Stroke Protection Research Articles

Hypoxia-Responsive Biomimetic Nanobubbles for Oxygen Delivery Promote Synergistic Ischemic Stroke Protection.

Effective, precise, and controllable oxygen delivery is crucial for regulating the oxygenation balance of brain tissue at the early stages of acute ischemic stroke (AIS) because the absence of oxygen may result in a series of highly interconnected vascular-neural pathological events, including oxidative stress, inflammation, and neuroapoptosis. In this study, platelet membrane-reassembled oxygen nanobubbles (PONBs) were constructed for oxygen delivery to protect AIS. Benefiting from the preserved natural targeting ability of platelet membranes, oxygen can be controlled release into the hypoxia lesion at the preperfusion stage due to vascular injury targeting and oxygen sustained diffusion capability after PONBs administration. Furthermore, synergizing with bioactive components carried by platelet membranes, PONBs can inhibit post-AIS vascular occlusion and maintain blood-brain barrier integrity, thereby facilitating enhanced oxygen delivery of PONBs, establishing a positive feedback loop between oxygen delivery and AIS protection. Additionally, the accumulation of PONBs enhances the ultrasound imaging contrast, enabling precise localization and dynamic monitoring of AIS lesions. Thus, PONBs represent a promising strategy for the diagnosis and treatment of AIS.

Investigating the Pharmacological Mechanisms of Total Flavonoids from Eucommia ulmoides Oliver Leaves for Ischemic Stroke Protection.

The aim of this study was to explore how the total flavonoids from Eucommia ulmoides leaves (EULs) regulate ischemia-induced nerve damage, as well as the protective effects mediated by oxidative stress. The cell survival rate was significantly improved compared to the ischemic group (p < 0.05) after treatment with the total flavonoids of EULs. The levels of reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA) decreased, while catalase (CAT) and glutathione (GSH) increased, indicating that the total flavonoids of EULs can significantly alleviate neurological damage caused by ischemic stroke by inhibiting oxidative stress (p < 0.01). The mRNA expression level of VEGF increased (p < 0.01), which was consistent with the protein expression results. Meanwhile, the protein expression of ERK and CCND1 increased (p < 0.01), suggesting that the total flavonoids of EULs could protect PC12 cells from ischemic injury via VEGF-related pathways. MCAO rat models indicated that the total flavonoids of EULs could reduce brain ischemia-reperfusion injury. In conclusion, this study demonstrates the potential mechanisms of the total flavonoids of EULs in treating ischemic stroke and their potential therapeutic effects in reducing ischemic injury, which provides useful information for ischemic stroke drug discovery.

Impact of Cerebral Embolic Protection Devices on Disabling Stroke After TAVR: Updated Results From the STS/ACC TVT Registry.

Cerebral embolic protection devices (EPDs) were developed to mitigate the risk of stroke during transcatheter aortic valve replacement (TAVR), but their benefit remains unproven. In the PROTECTED-TAVR trial (Stroke Protection With Sentinel During Transcatheter), EPD use did not reduce periprocedural stroke (primary study outcome) but led to a 62% reduction in the secondary end point of disabling stroke. Given these results, the impact of EPDs during TAVR remains unclear. We used STS/ACC TVT registry data to examine the association between EPD use and a proxy for disabling stroke among transfemoral TAVR patients between January 2018 and June 2023. The primary outcome was in-hospital disabling stroke-defined as stroke associated with either in-hospital death or discharge to a nonhome location. We evaluated the association between EPD use and disabling stroke using instrumental variable analysis with a site-level preference for EPD use as the instrument-a quasi-experimental approach that can support causal inference. In addition, we performed a propensity score-based comparison using overlap weighting as a secondary analysis. The study population consisted of 414 649 patients of whom 53 389 (12.9%) received an EPD. The unadjusted rate of in-hospital disabling stroke was 0.7% among the EPD group and 0.9% in the no-EPD group. EPD use was associated with a reduction in disabling stroke in both instrumental variable analysis (relative risk, 0.87 [95% CI, 0.73-1.00]) and propensity-weighted analysis (odds ratio, 0.79 [95% CI, 0.70-0.90]) but was not associated with a reduction in nondisabling stroke. In subgroup analyses, the benefit of EPD was greater among those with versus without prior stroke (Pinteraction<0.05 for both instrumental variable and propensity-weighted analyses). In the largest study to date, among patients undergoing TAVR, EPD use was associated with a small, borderline significant reduction in stroke associated with death or discharge to a nonhome location (a proxy for disabling stroke) that is likely to be causal in nature. Taken together with previous mechanistic and clinical studies, these findings provide credible evidence that EPDs benefit patients undergoing TAVR.

