Improve Stroke Outcomes Research Articles

Abstract TMP111: Physical Activity among Stroke Patients in the Discharge Educational Strategies for Reduction of Vascular Events (DESERVE) Study

Introduction: Previous research has emphasized the importance of physical activity in preventing secondary stroke. However, approaches to improving physical activity after stroke have been suboptimal, particularly among race-ethnic groups. Methods: The DESERVE study was an RCT of a skills-based educational intervention in a multi-ethnic cohort of mild stroke/ TIA patients. The current analysis compared physical activity at one year post-discharge between intervention and usual care arms in DESERVE. Patients reported whether or not they participated in any moderate or vigorous physical activity for at least 10 minutes in the past month. Participation in any physical activity was compared between trial arms overall and stratified by race/ethnicity using chi-square tests. Results: A total of 338 patients were included in the analysis (n=171 intervention, n=167 usual care; 29.2% non-Hispanic white, 34.2% non-Hispanic black, 33.9% Hispanic). Overall, 50.3% of patients participated in any physical activity in the past month. There was no difference in physical activity between the trial arms (p=0.91). Among Hispanics, participating in any physical activity was significantly greater in the intervention arm than in the usual care (intervention 43.6% vs. usual care 22.4%, p=0.01). There was no association between intervention arm and physical activity among non-Hispanic whites (intervention 58.1% vs. usual care 72.0%, p=0.16) and non-Hispanic blacks (intervention 50.9% vs. usual care 54.2%, p=0.74). Conclusion: Participation in a skills-based intervention was associated with significantly greater physical activity one year post-discharge among Hispanic stroke/TIA patients. Providing culturally-tailored, skills-based tools and strategies that focus on behavior modification, such as improving physical activity, has the potential to improve stroke outcomes and reduce stroke disparities.

Abstract TMP27: Tgfalpha Protects Oligodendrocytes Against Ischemic Injury and Promotes White Matter Integrity After Stroke

Introduction: The loss of white matter integrity after ischemic stroke contributes to long-term sensorimotor and cognitive deficits. Elucidating the mechanisms for white matter protection or recovery is therefore important to improve stroke outcomes. This study investigates the function of TGFα, a member of the epidermal growth factor family, in white matter recovery after stroke and elucidate the mechanisms of action. Methods: Cerebral ischemia was induced by transient (60 min) middle cerebral artery occlusion (tMCAO) in wild type and TGFα knockout mice. The spatiotemporal pattern of TGFα expression was evaluated by immunofluorescent staining at 1, 3, 5, 14, 21 and 35 days after tMCAO. Sensorimotor (rota-rod test, adhesive-remove test and open field test) and cognitive (Morris water-maze test) functions were assessed up to 35 days after stroke. White matter injury was quantified by MBP (myelin basic protein) and SMI32 (recognizes damaged non-phosphorylated neurofilament proteins) staining. The direct effect of TGFα on oligodendrocytes were evaluated in vitro using primary cultures. Live/dead cell staining and LDH (lactate dehydrogenase) assay were used to assess oligodendrocytes death after 90 min oxygen and glucose deprivation (OGD). Result: Cerebral ischemic induced an abrupt and transient increase of TGFα in the brain. The expression of TGFα was mainly increased in microglia and neurons. TGFα deficiency resulted in exacerbation in sensorimotor and cognitive deficits up to 35 days after tMCAO. MAP2 (microtubule-associated protein 2) staining at 3 days and 35 days showed lager tissue loss in TGFα knockout mice as compared with wild type stroke mice. Importantly. TGFα knockout mice also exhibited impaired white matter integrity, as revealed by the loss of MBP staining and elevation in SMI32 staining, at 35 days after stroke. Correlation analysis demonstrated positive correlation between white matter integrity and functional outcomes after stroke in TGFα knockout mice and wild type mice. In vitro study confirmed that TGFα (5, 10 or 20 ng/ml) protected oligodendrocyte precursor cells and oligodendrocytes against OGD. Conclusion: TGFα is important for maintaining white matter integrity and improving neurological recovery after stroke.

