Stroke Reperfusion Research Articles

Prolonged venous transit is associated with lower odds of excellent recovery after reperfusion in anterior large-vessel occlusion stroke.

Acute ischemic stroke due to anterior circulation large-vessel occlusion (AIS-LVO) remains a leading cause of disability despite successful reperfusion therapies. Prolonged venous transit (PVT) has emerged as a potential prognostic imaging biomarker in AIS-LVO. We aimed to investigate whether PVT is associated with a decreased likelihood of excellent functional outcome (modified Rankin Scale [mRS] score of 0-1 at 90 days) after successful reperfusion. In our prospectively collected, retrospectively reviewed database, we analyzed data from 104 patients with AIS-LVO who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b/2c/3) between September 2017 and September 2022. PVT was defined as a time to maximum (Tmax) of ≥10 s in the superior sagittal sinus and/or torcula on computed tomography perfusion (CTP) imaging. Patients were categorized into PVT-positive (PVT+) and PVT-negative (PVT-) groups. The primary outcome was excellent functional recovery at 90 days. Of the 104 patients, 30 (29%) were PVT+. Excellent functional outcome was achieved in 38 patients (37%). PVT+ patients had a significantly lower rate of excellent recovery compared to PVT- patients (11% vs. 39%; p < 0.001). After adjusting for possible confounders, PVT positivity was independently associated with lower odds of excellent recovery (adjusted odds ratio 0.11, 95% confidence interval 0.02 to 0.48; p = 0.006). Among patients with AIS-LVO who achieved successful reperfusion, PVT positivity was independently associated with a decreased likelihood of excellent functional outcome at 90 days. Assessment of PVT on CTP may provide valuable prognostic information and aid in clinical decision making for patients with AIS-LVO.

Outcomes of stenting after failed basilar artery thrombectomy for acute stroke: a nationwide registry-based cohort study.

Mechanical thrombectomy is the most effective treatment for restoring reperfusion in large vessel occlusion acute ischaemic stroke, even in patients with posterior circulation. However, the strategy for optimal treatment of patients with acute basilar artery occlusion (BAO) in difficult-to-treat cases in which thrombectomy has failed is unknown. The purpose of this study was to evaluate the clinical efficacy and safety of rescue intracranial stenting (RIS) in patients with acute BAO treated with thrombectomy. Stroke patients with acute BAO who had undergone failed mechanical thrombectomy in the ATTENTION registry were enrolled in this study. Univariable and multivariable regression analyses were performed to assess the clinical efficacy and safety of RIS. A total of 477 patients were included in the analysis, and 346 patients underwent RIS, of whom 167 (35.0%) patients had a favourable outcome. Symptomatic intracranial haemorrhage (sICH) occurred in 24 (5.0%) patients, and 172 (36.1%) patients died. There were no significant differences between the two groups of patients in the outcomes of modified Rankin Scale (mRS) 0-1 (p=0.541), mRS 0-2 (p=0.374), mRS 0-3 (p=0.600), or death (p=0.706). Patients in the RIS+ group had a significantly higher incidence of sICH (1.5% vs 6.4%; p=0.031). Nevertheless, after adjusting for confounders, RIS was not found to be an independent risk factor for sICH (adjusted odds ratio 4.189, 95% confidence interval: 0.960-18.286; p=0.057). In this national, multicentre, prospective study, RIS in patients with acute BAO who had undergone failed first-line thrombectomy was feasible, but we could not show significance regarding improved long-term outcomes. ChiCTR2000041117.

Current gaps in acute reperfusion therapies.

Advances in intravenous thrombolysis and endovascular thrombectomy have significantly reduced disability and improved outcomes associated with acute ischemic stroke. An expansion of indications for reperfusion therapies in select groups of patients to permit treatment in an extended time window, with large ischemic core, and with simplified imaging protocols have enabled a broader group of patients access to disability-sparing therapy. Cerebroprotection has had renewed development in the era of acute reperfusion. In this review, we highlight recent developments in stroke reperfusion research and related questions that are under study or remain unanswered.