Automated continuous rhythm monitoring with implantable cardiac monitor and real-time smartphone alerts during af episodes: SMART-ALERT study

Abstract Introduction The 'Pill-in-the-pocket' oral anticoagulation (OAC) strategy is based upon the concept of dynamic thromboembolic risk which increases during and shortly after an atrial fibrillation (AF) episode. Limiting OAC use in low-risk patients with infrequent AF may offer comparable stroke protection and reduce bleeding. However, this approach relies on precise continuous rhythm monitoring with real-time alerts to patients. LINQ II implantable cardiac monitor transmits regularly to Carelink via smartphone app, but lacks patient alerts. To address this limitation, we developed bespoke software that triages transmissions in Carelink and sends alerts via SMS to patients. Purpose This feasibility study evaluates the precision of the LINQ II in detecting AF and assesses the efficacy of bespoke software in delivering 'real-time' SMS alerts to participants' smartphones, and measures compliance with these alerts. Methods In this single-center feasibility study, individuals with frequent AF episodes underwent LINQII implantation. The bespoke software, operating in the cloud, systematically reviewed all Carelink transmissions at 5-min intervals. SMS alerts were triggered based on specific criteria: 1)AF &amp;gt;30 min; 2)only the initial AF episode &amp;gt;30 min within a 24h period was transmitted; and 3)AF episodes uploaded or detected after a 24h delay were disregarded. Participants confirmed receipt of the alert by responding to the SMS, and timestamps for these interactions were recorded in a database (Fig. 1). Results A total of 50 patients were prospectively enrolled, and LINQ II was implanted. The median age was 49 years, 62% male, 90% had paroxysmal AF. Over a 3-month mean follow-up, 4080 AF episodes &amp;gt;30 min occurred in 32 patients. Among these, 700 met the criteria for triggering an alert, with 72.14% sent to patients within 24 h. Alerts were not transmitted for 3 main reasons: smartphone failure to transmit to Carelink within a 24 h period, software issues connecting to Carelink (website maintenance), and updates in the webservers. The median time from an AF episode to the transmission of SMS alerts was 2.47 h, with 85.54% of alerts being sent within 12 hours. Once an SMS was sent, the median time for acknowledgment was 4.3 min. The median time from an AF episode to acknowledgment was 4.23 h (Fig. 2). Notably, 97.62% of episodes were acknowledged within 24 hours. Patients failed to acknowledge an SMS alert on only 3 occasions. Conclusions Safely delivering 'pill-in-the-pocket' OAC requires a closed-loop system where devices provide real-time alerts during during AF , thus minimising delays in initiating OAC. This feasibility study establishes that the integration of bespoke software with LINQ II exhibits promising efficacy with a high percentage of SMS alerts within 24 hours, exceptional patient compliance, and a median response time of only 4.3 min. Nonetheless, further efforts are needed for seamless integration with Carelink to enhance connectivity.

Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice

ABSTRACT Objectives The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. Methods C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. Results From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1β in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. Conclusion This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

Abstract TP301: Tmem30a - Mediated Mitigation of Phosphatidylserine Exposure May Be a Novel Therapeutic Target for Brain Protection in Ischemic Stroke

Cellular pathways of self-preservation are highly conserved and may represent powerful ways to protect tissue against injury and disease. Here, we use a combination of cell, mouse, rat, nonhuman primate, and human models to demonstrate the feasibility of evoking endogenous self-preservation pathways to protect brain tissue in stroke. The transmembrane protein 30A ( Tmem30a ), the β-subunit of P4-ATPases, helps maintain the asymmetric distribution of phospholipids in plasma membrane, especially phosphatidylserine (PS) in the inner leaflet. Tmem30a transcripts were increased in the penumbra in two types of animal models of stroke. The increased Tmem30a transcripts were associated with less PS exposure and neuron death in vitro and improved neurological outcomes and extended therapeutic window in vivo. Mechanistically, Tmem30a upregulation led to decreased levels of apoptosis-related markers. Moreover, we found that recombinant Annexin V protein can decrease PS exposure, reduce infarct volumes, and improve neurological impairments in wild mice after ischemia/reperfusion, but not in Tmem30a knockout mice and those receiving siRNA- Tmem30a . Lastly, we also observed that high Annexin V levels were associated with better outcomes in stroke patients with salvageable penumbra, but not in those without penumbral tissues. Overall, our findings reveal a previously unappreciated role of maintaining asymmetric distribution of phospholipids in protecting the penumbra in the context of clinically relevant reperfusion. Tmem30a is essential for PS-blocking dependent neuroprotection and might represent a potential new strategy for evoking endogenous self-preservation pathways to protect brain tissue after stroke.