Abstract TP100: Angiotensin Type 2 Receptor Stimulation With Compound 21 Improves Stroke Outcome in Female Rats: Possible Role for Peroxisome Proliferator-activated Receptor Gamma

Introduction: The angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neuro-protective, pro-angiogenic and anti-inflammatory after stroke in male rats. Here we aimed to study the effect of C21 treatment on ovary-intact female rats after stroke. Methods: Female Wistar rats were subjected to 3 h middle cerebral artery occlusion (MCAO) using a silicone-coated monofilament and treated at reperfusion with IP C21 0.03 mg/kg. Rats were sacrificed at 24 h and brains collected for infarct analysis. Another cohort of female rats were subjected to MCAO and treated at reperfusion with C21 for 2 days. Animals were followed up and sacrificed at 72 h. Behavioral tests (Bederson, Paw grasp, Beam walk and Rotarod) were performed at 24 h and 72 h, and whole brains were collected for western blotting. Results (mean±SEM): C21 treatment in females resulted in a decrease in infarct size, improvement in Bederson, Paw grasp and rotarod scores. Interestingly, C21 treatment showed a trend toward increased expression of the transcription factor PPARγ at 72 h in sham and stroked animals suggesting a novel crosstalk between the AT2R and PPARγ after ischemic stroke. In addition, stroke surgery resulted in a decrease in the AT2R expression. However, sham treated animals had an increase in the AT2R expression. Conclusions: AT2R stimulation using C21 improves stroke outcome in ovary-intact female rats.

Sema4D/PlexinB1 inhibition ameliorates blood-brain barrier damage and improves outcome after stroke in rats.

The inflammatory process in stroke is the major contributor to blood-brain barrier (BBB) breakdown. Previous studies indicated that semaphorin 4D (Sema4D), an axon guidance molecule, initiated inflammatory microglial activation and disrupted endothelial function in the CNS. However, whether Sema4D disrupts BBB integrity after stroke remains unclear. To study the effect of Sema4D on BBB disruption in stroke, rats were subjected to transient middle cerebral artery occlusion and targeted injection of lentivirus-mediated clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene disruption of PlexinB1. We found that Sema4D synchronously increased with BBB permeability and accumulated in the perivascular area after stroke. Suppressing Sema4D/PlexinB1 signaling in the periinfarct cortex significantly decreased BBB permeability as detected by MRI and fibrin deposition, and thereby improved stroke outcome. In vitro, we confirmed that Sema4D disrupted BBB integrity and endothelial tight junctions. Moreover, we found that Sema4D induced pericytes to acquire a CD11b-positive phenotype and express proinflammatory cytokines. In addition, Sema4D inhibited AUF1-induced proinflammatory mRNA decay effect. Taken together, our data provides evidence that Sema4D disrupts BBB integrity and promotes an inflammatory response by binding to PlexinB1 in pericytes after transient middle cerebral artery occlusion. Our study indicates that Sema4D may be a novel therapeutic target for treatment in the acute phase of stroke.-Zhou, Y.-F., Li, Y.-N., Jin, H.-J., Wu, J.-H., He, Q.-W., Wang, X.-X., Lei, H., Hu, B. Sema4D/PlexinB1 inhibition ameliorates blood-brain barrier damage and improves outcome after stroke in rats.

Prehospital Notification Procedure Improves Stroke Outcome by Shortening Onset to Needle Time in Chinese Urban Area.

Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) can improve clinical outcome in eligible patients with acute ischemic stroke (AIS). However, its efficacy is strongly time-dependent. This study was aimed to examine whether prehospital notification by emergency medical service (EMS) providers could reduce onset to needle time (ONT) and improve neurological outcome in AIS patients who received IVT. We prospectively collected the consecutive clinical and time data of AIS patients who received IVT during one year after the initiation of prehospital notification procedure (PNP). Patients were divided into three groups, including patients that transferred by EMS with and without PNP and other means of transportation (non-EMS). We then compared the effect of EMS with PNP and EMS use only on ONT, and the subsequent neurological outcome. Good outcome was defined as modified Rankin Scale score of 0-2 at 3-months. In 182 patients included in this study, 77 (42.3%) patients were transferred by EMS, of whom 41 (53.2%) patients entered PNP. Compared with non-EMS group, EMS without PNP group greatly shortened the onset to door time (ODT), but EMS with PNP group showed both a significantly shorter DNT (41.3 ± 10.7 min vs 51.9±23.8 min, t=2.583, p=0.012) and ODT (133.2 ± 90.2 min vs 174.8 ± 105.1 min, t=2.228, p=0.027) than non-EMS group. Multivariate analysis showed that the use of EMS with PNP (OR=2.613, p=0.036), but not EMS (OR=1.865, p=0.103), was independently associated with good outcome after adjusting for age and baseline NIHSS score. When adding ONT into the regression model, ONT (OR=0.994, p=0.001), but not EMS with PNP (OR=1.785, p=0.236), was independently associated with good outcome. EMS with PNP, rather than EMS only, improved stroke outcome by shortening ONT. PNP could be a feasible strategy for better stroke care in Chinese urban area.

How Nurses Can Partner With National Institutes of Health StrokeNet to Deliver Best Research and Care to Stroke Patients.

The National Institutes of Health (NIH) StrokeNet is a cooperative research network supported by National Institute of Neurological Disorders and Stroke and was established to facilitate maximization of efficiencies in stroke treatments. The main components include the National Coordinating Center at the University of Cincinnati, the National Data Management Center at the Medical University of South Carolina, and 25 Regional Coordinating Centers across the United States. Site selection is based on many criteria, a few being strong stroke research abilities and geographical location. The network was NIH funded and began building its infrastructure in 2013.1 Centers are submitting competitive renewal applications in the fall of 2017 for a second 5-year award. Benefits of the stroke research network are beginning to come to fruition. For decades, bedside and clinic nurses have inadvertently been exposed to clinical research involving alteplase and other investigational interventions to improve stroke outcomes. Nurses’ learning has likely been enhanced by working with various treatments and the need to acquire keen assessment skills. Benefits of first-hand involvement have increased understanding of processes, such as urgency of treatment times and risks of bleeding. These components are now recognized as stroke care standards.2 Guideline development by a group of experienced research nurses has facilitated knowledge dissemination.3 It is difficult to imagine that even indirect exposure to investigational treatments does not benefit nurses and ultimately patients. Being at the forefront of stroke research continues to have potential to expose nurses to the next generation of clinical practice. Comprehensive stroke centers are required by The Joint Commission to demonstrate use of evidence-based care stroke guidelines and participate in research.4 Nurses play a significant role in research and in strategies to limit bias and enhance objectivity of an investigation. However, there are times when nurses may struggle ethically with …

Selection bias in clinical stroke trials depending on ability to consent

BackgroundClinical trials are the hallmark of evidence-based medicine, but recruitment is often challenging, especially in stroke trials investigating patients not being able to give informed consent. In some nations, ethics committees will not approve of inclusion in a clinical study via consent of a legal representative. The ethical dilemma of including or excluding those patients has not been properly addressed, as there is little data on the effect of stroke characteristics on the ability to give informed consent.MethodsTo examine differences between patients able and unable to consent at inclusion to an acute stroke trial, we conducted a post-hoc analysis of monitoring records from a multicentric interventional trial. These records listed patients who gave informed consent by themselves and those who needed a legal representative to do so. This exemplary STRAWINSKI trial aimed at improving stroke outcome by biomarker-guided antibiotic treatment of stroke associated pneumonia and included patients within 40 h after stroke onset, suffering from MCA infarctions with an NIHSS score > 9 at admission. Standard descriptive and associative statistics were calculated to compare baseline characteristics and outcome measures between patients who were able to consent and those who were not.ResultsWe identified the person giving consent in 228 out of 229 subjects. Patients with inability to consent were older (p < 0.01), suffered from more left-hemispheric (p < 0.01) and more severe strokes (NIHSS, p < 0.01), were more likely to die during hospitalisation (p < 0.01) or have unfavourable outcome at discharge (mRS, p < 0.01), to develop fever (p < 0.01) and tended to be more susceptible to infections (p = 0.06) during the acute course of the disorder.ConclusionsDemographics, stroke characteristics and outcomes significantly affect stroke patients in their ability to consent. Where selection criteria and primary outcome measures of a trial are significantly affected by ability to consent, excluding patients unable to consent might be unethical.Trial registrationURL http://www.clinicaltrials.gov. Unique identifier: NCT01264549.