Enhancing Blood-Brain Barrier Integrity in Patients With Acute Ischemic Stroke Via Normobaric Hyperoxia.

Recent advancements in animal studies have demonstrated the potential of normobaric hyperoxia (NBO) as a promising intervention for preserving the integrity of the blood-brain barrier (BBB). However, there is still limited understanding of the effects of NBO on BBB function in patients with clinical stroke. Therefore, the objective of this study was to investigate the efficacy of NBO therapy in attenuating BBB damage and reducing brain injury in individuals undergoing endovascular treatment (EVT) for acute stroke. This study enrolled patients from the OPENS-1 (Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke) study, with 43 patients receiving NBO combined with EVT and 43 patients receiving EVT alone. The main outcome measures included serum levels of occludin, MMP-9 (matrix metalloproteinase-9), NSE (neuron-specific enolase), and S100b at 24 hours and 7 days, as well as the intracranial extravasation rate at 24 hours. Serum markers were assessed using ELISA, and intracranial contrast extravasation was visualized using dual-energy computed tomography scan. We analyzed a total of 86 patients and found that the 24-hour serum markers levels of BBB damage and brain injury were significantly lower in the group receiving NBO therapy combined with EVT compared with the group receiving EVT alone. Similarly, at 7 days, the levels of occludin, MMP-9, and NSE were lower in the NBO+EVT group. We also found that the 24-hour serum levels of occludin and MMP-9 were correlated with intracranial contrast extravasation. Additionally, the incidence of intracranial contrast extravasation was lower in the NBO+EVT group compared with the EVT group (35.9% versus 60.5%, P=0.031). This study offers valuable insights into the positive impact of NBO on maintaining BBB integrity and reducing brain injury in patients with acute stroke undergoing EVT.

Helicopter Emergency Medical Services (HEMS) Transportation Utilization for Acute Ischemic Strokes at a Community-Based Hospital in South Florida

Background: A comprehensive stroke center (CSC) servicing remote areas in South Florida became HEMS direct-from-field capable on October 15, 2020. This analysis reviews the utilization of this service and compares it to ground EMS (GEMS). Methods: This is a retrospective cohort study from October 15, 2020, to July 31, 2021, that collected HEMS adult stroke alert data and compared it to the prior year's summary GEMS stroke alert data. Using HEMS transportation logs, presenting stroke symptoms and prehospital assessment were abstracted, in addition to initial NIHSS, downgrade rate, stroke diagnosis percentage, treatment rate, and times. Results: The analysis included a total of 52 direct transport HEMS stroke alerts. Assessment tools utilized by HEMS included the Cincinnati stroke scale (4%) and the FAST-ED (37%); most cases (59%) did not document a stroke assessment tool. The median NIHSS was 10, with 37% presenting a score &lt;6. Cases were downgraded upon arrival in 27% and after CT imaging in 15% of cases. Significantly (p&lt;.001), more HEMS cases were diagnosed as stroke (69%) compared to GEMS (57%). Stroke treatment rates remained similar (HEMS=23%; GEMS=24%). Median door-to-needle times were significantly faster for HEMS (15 min) than GEMS (25 min) (p&lt;.05). Median door-to-puncture times were clinically faster for HEMS (61mins) than GEMS (66 mins). Conclusion: Prehospital triage could be improved to better detect the 77% of patients who are not eligible for acute stroke reperfusion treatments and may benefit from ground as opposed to air transportation. The current HEMS triage, although not consistently documented, appropriately selects stroke victims, but not necessarily those who need air transport to a higher care level. Patients arriving via HEMS receive similar access to stroke treatment and, if treated, significantly faster treatment times.

Blood-Brain Barrier-Penetrating Metal-Organic Framework Antioxidant Nanozymes for Targeted Ischemic Stroke Therapy.