Abstract TP296: Circadian Rhythm Influences Stroke Outcomes Through Reverbα Remodeling

Background: Stroke leads to disability and death worldwide and evidence suggested that stroke severity is affected by the time dimension of the stroke. Rev-Erbα regulates the core circadian clock through repression of the positive clock element Bmal1 and controls circadian rhythm. However, it is unclear if Rev Erbα agonist (SR9009) treatment alleviates stroke severity in mice. Hypothesis: We found that at ZT06 stroke reduces the level of Rev-Erbα and elevates the inflammation and stroke severity. Therefore, we hypothesized that SR9009 treatment may reduce the inflammation and stroke severity in a mouse suture occlusion model. Methods: 10 to 12 weeks C57BL/6J (Wild Type, n=5-10 mice/group) mice were randomly assigned to do stroke at the different time points of the day following zeitgeber time at ZT06 and Z18. Cerebral Ischemia was induced by occlusion of the middle cerebral artery (MCAO) for 60 min. stroke mice were treated with SR9009 (100mg/kg). Mice were treated at 1 hour and 24h after MCAO. The neurobehavioral assay was performed for the neurological deficit, motor deficit, and animal activity. Forty-eight hours after the stroke, TTC staining was done to estimate brain infarction, and the infarct area was measured using NIH-Image J software. Results: We found Rev Erbα were significantly ( p&lt;0.001 ) higher at ZT06 in naïve mice though Rev Erbα mRNA level significantly decreased at ZT06 ( p&lt;0.05 ) and ZT18 (p&lt;0.05) stroke in comparison to sham. Interestingly treatment with SR9009 reduces stroke volume at ZT06 [F=14.99 (3, 23) p&lt;0.001 ) in comparison to vehicle-treated stroke though no significant changes were observed at ZT18. There were no significant ( p&gt;0.05 ) effects of SR9009 on neurological deficit score, motor function, and corner test. Conclusion: This study demonstrates that SR9009 treatment reduces stroke volume and protection depends on the circadian time of stroke.

A pilot study to evaluate the quality of care in oral anticoagulant and antiplatelet use in patients with permanent atrial fibrillation in Irish general practice

Abstract Aim: The aim of this pilot study is to determine the pattern of oral anticoagulant and antiplatelet use in patients with permanent atrial fibrillation (AF) in Irish general practice. Background: Worldwide, AF is the most common sustained cardiac arrhythmia in adults and poses a significant burden to patients, physicians and healthcare systems. There is a five-fold increased risk of stroke with AF, and AF-related strokes are associated with higher levels of both morbidity and mortality compared to other stroke subtypes. Thankfully, appropriate use of oral anticoagulation (OAC) for AF can reduce the risk of stroke by up to 64%. However, we know that patients are commonly undertreated with OAC, prescribed inappropriate doses of OAC and have prolonged use of an antiplatelet agent in addition to OAC without indication. Methods: A descriptive, cross-sectional observational study was undertaken. Proportionate sampling was used across 11 practices from the Ireland East practice-based research network. The general practitioners completed a report form on each patient provided by the research team by undertaking a retrospective chart review. Findings: Eleven practices participated with a total number of 1855 patients with AF. We received data on 153 patients. The main findings from this pilot project are that: 1. 11% of patients were undertreated with OAC 2. 20 % of patients were on an incorrect non-vitamin K antagonist oral anticoagulant dose 3. 28 patients (18%) were inappropriately prescribed combination antithrombotic therapy Undertreatment and underdosing of OAC expose patients to higher risk of thromboembolic events, bleeding and all-cause mortality. Prolonged combination antithrombotic therapy is associated with serious increased risk of bleeding with no additional stroke protection. This pilot project highlights several gaps between guidelines and clinical practice. By identifying these areas, we hope to develop a targeted quality improvement intervention using the electronic health records in general practice to improve the care that those with AF receive.

Left atrial appendage occlusion indicated by increased thrombotic risk versus increased bleeding risk: a comparison of the stroke despite anticoagulation (STR-OAC) and EWOLUTION cohorts

