. Patient was discharged after 19 days after improvement of her pulmonary status with modified Rankin Scale = 1. Conclusion Patients infected by COVID-19 can develop LVO that is multifactorial in etiology. Mechanical thrombectomy in a COVID-19 confirmed patient presenting with AIS due to LVO is feasible with current mechanical thrombectomy devices. A change in stroke workflow and protocols is now necessary in order to deliver the appropriate life-saving therapy for COVID-19 positive patients while protecting medical providers.

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Revascularization and functional outcomes after mechanical thrombectomy for acute ischemic stroke in elderly patients

Journal of Neurosurgery ◽

10.3171/2018.12.jns182399 ◽

2020 ◽

Vol 132 (4) ◽

pp. 1182-1187 ◽

Cited By ~ 1

Author(s):

Carrie E. Andrews ◽

Nikolaos Mouchtouris ◽

Evan M. Fitchett ◽

Fadi Al Saiegh ◽

Michael J. Lang ◽

...

Keyword(s):

Ischemic Stroke ◽

Elderly Patients ◽

Acute Ischemic Stroke ◽

Mechanical Thrombectomy ◽

Multivariate Logistic Regression Analysis ◽

Standard Of Care ◽

Stroke Severity ◽

Vessel Occlusion ◽

Younger Patients ◽

Success Of Treatment

OBJECTIVEMechanical thrombectomy (MT) is now the standard of care for acute ischemic stroke (AIS) secondary to large-vessel occlusion, but there remains a question of whether elderly patients benefit from this procedure to the same degree as the younger populations enrolled in the seminal trials on MT. The authors compared outcomes after MT of patients 80–89 and ≥ 90 years old with AIS to those of younger patients.METHODSThe authors retrospectively analyzed records of patients undergoing MT at their institution to examine stroke severity, comorbid conditions, medical management, recanalization results, and clinical outcomes. Univariate and multivariate logistic regression analysis were used to compare patients < 80 years, 80–89 years, and ≥ 90 years old.RESULTSAll groups had similar rates of comorbid disease and tissue plasminogen activator (tPA) administration, and stroke severity did not differ significantly between groups. Elderly patients had equivalent recanalization outcomes, with similar rates of readmission, 30-day mortality, and hospital-associated complications. These patients were more likely to have poor clinical outcome on discharge, as defined by a modified Rankin Scale (mRS) score of 3–6, but this difference was not significant when controlled for stroke severity, tPA administration, and recanalization results.CONCLUSIONSOctogenarians, nonagenarians, and centenarians with AIS have similar rates of mortality, hospital readmission, and hospital-associated complications as younger patients after MT. Elderly patients also have the capacity to achieve good functional outcome after MT, but this potential is moderated by stroke severity and success of treatment.

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Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽

10.3390/cells10040767 ◽

2021 ◽

Vol 10 (4) ◽

pp. 767

Author(s):

Courtney Davis ◽

Sean I. Savitz ◽

Nikunj Satani

Keyword(s):

Ischemic Stroke ◽

Extracellular Vesicles ◽

Neurovascular Unit ◽

Culture Conditions ◽

Therapeutic Effects ◽

Stroke Treatment ◽

Inflammatory Molecules ◽

The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

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