Overproduction of reactive oxygen species (ROS) during reperfusion in ischemic stroke (IS) severely impedes neuronal survival and results in high rates of morbidity and disability. The effective blood-brain barrier (BBB) penetration and brain delivery of antioxidative agents remain the biggest challenge in treating ischemic reperfusion-induced cerebrovascular and neural injury. In this study, a metal-organic framework (MOF) nanozyme (MIL-101-NH2(Fe/Cu)) with ROS scavenging activities to encapsulate neuroprotective agent rapamycin is fabricated and decorating the exterior with BBB-targeting protein ligands (transferrin), thereby realizing enhanced drug retention and controlled release within ischemic lesions for the synergistic treatment of IS. Through the receptor-mediated transcellular pathway, the transferrin-coated MOF nanoparticles achieved efficient transport across the BBB and targeted accumulation at the cerebral ischemic injury site of mice with middle cerebral artery occlusion/reperfusion (MCAO/R), wherein the nanocarrier exhibited catalytic activities of ROS decomposition into O2 and H2O2-responsive rapamycin release. By its BBB-targeting, antioxidative, anti-inflammatory, and antiapoptotic properties, the MOF nanosystem addressed multiple pathological factors of IS and realized remarkable neuroprotective effects, leading to the substantial reduction of cerebral infarction volume and accelerated recovery of nerve functions in the MCAO/R mouse model. This MOF-based nanomedicine provides valuable design principles for effective IS therapy with multi-mechanism synergies.

Intra-arterial tenecteplase after successful endovascular therapy (ANGEL-TNK): protocol of a multicentre, open-label, blinded end-point, prospective, randomised trial

BackgroundDespite successful reperfusion after thrombectomy for large vessel occlusion (LVO) stroke, up to half of patients are dependent or dead at 3-month follow-up.The aim of the current study is to...

Workflow and Short-Term Functional Outcomes in Simultaneous Acute Code Stroke Activation and Stroke Reperfusion Therapy.

The burden of simultaneous acute code stroke activation (ACSA) is not known. We aim to assess the effect of simultaneous ACSA on workflow metrics and home time at 90 days in patients undergoing reperfusion therapies in the emergency department. Simultaneous ACSA was defined as code activation within 60 min of the arrival of any patient receiving intravenous thrombolysis, within 150 min of the arrival of any patient receiving endovascular thrombectomy, within 45 min of the arrival of any patient receiving no reperfusion therapies (based on mean local door-to-needle and door-to-puncture times). Simultaneous ACSA was further graded as 1, 2 and 3. We assessed workflow metrics as door-to-CT (DTC) time, in minutes, and functional outcome as home time at 90 days. A total of 2605 patients were assessed as ACSA at a mean ± SD activations of 130.8 ± 17.1/month and 859 (33%) were simultaneous. Among all ACSA, 545 (20.9%) underwent acute reperfusion therapy with a mean age of 70.6 ± 14.2 years, 45.9% (n = 254) were female with a median (IQR) NIHSS of 13 (8-18). A total of 220 (40.4%) patients underwent simultaneous treatments. The median DTC time, in minutes, was prolonged in grade 3 simultaneous ACSA (18 (13, 28)) compared to non-simultaneous ACSA (15 (11, 21) β = 0.23, p < 0.0001). There was no difference in the median home time at 90 days between the simultaneous (58, 0-84.5 days) and non-simultaneous (54, 0-85 days) patients. Simultaneous ACSA is frequent in patients receiving acute reperfusion therapies. An optimal workflow in high-volume centers may help mitigate the clinical and system burden associated with simultaneity.

Emerging Adjuvant Thrombolytic Therapies for Acute Ischemic Stroke Reperfusion.

Thrombolytic therapies for acute ischemic stroke are widely available but only result in recanalization early enough, to be therapeutically useful, in 10% to 30% of cases. This large gap in treatment effectiveness could be filled by novel therapies that can increase the effectiveness of thrombus clearance without significantly increasing the risk of harm. This focused update will describe the current state of emerging adjuvant treatments for acute ischemic stroke reperfusion. We focus on new treatments that are designed to (1) target different components that make up a stroke thrombus, (2) enhance endogenous fibrinolytic systems, (3) reduce stagnant blood flow, and (4) improve recanalization of distal thrombi and postendovascular thrombectomy.

Days Alive and Out of Hospital as an Outcome Measure in Patients Receiving Hyperacute Stroke Intervention.