Abstract Background Left atrial appendage occlusion (LAAO) provides mechanical cardioembolic protection, especially attractive for atrial fibrillation (AF) patients that cannot use oral anticoagulation therapy (OAC). Patients with prior stroke despite OAC are at high risk for recurrence and may also benefit from LAAO as (adjunctive) therapy. Purpose To investigate the efficacy of LAAO in AF patients with prior stroke on OAC compared to LAAO in AF patients with a contra-indication to OAC. Methods The STR-OAC LAAO is an international collaboration combining patients that underwent successful percutaneous LAAO because of a thrombo-embolic event or LAA thrombus on OAC from multiple LAAO registries (n=439). This cohort was compared to patients from the previously published EWOLUTION registry comprising of patients that successfully underwent LAAO because of a contra-indication for long-term OAC (n=1005). Thrombotic endpoints were prespecified and (non-procedural) major bleeding was defined as BARC score&amp;gt;2. Annualized event rates were calculated and compared to historical data based on individual patient risk scores. Results Both cohorts were comparable in terms of age and sex (Table 1). CHA2DS2-VASc and HAS-BLED scores were higher in the STR-OAC cohort. After LAAO indicated by a thrombotic event despite OAC, 33% of patients had a planned lifelong hybrid strategy approach of concomitant LAAO and OAC. Consequently, STR-OAC patients often continued OAC (with or without antiplatelet therapy), whereas EWOLUTION patients were more frequently discharged with antiplatelet therapy only. The annualized event rate (AER) for composite thrombotic events was slightly higher in the STROAC-LAAO compared to the EWOLUTION patients (4.2% versus 2.0%), possibly due to the higher thrombotic risk of this population. Major bleeding occurred more frequently in the EWOLUTION compared to STROAC-LAAO patients (AER 2.6% versus 1.1%, Table 2). In comparison to historically expected event rates, relative risk reduction (RRR) for thrombo-embolic events was 65% in the STR-OAC cohort, and 80% in the EWOLUTION cohort (Fig. 1). Annualized major bleeding rates were reduced with 81% and 46% in the STR-OAC-LAAO and EWOLUTION cohorts, respectively. Conclusions LAAO in AF patients with a thrombotic event despite OAC provides ischemic stroke protection similar to a guideline-recommended population with high bleeding risk. RRR for thrombotic events was more pronounced in the population contra-indicated for long-term OAC, while RRR for major bleeding was more pronounced in the patients that experienced a thrombotic event on OAC. Randomized trial data could endorse thrombotic event despite OAC as an indication for LAAO.Table 1&amp;2Figure 1

Pre-stroke exercise does not reduce atrophy in healthy young adult mice

Stroke is the main cause of acquired disability in adults. Exercise reduces the risk for stroke and protects against functional loss after stroke. An exercise-induced reduction in key risk factors probably contributes to the protective effect, but direct effects on the brain may also contribute to stroke protection. We previously reported that exercise increases angiogenesis and neurogenesis through activation of the lactate receptor HCA1. Here we exposed young adult wild-type mice and HCA1 knockout mice to interval exercise at high or medium intensity, or to intraperitoneal injections of L-lactate or saline for seven weeks before we induced experimental stroke by permanent occlusion of the distal medial cerebral artery (dMCA). The resulting cortical atrophy measured three weeks after stroke was unaffected by exercise or L-lactate pre-treatments, and independent of HCA1 activation. Our results suggest that the beneficial effect of exercise prior to stroke where no reperfusion occurs is limited in individuals who do not carry risk factors.

Transcarotid artery revascularization for the management of blunt cerebrovascular injuries-is it a game changer?