New Opportunities of Endovascular Recanalization Techniques in the Management of Ischemic Stroke

Currently, there are a limited number of treatments for ischemic stroke. Intravenous thrombolytic therapy is the most effective method. However, its efficacy is very low in the case of stroke caused by occlusion of large intracranial arteries. Previous studies of endovascular recanalization techniques in the treatment of stroke, particularly randomized controlled trials (RCTs), such as IMS-3, SYNTHESIS Expansion, and MR RESCUE, have shown negative results. The results of other RCTs (MR CLEAN, ESCAPE, EXTENDIA, SWIFT PRIME, and REVASCAT) published in 2015 demonstrated that, in the case of careful selection of patients with verified occlusion of large intracranial arteries, endovascular recanalization significantly improves stroke outcomes.

LDL receptor blockade reduces mortality in a mouse model of ischaemic stroke without improving tissue-type plasminogen activator-induced brain haemorrhage: towards pre-clinical simulation of symptomatic ICH

BackgroundSymptomatic intracerebral haemorrhage (sICH) following tissue-type plasminogen activator (rt-PA) administration is the most feared and lethal complication of thrombolytic therapy for ischaemic stroke, creating a significant obstacle for a broader uptake of this beneficial treatment. rt-PA also undermines cerebral vasculature stability in a multimodal process which involves engagement with LDL receptor-related protein 1 (LRP-1), potentially underlying the development of sICH.Aims and methodsWe aimed to simulate rt-PA-induced haemorrhagic transformation (HT) in a mouse model of stroke and to assess if it drives symptomatic neurological deterioration and whether it is attenuated by LDL receptor blockade. rt-PA (10 mg/kg) or its vehicle, with or without the LDL receptor antagonist, receptor-associated protein (RAP; 2 mg/kg), were intravenously injected at reperfusion after 0.5 or 4 h of middle cerebral artery occlusion (MCAo). Albumin and haemoglobin content were measured in the perfused mouse brains 24 h post MCAo as indications of blood–brain barrier (BBB) compromise and HT, respectively.Resultsrt-PA did not elevate brain albumin and haemoglobin levels in sham mice or in mice subjected to 0.5 h MCAo. In contrast, administration of rt-PA after prolonged MCAo (4 h) caused a marked increase in HT (but similar changes in brain albumin) compared to vehicle, mimicking the clinical shift from a safe to detrimental intervention. Interestingly, this HT did not correlate with functional deficit severity at 24 h, suggesting that it does not play a symptomatic role in our mouse stroke model. Co-administration of RAP with or without rt-PA reduced mortality and neurological scores but did not effectively decrease brain albumin and haemoglobin levels.ConclusionDespite the proven causative relationship between severe HT and neurological deterioration in human stroke, rt-PA-triggered HT in mouse MCAo does not contribute to neurological deficit or simulate sICH. Model limitations, such as the long duration of occlusion required, the type of HT achieved and the timing of deficit assessment may account for this mismatch. Our results further suggest that blockade of LDL receptors improves stroke outcome irrespective of rt-PA, blood–brain barrier breakdown and HT.

If Time Is Brain Where Is the Improvement in Prehospital Time after Stroke?