Patient outcome after stroke is frequently assessed with clinical scales such as the modified Rankin Scale score (mRS). Days alive and out of hospital at 90 days (DAOH-90), which measures survival, time spent in hospital or rehabilitation settings, readmission and institutionalization, is an objective outcome measure that can be obtained from large administrative data sets without the need for patient contact. We aimed to assess the comparability of DAOH with mRS and its relationship with other prognostic variables after acute stroke reperfusion therapy. Consecutive patients with ischemic stroke treated with intravenous thrombolysis or endovascular thrombectomy were analyzed. DAOH-90 was calculated from a national minimum data set, a mandatory nationwide administrative database. mRS score at day 90 (mRS-90) was assessed with in-person or telephone interviews. The study included 1278 patients with ischemic stroke (714 male, median age 70 [59-79], median National Institutes of Health Stroke Scale score 14 [9-20]). Median DAOH-90 was 71 [29-84] and median mRS-90 score was 3 [2-5]. DAOH-90 was correlated with admission National Institutes of Health Stroke Scale score (Spearman rho -0.44, P<0.001) and Alberta Stroke Program Early CT [Computed Tomography] Score (Spearman rho 0.24, P<0.001). There was a strong association between mRS-90 and DAOH-90 (Spearman rho correlation -0.79, P<0.001). Area under receiver operating curve for predicting mRS score >0 was 0.86 (95% CI, 0.84-0.88), mRS score >1 was 0.88 (95% CI, 0.86-0.90) and mRS score >2 was 0.90 (95% CI, 0.89-0.92). In patients with stroke treated with reperfusion therapies, DAOH-90 shows reasonable comparability to the more established outcome measure of mRS-90. DAOH-90 can be readily obtained from administrative databases and therefore has the potential to be used in large-scale clinical trials and comparative effectiveness studies.

External validation of clinical risk prediction score for elderly treated with endovascular thrombectomy

Background and aimThe thrombectomy in the elderly prediction score (TERPS) for functional outcome after anterior circulation endovascular therapy (EVT) in patients ≥ 80 years was recently developed. The aim of this study was to assess predictors of functional outcome in the elderly and validate the prediction model.MethodsConsecutive patients treated with EVT from the Oslo Acute Reperfusion Stroke Study were evaluated for inclusion. Clinical and radiological parameters were used to calculate the TERPS, and functional outcome were assessed at 3-month follow-up.ResultsOut of 1028 patients who underwent EVT for acute ischemic stroke from January 2017 to July 2022, 218 (21.2%) patients ≥ 80 years with anterior ischemic stroke were included. Fair outcome, defined as modified Rankin scale ≤ 3 (mRS), was achieved in 117 (53.7%). In bivariate analyses, male sex (p 0.035), age (p 0.025), baseline National Institute of Health Stroke Scale (NIHSS, p < 0.001), pre-stroke mRS (p 0.002) and Alberta Stroke Program Early Computed Tomography score (ASPECTS, p 0.001) were associated with fair outcome. Significant predictors for fair outcome in regression analyses were lower pre-stroke mRS, adjusted odd ratio, (aOR) 0.67 (95% CI 0.50–0.91, p 0.01), NIHSS, aOR 0.92 (95% CI 0.87–0.97, p 0.002), and higher ASPECTS, aOR 1.22 (95% CI 1.03–1.44, p 0.023). The area under the curve (AUC) using TERPS was 0.74 (95% CI 0.67–0.80).ConclusionsThe risk prediction score TERPS showed moderate performance in this external validation. Other variables may still be included to improve the model and validation using other cohorts is recommended.Trial registrationNCT06220981.

Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial.

Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

Assessment of associations between neutrophil extracellular trap biomarkers in blood and thrombi in acute ischemic stroke patients

Inflammation including immunothrombosis by neutrophil extracellular traps (NETs) has important implications in acute ischemic stroke and can affect reperfusion status, susceptibility to stroke associated infections (SAI) as well as functional clinical outcome. NETs were shown to be prevalent in stroke thrombi and NET associated markers were found in stroke patients’ blood. However, little is known whether blood derived NET markers reflect the amount of NETs in thrombi. Conclusions from blood derived markers to thrombus composition might open avenues for novel strategies in diagnostic and therapeutic approaches. We prospectively recruited 166 patients with acute ischemic stroke undergoing mechanical thrombectomy between March 2018 and May 2021. Available thrombi (n = 106) were stained for NET markers DNA-histone-1 complexes and myeloperoxidase (MPO). Cell free DNA (cfDNA), deoxyribonuclease (DNase) activity, MPO-histone complexes and a cytokine-panel were measured before thrombectomy and after seven days. Clinical data, including stroke etiology, reperfusion status, SAI and functional outcome after rehabilitation, were collected of all patients. NET markers were present in all thrombi. At onset the median concentration of cfDNA in blood was 0.19 µg/ml increasing to 0.30 µg/ml at 7 days. Median DNase activity at onset was 4.33 pmol/min/ml increasing to 4.96 pmol/min/ml at 7 days. Within thrombi DNA-histone-1 complexes and MPO correlated with each other (ρ = 0.792; p < 0.001). Moreover, our study provides evidence for an association between the amount of NETs and endogenous DNase activity in blood with amounts of NETs in cerebral thrombi. However, these associations need to be confirmed in larger cohorts, to investigate the potential clinical implications for individualized therapeutic and diagnostic approaches in acute ischemic stroke.Graphical

B.1 CT Or MRI protocol for acute stroke reperfusion with EVT (COMPARE): an international retrospective cohort study

Background: Patients with an acute ischemic stroke (AIS) are selected to receive reperfusion therapy using either computed tomography (CT-CTA) or magnetic brain imaging (MRI). The aim of this study was to compare CT and MRI as the primary imaging modality for AIS patients undergoing EVT. Methods: Data for AIS patients between January 2018 and January 2021 were extracted from two prospective multicenter EVT cohorts: the ETIS registry in France (MRI) and the OPTIMISE registry in Canada (CT). Demographics, procedural data and outcomes were collected. We assessed the association of qualifying imaging (CT vs. MRI) with time metrics and functional outcome. Results: From January 2018 to January 2021, 4059 patients selected by MRI and 1324 patients selected by CT were included in the study. Demographics were similar between the two groups. The median imaging-to-arterial puncture time was 37 minutes longer in the MRI group. Patients selected by CT had more favorable 90-day functional outcomes (mRS 0-2) as compared to patients selected by MRI (48.5% vs 44.4%; adjusted OR (aOR), 1.54, 95%CI 1.31 to 1.80, p&lt;0.001). Conclusions: Patients with AIS undergoing EVT who were selected with MRI as opposed to CT had longer imaging-to-arterial-puncture delays and worse functional outcomes at 90 days.

Collaterals and stroke reperfusion: Too few leads to too much

Adequate reperfusion after ischemic stroke is a major determinant of functional outcome yet remains unpredictable and insufficient for most survivors. In this issue of Neuron, Binder etal.1 identify leptomeningeal collaterals (LMCs) in mice and human patients as a key factor in regulating reperfusion and hemorrhagic transformation following stroke.

NK1 tachykinin receptor antagonist treatment reduces cerebral edema and intracranial pressure in an ovine model of ischemic stroke

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1–3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.

Iron promotes both ferroptosis and necroptosis in the early stage of reperfusion in ischemic stroke

Programmed cell death contributes to neurological damage in ischemic stroke, especially during the reperfusion stage. Several cell death pathways have been tested preclinically and clinically, including ferroptosis, necroptosis, and apoptosis. However, the sequence and complex interplay between cell death pathways during ischemia/reperfusion remains under investigation. Here, we unbiasedly investigated cell death pathways during ischemia/reperfusion by utilizing RNA sequencing analysis and immunoblot assays and revealed that ferroptosis and necroptosis occurred early post-reperfusion, followed by apoptosis. Ferroptosis inhibitor Liproxstatin-1 effectively inhibited necroptosis during reperfusion, while the necroptosis inhibitor Necrostatin-1 suppressed protein expression consistent with ferroptosis activation. Protein–protein interaction analysis and iron chelation therapy by deferoxamine mesylate indicate that iron is capable of promoting both ferroptosis and necroptosis in middle cerebral artery occlusion/repression modeled mice. Treatment of cells with iron led to a disruption in redox balance with activated necroptosis and increased susceptibility to ferroptosis. Collectively, these data uncovered a complex interplay between ferroptosis and necroptosis during ischemic stroke and indicated that multiple programmed cell death pathways may be targeted co-currently.