In their 10 patient case series, Walker et al, describe excellent outcomes from the use of transcarotid artery revascularization (TCAR) for the treatment of patients with severe blunt cerebrovascular injuries (BCVI).1Dr. Patrick Walker et al. Transcarotid Artery Revascularization in Blunt Carotid Injury. J Vasc Surg Cases Innov Tech. 20XX, 1(1), XX-XX. doi: XXXX.Google Scholar. For a single center over only 2 years this is a large cohort for a relatively rare problem. It is important to note that the primary treatment for BCVI is antithrombotic therapy with antiplatelets and/or anticoagulation. It has been shown that transfemoral carotid artery stenting for BCVI is rarely necessary or beneficial over antithrombotic therapy and the EAST guidelines recommend against routine stenting of grade II or III BCVI.(2)Burlew C.C. Biffl W.L. Moore E.E. Pieracci F.M. Beauchamp K.M. Stovall R. Wagenaar A.E. Jurkovich G.J. Endovascular stenting is rarely necessary for the management of blunt cerebrovascular injuries.J Am Coll Surg. 2014; 218: 1012-1017https://doi.org/10.1016/j.jamcollsurg.2014.01.042Crossref PubMed Scopus (45) Google Scholar,(3)Kim D.Y. Biffl W. Bokhari F. Brakenridge S. Chao E. Claridge J.A. Fraser D. Jawa R. Kasotakis G. Kerwin A. et al.Evaluation and management of blunt cerebrovascular injury: A practice management guideline from the Eastern Association for the Surgery of Trauma.J Trauma Acute Care Surg. 2020; 88: 875-887https://doi.org/10.1097/TA.0000000000002668Crossref PubMed Scopus (32) Google Scholar The Denver group found an alarmingly high 45% occlusion rate in patients treated with stenting vs. only 5% in those treated with antithrombotic therapy and concluded that stenting for BCVI had an unacceptable risk profile.(4)Cothren C.C. Moore E.E. Ray C.E. Ciesla D.J. Johnson J.L. Moore J.B. Burch J.M. Carotid artery stents for blunt cerebrovascular injury: risks exceed benefits.Arch Surg. 2005; 140 (; discussion 485-486): 480-485https://doi.org/10.1001/archsurg.140.5.480Crossref PubMed Scopus (111) Google Scholar It seems clear that stenting is rarely indicated for BCVI and this is consistent with the experience of the Maryland Shock Trauma study, as the authors point out that their center diagnoses approximately 300 carotid BCVIs per year, of which only 2-3% were selected for TCAR. It's possible that TCAR may be associated with a lower stroke and complication rate in BCVI patients in a similar manner to its benefits for carotid occlusive disease. Namely, by the use of dynamic flow reversal, which was found by Naazie, et al. in their Vascular Quality Initiative study to be the primary mechanism for stroke protection in TCAR.(5)Naazie I.N. Magee G.A. Mathlouthi A. Elsayed N. Dakour-Aridi H. Malas M.B. Primary mechanism of stroke reduction in transcarotid artery revascularization is dynamic flow reversal.J Vasc Surg. 2021; 74: 187-194https://doi.org/10.1016/j.jvs.2020.10.082Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Although the focus of this series is on the novel use of TCAR in the setting of BCVI requiring stenting, the authors describe another innovation, which is the use of Supera stents (Abbott, Plymouth, MN). The authors state that they prefer Supera stents for this application because of its flexibility and length, as they often stent up to the skull base to treat the entirety of the injury. At first glance, this seems to be an usual choice, but their results suggest that the authors may be on to something. Further study is necessary to determine if TCAR is a gamechanger for the management of BCVI and which of these two innovations is the primary reason for improved outcomes. Transcarotid Artery Revascularization in Blunt Carotid InjuryJournal of Vascular Surgery Cases, Innovations and TechniquesPreviewTranscarotid artery revascularization (TCAR) with flow reversal has substantially changed the management of carotid artery stenosis, enabling an endovascular approach with a periprocedural stroke rate as low or lower than that of open carotid surgery. The use of TCAR in blunt carotid injury has not yet been described. Full-Text PDF Open Access

The Ketogenic Diet but not Hydroxycitric Acid Keeps Brain Mitochondria Quality Control and mtDNA Integrity Under Focal Stroke.

Mitochondrial dysfunction in the ischemic brain is one of the hallmarks of stroke. Dietary interventions such as the ketogenic diet and hydroxycitric acid supplementation (a caloric restriction mimetic) may potentially protect neurons from mitochondrial damage induced by focal stroke in mice. We showed that in control mice, the ketogenic diet and the hydroxycitric acid did not impact significantly on the mtDNA integrity and expression of genes involved in the maintenance of mitochondrial quality control in the brain, liver, and kidney. The ketogenic diet changed the bacterial composition of the gut microbiome, which via the gut-brain axis may affect the increase in anxiety behavior and reduce mice mobility. The hydroxycitric acid causes mortality and suppresses mitochondrial biogenesis in the liver. Focal stroke modelling caused a significant decrease in the mtDNA copy number in both ipsilateral and contralateral brain cortex and increased the levels of mtDNA damage in the ipsilateral hemisphere. These alterations were accompanied by a decrease in the expression of some of the genes involved in maintaining mitochondrial quality control. The ketogenic diet consumption before stroke protects mtDNA in the ipsilateral cortex, probably via activation of the Nrf2 signaling. The hydroxycitric acid, on the contrary, increased stroke-induced injury. Thus, the ketogenic diet is the most preferred variant of dietetic intervention for stroke protection compared with the hydroxycitric acid supplementation. Our data confirm some reports about hydroxycitric acid toxicity, not only for the liver but also for the brain under stroke condition.

Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates

Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. Understanding the molecular alterations in cerebral microvessels in stroke will provide original opportunities for scientific investigation of novel therapeutic strategies. Toward this goal, using a recently optimized method which minimizes cell activation and preserves endothelial cell interactions and RNA integrity, we conducted a genome-wide transcriptomic analysis of cerebral microvessels in a mouse model of stroke and compared these transcriptomic alterations with the ones observed in human, nonfatal, brain stroke lesions. Results from these unbiased comparative analyses have revealed the common alterations in mouse stroke microvessels and human stroke lesions and identified shared molecular features associated with vascular disease (e.g., Serpine1/Plasminogen Activator Inhibitor-1, Hemoxygenase-1), endothelial activation (e.g., Angiopoietin-2), and alterations in sphingolipid metabolism and signaling (e.g., Sphigosine-1-Phosphate Receptor 2). Sphingolipid profiling of mouse cerebral microvessels validated the transcript data and revealed the enrichment of sphingomyelin and sphingoid species in the cerebral microvasculature compared to brain and the stroke-induced increase in ceramide species. In summary, our study has identified novel molecular alterations in several microvessel-enriched, translationally relevant, and druggable targets, which are potent modulators of endothelial function. Our comparative analyses have revealed the presence of molecular features associated with cerebral microvascular dysfunction in human chronic stroke lesions. The results shared here provide a detailed resource for therapeutic discovery of candidates for neurovascular protection in stroke and potentially, other pathologies exhibiting cerebral microvascular dysfunction.

Retinoic Acid-Loaded Nanoparticles Promote Neurovascular Protection in Stroke.

HomeStrokeVol. 54, No. 4Retinoic Acid–Loaded Nanoparticles Promote Neurovascular Protection in Stroke No AccessResearch ArticleRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialNo AccessResearch ArticleRequest AccessFull TextRetinoic Acid–Loaded Nanoparticles Promote Neurovascular Protection in Stroke Marta Machado-Pereira, Alba Grayston, Miguel Garcia-Gabilondo, Vitor Francisco, Ana Cristóvão, João Marto, Helena Vieira, Miguel Viana-Baptista, Lino Ferreira, Liliana Bernardino, Anna Rosell and Raquel Ferreira Marta Machado-PereiraMarta Machado-Pereira https://orcid.org/0000-0002-8986-8679 Health Sciences Research Centre (M.M.-P., A.C., L.B., R.F.), University of Beira Interior, Portugal. Search for more papers by this author , Alba GraystonAlba Grayston https://orcid.org/0000-0002-1466-0099 Health Sciences Research Centre (M.M.-P., A.C., L.B., R.F.), University of Beira Interior, Portugal. Neurovascular Research Laboratory, Vall d’Hebron Institut de Recerca, Universitat Autónoma de Barcelona, Spain (A.G., M.G.-G., A.R.). Search for more papers by this author , Miguel Garcia-GabilondoMiguel Garcia-Gabilondo https://orcid.org/0000-0002-2015-2621 Neurovascular Research Laboratory, Vall d’Hebron Institut de Recerca, Universitat Autónoma de Barcelona, Spain (A.G., M.G.-G., A.R.). Search for more papers by this author , Vitor FranciscoVitor Francisco https://orcid.org/0000-0002-2704-9950 Center for Neuroscience and Cell Biology (V.F., L.F.), University of Coimbra, Portugal. Faculty of Medicine (V.F., L.F.), University of Coimbra, Portugal. Search for more papers by this author , Ana CristóvãoAna Cristóvão https://orcid.org/0000-0001-5806-4478 NeuroSoV, UBImedical (A.C.), University of Beira Interior, Portugal. Search for more papers by this author , João MartoJoão Marto https://orcid.org/0000-0003-2277-5950 Department of Neurology, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Portugal (J.M., M.V.-B.). NMS Research, Nova Medical School Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Portugal (J.M., H.V., M.V.-B., R.F.). Search for more papers by this author , Helena VieiraHelena Vieira https://orcid.org/0000-0001-9415-3742 NMS Research, Nova Medical School Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Portugal (J.M., H.V., M.V.-B., R.F.). Applied Molecular Biosciences Unit (H.V.), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Portugal. Associate Laboratory i4HB – Institute for Health and Bioeconomy, Department of Chemistry (H.V.), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Portugal. Search for more papers by this author , Miguel Viana-BaptistaMiguel Viana-Baptista https://orcid.org/0000-0001-6166-2073 Department of Neurology, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Portugal (J.M., M.V.-B.). NMS Research, Nova Medical School Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Portugal (J.M., H.V., M.V.-B., R.F.). Search for more papers by this author , Lino FerreiraLino Ferreira https://orcid.org/0000-0001-8985-9302 Center for Neuroscience and Cell Biology (V.F., L.F.), University of Coimbra, Portugal. Faculty of Medicine (V.F., L.F.), University of Coimbra, Portugal. Search for more papers by this author , Liliana BernardinoLiliana Bernardino Liliana Bernardino, PhD, Health Sciences Research Centre, University of Beira Interior, Portugal, Email E-mail Address: [email protected] https://orcid.org/0000-0003-3395-5973 Health Sciences Research Centre (M.M.-P., A.C., L.B., R.F.), University of Beira Interior, Portugal. Search for more papers by this author , Anna RosellAnna Rosell Neurovascular Research Laboratory, Vall d’Hebron Institut de Recerca, Universitat Autónoma de Barcelona, Spain (A.G., M.G.-G., A.R.). Search for more papers by this author and Raquel FerreiraRaquel Ferreira Correspondence to: Raquel Ferreira, PhD, NOVA Medical School Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria 130, 1169-056 Portugal, Email E-mail Address: [email protected] https://orcid.org/0000-0003-1014-0499 Health Sciences Research Centre (M.M.-P., A.C., L.B., R.F.), University of Beira Interior, Portugal. NMS Research, Nova Medical School Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Portugal (J.M., H.V., M.V.-B., R.F.). Now with Technophage, Lisbon, Portugal (R.F.). Search for more papers by this author Originally published13 Mar 2023https://doi.org/10.1161/STROKEAHA.122.041839Stroke. 2023;54:e149–e151FootnotesFor Sources of Funding and Disclosures, see page e150.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.122.041839.Correspondence to: Raquel Ferreira, PhD, NOVA Medical School Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria 130, 1169-056 Portugal, Email raquel.[email protected]unl.ptLiliana Bernardino, PhD, Health Sciences Research Centre, University of Beira Interior, Portugal, Email [email protected]ubi.pt

Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures.

Ischemic stroke causes brain endothelial cell (BEC) death and damages tight junction integrity of the blood-brain barrier (BBB). We harnessed the innate mitochondrial load of BEC-derived extracellular vesicles (EVs) and utilized mixtures of EV/exogenous 27 kDa heat shock protein (HSP27) as a one-two punch strategy to increase BEC survival (via EV mitochondria) and preserve their tight junction integrity (via HSP27 effects). We demonstrated that the medium-to-large (m/lEV) but not small EVs (sEV) transferred their mitochondrial load, that subsequently colocalized with the mitochondrial network of the recipient primary human BECs. Recipient BECs treated with m/lEVs showed increased relative ATP levels and mitochondrial function. To determine if the m/lEV-meditated increase in recipient BEC ATP levels was associated with m/lEV mitochondria, we isolated m/lEVs from donor BECs pre-treated with oligomycin A (OGM, mitochondria electron transport complex V inhibitor), referred to as OGM-m/lEVs. BECs treated with naïve m/lEVs showed a significant increase in ATP levels compared to untreated OGD cells, OGM-m/lEVs treated BECs showed a loss of ATP levels suggesting that the m/lEV-mediated increase in ATP levels is likely a function of their innate mitochondrial load. In contrast, sEV-mediated ATP increases were not affected by inhibition of mitochondrial function in the donor BECs. Intravenously administered m/lEVs showed a reduction in brain infarct sizes compared to vehicle-injected mice in a mouse middle cerebral artery occlusion model of ischemic stroke. We formulated binary mixtures of human recombinant HSP27 protein with EVs: EV/HSP27 and ternary mixtures of HSP27 and EVs with a cationic polymer, poly (ethylene glycol)-b-poly (diethyltriamine): (PEG-DET/HSP27)/EV. (PEG-DET/HSP27)/EV and EV/HSP27 mixtures decreased the paracellular permeability of small and large molecular mass fluorescent tracers in oxygen glucose-deprived primary human BECs. This one-two punch approach to increase BEC metabolic function and tight junction integrity may be a promising strategy for BBB protection and prevention of long-term neurological dysfunction post-ischemic stroke.

Direct oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation and CKD G3-G5D.

The use of direct oral anticoagulants (DOAC) in patients with non-valvular atrial fibrillation (NVAF) and advanced chronic kidney disease (CKD) including dialysis is growing. Several studies have shown favorable results of DOAC compared with warfarin regarding bleeding risk but no difference in stroke protection. However, these studies had poor time in therapeutic range (TTR), in the warfarin comparison group. This was a Swedish national cohort study investigating the risk of ischemic stroke and major bleeding on DOAC compared with warfarin in patients with NVAF, glomerular filtration rate category 3-5D (G3-G5D), kidney transplant recipients excluded, between 2009 and 2018. Data extracted from high-quality national healthcare registries including the Swedish Renal Registry, AuriculA (the Swedish national quality register for AF and anticoagulation) and The Stroke Register. At enrolment, of 2453 patients 59% were treated with warfarin (mean TTR 67%) and 41% with DOAC. Overall, 693 (28.3%) had G3, 1113 (45.4%) G4, 222 (9.1%) G5 and 425 (17.3%) G5D. DOAC compared with warfarin showed lower hazard of major bleeding [hazard ratio 0.71 (95% confidence interval 0.53-0.96)] but no difference in ischemic stroke risk. Mortality was increased during DOAC treatment [1.24 (1.01-1.53)], presumably not a causal association since fewer fatal bleedings occurred on DOAC. DOAC treatment, compared with warfarin, is associated with almost 30% lower risk of bleeding in patients with NVAF and CKD G3-G5D. The stroke risk is comparable between the treatments. This is the first study comparing DOAC and well-managed warfarin (TTR 67%) in advanced CKD. Ongoing and planned randomized controlled trials need to confirm the possible benefit of DOAC.