Despite the availability of thrombolytic and endovascular therapy for acute ischemic stroke, many patients are ineligible due to delayed hospital arrival. The identification of factors related to either early or delayed hospital arrival may reveal potential targets of intervention to reduce prehospital delay and improve access to time-critical thrombolysis and clot retrieval therapy. Here, we have reviewed studies reporting on factors associated with either early or delayed hospital arrival after stroke, together with an analysis of stroke onset to hospital arrival times. Much effort in the stroke treatment community has been devoted to reducing door-to-needle times with encouraging improvements. However, this review has revealed that the median onset-to-door times and the percentage of stroke patients arriving before the logistically critical 3 h have shown little improvement in the past two decades. Major factors affecting prehospital time were related to emergency medical pathways, stroke symptomatology, patient and bystander behavior, patient health characteristics, and stroke treatment awareness. Interventions addressing these factors may prove effective in reducing prehospital delay, allowing prompt diagnosis, which in turn may increase the rates and/or efficacy of acute treatments such as thrombolysis and clot retrieval therapy and thereby improve stroke outcomes.

The PRE-hospital Stroke Treatment Organization.

Background The PRE-hospital Stroke Treatment Organization was formed in 2016 as an international consortium of medical practitioners involved in pre-hospital treatment of patients with acute stroke. Aims PRE-hospital Stroke Treatment Organization's mission is to improve stroke outcomes by supporting research and advocacy for pre-hospital stroke treatment in Mobile Stroke Units. PRE-hospital Stroke Treatment Organization will provide a platform to enhance collaborative research across the spectrum of acute stroke management in the pre-hospital setting. PRE-hospital Stroke Treatment Organization will also facilitate the appropriate proliferation and distribution of Mobile Stroke Units by providing a forum for professional communication, resource for public education, and stimulus for government, industry, and philanthropic support. Summary of review In this "white paper", we describe the evidence supporting pre-hospital stroke treatment, progress to date, practical issues such as application in various environments and staffing, planned research initiatives, and organizational structure. Conclusions PRE-hospital Stroke Treatment Organization is not-for-profit, with membership open to anyone involved (or hoping to become involved) in pre-hospital stroke care. PRE-hospital Stroke Treatment Organization has a Steering Committee comprised of members from Europe, U.S., Canada, Australia, and other regions having a Mobile Stroke Unit in operation. PRE-hospital Stroke Treatment Organization convenes satellite meetings for membership at the International Stroke Conference and European Stroke Congress each year to address the PRE-hospital Stroke Treatment Organization mission. The first research collaborations agreed upon are to: (1) develop a list of common data elements to be collected by all Mobile Stroke Unit programs and entered into a common research database, and (2) develop a protocol for investigating the natural history of hyper-acute Intracerebral Hemorrhage.

Abstract P119: Hypertension Trends in Florida Stroke Patients. The Florida Puerto Rico Collaboration to Reduce Stroke Disparities

Aim: To describe hypertension prevalence (HTN) in a race diverse stroke registry and investigate associated presentation in patients admitted for acute ischemic stroke (AIS) and hemorrhagic stroke in Florida hospitals participating in the Florida Collaboration to Reduce Stroke Disparities (CReSD). Background: HTN affects about 30% of U.S. adults and this prevalence doubles among stroke survivors. HTN is a major risk factor for incident stoke and recurrent stroke. Quantifying the prevalence of HTN in stroke survivors is important to guide secondary stroke prevention. Methods: 121,333 stroke cases were analyzed from 69 FL hospitals participating in the AHA Get With the Guidelines-Stroke Program and FL CReSD Stroke Registry. Hypertension was defined as systolic blood pressure &gt;140mmHg. Demographics and CV risk factors were collected at admission. We investigated the differences in HTN prevalence between race groups: white (65%), black (20%) and Hispanic (15%) as well as between age groups: 18-60, 61-80 and &gt;80 years old. Temporal trends of HTN prevalence were also analyzed from 2010 to 2016. Results: In our stroke population, mean age was 70±15 and 60,667 were women (50%). HTN prevalence was 65% (78,553/121,333). Patients with HTN were significantly older (mean age 72±14 vs. 67±16 in non-HTN patients) and presented significantly higher prevalence of other CV risk factors such as diabetes, hyperlipidemia and had more previous stroke/TIAs. Women had greater prevalence of HTN (66% vs. 64% in males) in all age groups. Greater HTN prevalence was in blacks (70%) compared to white (64%) and Hispanics (58%) in all age groups. Interestingly, a significantly higher prevalence of HTN was found in AIS compared to hemorrhagic stroke but a higher SBP was observed in hemorrhagic strokes compared to AIS. Prevalence of HTN decreased of 8% from 2010 to 2016. Largest decline was observed among women (9%) and blacks (13%). Conclusions: In our large Stroke Registry we observed higher prevalence of HTN in women, blacks and AIS. We also observe a decreasing trend over the past 7 years, especially among women and minorities (blacks and Hispanics). These findings provide an opportunity to design and implement interventions to reduce disparities in HTN and improve stroke outcome.