Experımental Study: The Effect Of 20% Intralıpıd Emulsıon Therapy In Cerebral Ischemıc Reperfusıon

ABSTRACT Background This experimental study was conducted to investigate the effect of 20% Intralipid Emulsion (ILE) treatment on Cerebral Ischemia Reperfusion Injury (CIRI) after reperfusion in acute ischemic stroke. Methods In this experimental study, seven rats without any intervention (control group), seven rats (sham group) for which CIRI was created after the common carotid artery was ligated for 2 hours, and seven rats who were treated with 20% ILE after CIRI (CIRI + ILE group) were sacrificed after 24 hours, and histopathological findings were investigated. Results In rats that were not treated after CIRI, 52.7% had level-1, 32.7% had level-2. and 14.5% had level-3. histopathological findings. While 72.2% of the rats treated with ILE had level-1 and 27.8% had level-2 findings, no level-3 histopathological findings were detected in any of the rats. While no signs of coagulative necrosis, spongiosis of surrounding tissue and polymorphonuclear leukocytes were observed histopathological in any of the rats given ILE, there was no macrophages finding in 85.6% of the rats. ILE treatment also reduced the histopathological findings of eosinophilic neurons, astrogliosis, neovascularization, vascular thrombosis and mononuclear inflammatory cells. Conclusion This study showed that 20% ILE treatment reduces the histopathological damage seen in cerebral ischemia and CIRI.

The Relevance of Reperfusion Stroke Therapy for miR-9-3p and miR-9-5p Expression in Acute Stroke-A Preliminary Study.

Reperfusion stroke therapy is a modern treatment that involves thrombolysis and the mechanical removal of thrombus from the extracranial and/or cerebral arteries, thereby increasing penumbra reperfusion. After reperfusion therapy, 46% of patients are able to live independently 3 months after stroke onset. MicroRNAs (miRNAs) are essential regulators in the development of cerebral ischemia/reperfusion injury and the efficacy of the applied treatment. The first aim of this study was to examine the change in serum miRNA levels via next-generation sequencing (NGS) 10 days after the onset of acute stroke and reperfusion treatment. Next, the predictive values of the bioinformatics analysis of miRNA gene targets for the assessment of brain ischemic response to reperfusion treatment were explored. Human serum samples were collected from patients on days 1 and 10 after stroke onset and reperfusion treatment. The samples were subjected to NGS and then validated using qRT-PCR. Differentially expressed miRNAs (DEmiRNAs) were used for enrichment analysis. Hsa-miR-9-3p and hsa-miR-9-5p expression were downregulated on day 10 compared to reperfusion treatment on day 1 after stroke. The functional analysis of miRNA target genes revealed a strong association between the identified miRNA and stroke-related biological processes related to neuroregeneration signaling pathways. Hsa-miR-9-3p and hsa-miR-9-5p are potential candidates for the further exploration of reperfusion treatment efficacy in stroke patients.

Leptomeningeal collaterals regulate reperfusion in ischemic stroke and rescue the brain from futile recanalization

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet-unknown functions. We applied laser speckle imaging, ultrafast ultrasound, and two-photon microscopy in a thrombin-based mouse model of stroke and fibrinolytic treatment to show that LMCs maintain cerebral autoregulation and allow for gradual reperfusion, resulting in small infarcts. In mice with poor LMCs, distal arterial segments collapse, and deleterious hyperemia causes hemorrhage and mortality after recanalization. In silico analyses confirm the relevance of LMCs for preserving perfusion in the ischemic region. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion and preventing futile recanalization after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for beneficial reperfusion after stroke.