Supplementation with Tribulus Terrestris Extract Exhibits Protective Effects on MCAO Rats via Modulating Inflammation-Related Metabolic and Signaling Pathways.

The extract of Tribulus terrestris (TT) has been used as a component of several nutritional supplements for enhancing human vitality. However, its protective effect on ischemic stroke has yet to be fully investigated. In this study, the middle cerebral artery occlusion (MCAO) rat model was established and treated with gross saponin of TT fruit (GSTTF) by gavage to explore its anti-ischemic stroke efficacy. Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was applied to profile the brain tissue metabolite changes and further obtain the metabolic pathways that were greatly involved in the efficacy of GSTTF. Subsequent molecular biology experiments were applied to validate the findings from metabolomics analysis. The results showed that GSTTF administration remarkably decreased the infarction volume of brain tissue and improved the neurobehavioral scores of MCAO rats. Metabolomics analysis revealed that pathways, including glycerophospholipid metabolism, sphingolipid metabolism, and arachidonic acid metabolism, were considered associated with the protective effect of GSTTF against MCAO, which were greatly involved in the inflammatory responses. The results of the biochemistry analysis showed that GSTTF treatment significantly reduced the levels of TNF-α and IL-6 in brain tissue after MCAO. The anti-inflammatory mechanism of GSTTF was further investigated, which revealed that GSTTF could inhibit the TLR4/MyD88/NF-κB signaling pathway to exert protective effects on MCAO. This study provides the underlying anti-inflammatory mechanism of GSTTF for ischemic stroke protection, which has important implications for the development of GSTTF-related functional foods or food supplements.

Training standards for neurointerventional procedures regarding endovascular treatment and secondary endovascular protection of acute ischemic stroke

Training standards for neurointerventional procedures regarding endovascular treatment and secondary endovascular protection of acute ischemic stroke

Effect of Chronic Antiplatelet and Anticoagulant Medication in Neck Hematoma and Perioperative Outcomes after Carotid Endarterectomy

A retrospective analysis of neck hematoma, stroke, and mortality after symptomatic and asymptomatic carotid endarterectomy (CEA) was conducted, to determine the most appropriate perioperative medication for these patients. Thirty-day outcomes of moderate and severe neck bleeding were also investigated. Patients undergoing CEA in a Vascular Surgery department were analyzed (2015-2019). Preprocedure antithrombotic medication (from the 5 days prior to surgery) was identified. End point predictors were identified by univariate and multivariable analyses and adjusted for confounders. A total of 304 CEA were included. Almost half of the included patients (49.67%) were under low-dose aspirin, 17.55% other single antiplatelet agent, 12.59% dual antiplatelet therapy, 8.61% anticoagulation, and 10.92% no antithrombotic therapy. There was a 8.22% rate of important hematoma, including 4.93% severe (requiring surgical exploration) hematomas and a 30-day all-stroke incidence of 2.94% in symptomatic and 1.79% asymptomatic patients (P=0.51). When compared to aspirin, severe hematoma was more prevalent with single clopidogrel or triflusal (relative risk [RR] 4.25, P=0.11), dual antiplatelet group (RR 11.84, P=0.002), and anticoagulation (RR 8.604, P=0.02). Dual antiaggregation and anticoagulation did not confer postoperative stroke protection compared to single aspirin in either symptomatic or asymptomatic patients. Nonsignificant higher intrahospital mortality was noted in no medication, dual antiplatelet, and anticoagulation groups in contrast to aspirin. Severe neck bleeding was associated with increased congestive heart failure (9.26-fold, P=0.03) and longer hospital stay (11.20±24.69days vs. 3.18±4.79 with no bleeding, P<0.001), with a tendency for higher hospital readmission at 30 days (4.66-fold, P=0.13). Mortality and stroke rates were similar. Double antiaggregation and anticoagulation did not confer better perioperative outcomes after elective CEA in our study. These regimens were associated with an increased risk of neck hematoma, especially severe bleeding, with similar rates of neurologic events in both symptomatic and asymptomatic patients and no mortality benefit. Monotherapy with aspirin appears to be the safest perioperative antithrombotic regimen for elective CEA.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.