Is age a key factor contributing to the disparity between success of neuroprotective strategies in young animals and limited success in elderly stroke patients? Focus on protein homeostasis

Neuroprotection strategies to improve stroke outcome have been successful in the laboratory but not in clinical stroke trials, and thus have come under scrutiny by the medical community. Experimental stroke investigators are therefore under increased pressure to resolve this problem. Acute ischemic stroke represents a severe form of metabolic stress that activates many pathological processes and thereby impairs cellular functions. Traditionally, neuroprotection strategies were designed to improve stroke outcome by interfering with pathological processes triggered by ischemia. However, stroke outcome is also dependent on the brain’s capacity to restore cellular functions impaired by ischemia, and this capacity declines with age. It is, therefore, conceivable that this age-dependent decline in the brain’s self-healing capacity contributes to the disparity between the success of neuroprotective strategies in young animals, and limited success in elderly stroke patients. Here, prosurvival pathways that restore protein homeostasis impaired by ischemic stress should be considered, because their capacity decreases with increasing age, and maintenance of proteome fidelity is pivotal for cell survival. Boosting such prosurvival pathways pharmacologically to restore protein homeostasis and, thereby, cellular functions impaired by ischemic stress is expected to counterbalance the compromised self-healing capacity of aged brains and thereby help to improve stroke outcome.

Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery.

Exogenous human neural progenitor cells (hNPCs) are promising stroke therapeutics, but optimal delivery conditions and exact recovery mechanisms remain elusive. To further elucidate repair processes and improve stroke outcomes, we developed an electrically conductive, polymer scaffold for hNPC delivery. Electrical stimulation of hNPCs alters their transcriptome including changes to the VEGF-A pathway and genes involved in cell survival, inflammatory response, and synaptic remodeling. In our experiments, exogenous hNPCs were electrically stimulated (electrically preconditioned) via the scaffold 1 day prior to implantation. After invitro stimulation, hNPCs on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. Electrically preconditioned hNPCs improved functional outcomes compared to unstimulated hNPCs or hNPCs where VEGF-A was blocked during invitro electrical preconditioning. The ability to manipulate hNPCs via a conductive scaffold creates a new approach to optimize stem cell-based therapy and determine which factors (such as VEGF-A) are essential for stroke recovery.

Telehealth, Wearable Sensors, and the Internet: Will They Improve Stroke Outcomes Through Increased Intensity of Therapy, Motivation, and Adherence to Rehabilitation Programs?

Stroke, predominantly a condition of older age, is a major cause of acquired disability in the global population and puts an increasing burden on health care resources. Clear evidence for the importance of intensity of therapy in optimizing functional outcomes is found in animal models, supported by neuroimaging and behavioral research, and strengthened by recent meta-analyses from multiple clinical trials. However, providing intensive therapy using conventional treatment paradigms is expensive and sometimes not feasible because of social and environmental factors. This article addresses the need for cost-effective increased intensity of practice and suggests potential benefits of telehealth (TH) as an innovative model of care in physical therapy. We provide an overview of TH and present evidence that a web-supported program, used in conjunction with constraint-induced therapy (CIT), can increase intensity and adherence to a rehabilitation regimen. The design and feasibility testing of this web-based program, "LifeCIT," is presented. We describe how wearable sensors can monitor activity and provide feedback to patients and therapists. The methodology for the development of a wearable device with embedded inertial and mechanomyographic sensors, algorithms to classify functional movement, and a graphical user interface to present meaningful data to patients to support a home exercise program is explained. We propose that wearable sensor technologies and TH programs have the potential to provide most-effective, intensive, home-based stroke rehabilitation.

A high-urgency stroke code reduces in-hospital delays in acute ischemic stroke: a single-centre experience.

Timely treatment is essential in acute ischemic stroke as the chances of recovery diminish over time, so efforts are necessary to streamline in-hospital pathways and reduce delays. Here, we analyse the interventions to reduce door-to-needle time in stroke patients suitable for intravenous thrombolysis at the Emergency Department of San Carlo Borromeo Hospital, Milan, Italy. All stroke patients consecutively treated with intravenous thrombolysis at our centre from January 1, 2013 to December 31, 2015 were included in this analysis. The main interventions adopted were (1) continuous education of personnel, (2) reconsideration of blood tests and identify the ones really affecting treatment decision, (3) approval of a new high-urgency Stroke Code activated as soon as the triage nurse comes to know of a potential thrombolysis candidate. Median door-to-needle time progressively decreased from 103min (iqr 78-120) in 2013, to 92min (iqr 72-112) in 2014, and to 37min (iqr 27-58) with the new Stroke Code (p<0.001) in 2015. Simultaneously, median onset-to-treatment time decreased from 177min (iqr 142-188) in 2013, to 155min (iqr 141-198) in 2014, and to 114min (iqr 86-160) with the new Stroke Code (p<0.001 and p 0.005, respectively). We did not observe any significant difference in bleeding risks or deaths, whereas the likelihood of favourable outcome (mRS 0-2) increased. Streamlining in-hospital pathways with progressive interventions significantly decreases door-to-needle time and onset-to-treatment time and may contribute to improve stroke outcomes.

Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension.

Stroke is a leading cause of adult disability worldwide. Improving stroke outcome requires an orchestrated interplay that involves up regulation of pro-survival pathways and a concomitant suppression of pro-apoptotic mediators. In this investigation, we assessed the involvement of eNOS in the AT1 blocker-mediated protective and pro-recovery effects in animals with hypertension. We also evaluated the effect of acute eNOS inhibition in hypertensive animals. To achieve these goals, spontaneously hypertensive rats (SHR) were implanted with blood pressure transmitters, and randomized to receive either an eNOS inhibitor (L-NIO) or saline one hour before cerebral ischemia induction. After 3 hours of ischemia, animals were further randomized to receive either candesartan or saline at the time of reperfusion and sacrificed either 24 hours or 7 days later. Candesartan induced an early protective effect that was independent of eNOS inhibition (50% improvement in motor function). However, the protective effect of candesartan was associated with about five fold up regulation of BDNF expression and about three fold reduction in ER stress markers, in an eNOS dependent manner. The early benefit of a single dose of candesartan, present at 24 hours after stroke, was diminished at 7 days, perhaps due to a failure to induce an angiogenic response in these hypertensive animals. In conclusion, our findings demonstrate an early prorecovery effect of candesartan at both functional and molecular levels. Candesartan induced prorecovery signaling was mediated through eNOS. This effect was not maintained at 7 days after experimental ischemia.

Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.

Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for poststroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10-12 month old), acyclic female rats were injected with recombinant adeno-associated virus serotype 5 (AAV5) packaged with the coding sequence of the human (h)IGF-1 gene downstream of an astrocyte-specific promoter glial fibrillary acidic protein (GFAP) (AAV5-GFP-hIGF-1) into the striatum and cortex. The AAV5-control consisted of an identical shuttle vector construct without the hIGF-1 gene (AAV5-GFAP-control). Six to eight weeks later, animals underwent transient (90 min) middle cerebral artery occlusion via intraluminal suture. While infarct volume was not altered, AAV5-GFAP-hIGF-1 treatment significantly improved blood pressure and neurological score in the early acute phase of stroke (2 days) and sensory-motor performance at both the early and late (5 days) acute phase of stroke. AAV5-GFAP-hIGF-1 treatment also reduced circulating serum levels of GFAP, a biomarker for blood brain barrier permeability. Flow cytometry analysis of immune cells in the brain at 24 hr poststroke showed that AAV5-GFAP-hIGF-1 altered the type of immune cells trafficked to the ischemic hemisphere, promoting an anti-inflammatory profile. Collectively, these studies show that targeted enhancement of IGF-1 in astrocytes of middle-aged females improves stroke-induced behavioral impairment and neuroinflammation.

Increased infections with β-blocker use in ischemic stroke, a β2-receptor mediated process?

Strokes promote immunosuppression, partially from increased sympathetic activity. Altering sympathetic drive with β-blockers has variably been shown to improve stroke outcomes. This study adds to this literature using propensity score matching to limit confounding and by examining the effects of selective and non-selective β-blockers. Prospective data from acute ischemic stroke admissions at a single center from July 2010-June 2015 were analyzed. Outcomes included infection (urinary tract infection [UTI], pneumonia, or bacteremia), discharge modified Rankin Score (mRS), and in-hospital death. Any selective and non-selective β-blocker use during the first 3days of admission were investigated with propensity score matching. A sensitivity analysis was also performed. This study included 1431 admissions. Any β-blocker use was associated with increased infections (16.4 vs. 10.7%, p=0.030). Non-selective β-blocker use was associated with increased infections (18.9 vs. 9.7%, p=0.005) and UTIs (13.0 vs. 5.5%, p=0.009). Selective β-blocker use was not associated with infection. There were no associations between β-blocker use and in-hospital death or discharge mRS. In the sensitivity analysis, the association between non-selective β-blocker use and urinary tract infections persisted (12.5 vs. 4.2%, p=0.044). No associations with death or mRS were found. Early β-blocker use after ischemic stroke may increase the risk ofinfection but did not change disability or mortality risk. The mechanism may be mediated by β2-adrenergic receptor antagonism given the different effects seen with selective versus non-selective β-blocker use.

Abstract WP296: Short Term Acute Preconditioning Exercise Improves Stroke Outcomes and Reduces Neurovascular Injury via Increased Endothelial Nitric Oxide Synthase Activity

Physical exercise is becoming a prominent therapeutic strategy to improve stroke outcomes. It was previously shown that long term exercise reduces infarct volume, but this was never tested in acute short term preconditioning exercise in a thromboembolic model of stroke. Exercise induced shear stress improves vascular function through increased activity of endothelial nitric oxide synthase (eNOS) and its upstream principal activator, AMP-activated protein kinase (AMPK). However, this was not previously tested in a stroke setting. Accordingly, we tested the hypothesis that acute short term preconditioning exercise improves stroke outcomes through increased AMPK and eNOS activity. Methods: Male Wistar rats (300g) were subjected to treadmill exercise for four days (25 minutes/day), break for 2 days and then one acute bout for 30 minutes. Exercised animals were subjected to thromboembolic stroke at 1h, 6h or 24h after the last exercise session. At 24h, control (sedentary) and exercised rats were tested for neurological outcomes, infarct size and edema. Western Blotting was used to measure the expression of active eNOS (p-S1177-eNOS) and active AMPK (p-T172-AMPK). Results: Acute exercise significantly reduced infarct size and edema and improved functional outcomes compared to control. It also significantly increased the expression of peNOS and pAMPK in the brain, cerebral vessels and aorta (Table). Conclusion: Acute exercise preconditioning significantly reduced neurovascular injury and improved functional outcome after stroke through increased eNOS activity. Our findings are novel to point out the role of preconditioning exercise induced AMPK and eNOS activation in improving stroke outcomes.