Abstract P781: Ischemic Postconditioning Protects Against Hemorrhagic Transformation Induced by Hyperglycemia in Ischemic Stroke

Background: Hyperglycemia occurs in over 40% of ischemic stroke patients, which induces hemorrhagic transformation (HT) and worsens stroke outcomes. The management of hyperglycemia with insulin did not show favorable outcomes. Thus, strategies for managing hyperglycemia-exacerbated stroke injury are urgently needed. We previously demonstrated that ischemic postconditioning (IPostC) (repeated transient interruption of cerebral blood flow during reperfusion) can reduce brain infarct size and improve neurological outcomes. In this study, we hypothesized that IPostC can reduce HT in ischemic stroke with acute hyperglycemia. Method: Male mice were subjected to middle cerebral artery occlusion (MCAO) for 1 hour, followed by reperfusion to mimic ischemic stroke. Glucose was injected before MCAO to induce hyperglycemia. IPostC was initiated upon reperfusion with 3 cycles of 30-second reperfusion followed by 10 seconds of MCA occlusion. Brain infarct was visualized by TTC staining and quantitated using Image J. Hemorrhagic transformation was evaluated by hemorrhagic scores. Result: Acute hyperglycemia significantly increased the brain infarct size (by 25%, p<0.01), brain edema (p<0.001) and hemorrhagic transformation (HT) (average HT scores: 0.75 in MCAO group vs 15.6 in MCAO plus hyperglycemia group, p<0.001), Mice with hyperglycemia also exhibited more severe neurological deficit and higher mortality rate at 24 hours after MCAO. 2) IPostC treatment significantly reduced brain infarct size (p<0.01), brain edema (p<0.05) and attenuated HT (p<0.001). Neurological deficit and mortality rate was reduced with IPostC treatment. Conclusion: Our findings suggest that IPostC can counteract the effects of acute hyperglycemia and reduce brain injury, edema and HT after stroke. Grant/Other Support: NIH Grant R01NS064136C

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The Hsp90 Inhibitor 17-DMAG Attenuates Hyperglycemia-Enhanced Hemorrhagic Transformation in Experimental Stroke

BioMed Research International ◽

10.1155/2021/6668442 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Jiaming Zhang ◽

Kai Wang ◽

Jia Qi ◽

Xiaodong Cao ◽

Feng Wang

Keyword(s):

Ischemic Stroke ◽

Hsp90 Inhibitor ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Vital Role ◽

Experimental Stroke ◽

Acute Hyperglycemia ◽

Inflammatory Molecules ◽

Cerebral Artery Occlusion ◽

The Brain

Introduction. Hemorrhagic transformation (HT) is one of the most common complications of ischemic stroke which is exacerbated by hyperglycemia. Oxidative stress, inflammatory response, and matrix metalloproteinases (MMPs) have been evidenced to play a vital role in the pathophysiology of HT. Our previous study has reported that 17-DMAG, an Hsp90 inhibitor, protects the brain against ischemic injury via inhibiting inflammation and reducing MMP-9 after ischemia. However, whether 17-DMAG would attenuate HT in hyperglycemic middle cerebral artery occlusion (MCAO) rats is still unknown. Methods. Acute hyperglycemia was induced by an injection of 50% dextrose. Rats were pretreated with 17-DMAG before MCAO. Infarction volume, hemorrhagic volume neurological scores, expressions of inflammatory molecules and tight junction proteins, and activity of MMP-2 and MMP-9 were assessed 24 h after MCAO. Results. 17-DMAG was found to reduce HT, improve neurological function, and inhibit expressions of inflammatory molecules and the activation of MMPs at 24 h after MCAO. Conclusion. These results implicated that Hsp90 could be a novel therapeutic target in HT following ischemic stroke.

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Abstract WMP81: Low Dose tPA Worsens The Short Term Outcomes After Thromboembolic Stroke In Both Male And Female Diabetic Animals

Stroke ◽

10.1161/str.48.suppl_1.wmp81 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Weiguo Li ◽

John Paul Valenzuela ◽

Guangkuo Dong ◽

Rebecca Ward ◽

Susan C Fagan ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Size ◽

Functional Outcome ◽

Low Dose ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Diabetic Rats ◽

Embolic Stroke ◽

Neurological Deficits ◽

Male And Female

Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tPA treatment. We previously showed that low dose tPA decreased infarct size and improved functional outcome in both male and female control rats with embolic stroke. In the current study, we hypothesized that low dose tPA will also improve the functional recovery after the embolic stroke in both male and female animals with diabetes. Diabetes was induced in age matched male and female Wistar rats with high fat diet and low dose streptozotocin (30 mg/kg, i.p.). Embolic stroke was induced with middle cerebral artery occlusion. The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. The blood flow has increased in the tPA treated animals in the first 1 to 1.5 hr after treatment. The infarct size and edema was not significantly different in untreated animals, but HT was greater in female diabetic rats. The tPA treatment worsened HT in both genders with no change in infarct size. Decline in ART was worsened with tPA treatment in both sexes. Our data suggest that the low dose tPA after ischemic stroke has detrimental effects on the cerebrovascular recovery and functional outcome in both male and female animals with diabetes.

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Inducing Hemorrhagic Transformation Following Middle Cerebral Artery Occlusion via Acute Hyperglycemia in Rats

Springer Series in Translational Stroke Research - Animal Models of Acute Neurological Injury ◽

10.1007/978-3-030-16082-1_12 ◽

2019 ◽

pp. 173-187

Author(s):

Devin W. McBride ◽

Derek Nowrangi ◽

Wing Mann Ho ◽

Jiping Tang ◽

John H. Zhang

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Acute Hyperglycemia ◽

Cerebral Artery Occlusion

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Abstract W P63: Intravenous Thrombolysis for Acute Ischemic Stroke in Nonagenarians

Stroke ◽

10.1161/str.46.suppl_1.wp63 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Raul Guisado ◽

Reza Malek ◽

Ursula Kelly-Tolley ◽

Arash Padidar ◽

Harmeet Sachdev

Keyword(s):

Ischemic Stroke ◽

Mortality Rate ◽

Acute Ischemic Stroke ◽

Ct Perfusion ◽

Intravenous Thrombolysis ◽

Hemorrhagic Transformation ◽

Early Improvement ◽

Hospital Patients ◽

Contrast Ct ◽

Overall Mortality

The safety and effectiveness of intravenous thrombolysis for acute ischemic stroke (AIS) has been established for populations older than 80 years of age . However, management of AIS in nonagenerians is not clear. Previous reports suggest that the rate of ICH after i.v. alteplase is not increased and the rate of early improvement is similar in nonagenerians compared to younger groups, but there is concern with overall mortality and functional outcomes. We report on 20 consecutive patients with AIS treated with i.v. alteplase within 3 hours of onset in two Comprehensive Stroke Centers in San Jose, CA. Methods: Patients were immediately evaluated by members of the Stroke Team of each hospital. . Patients were eligible if they had disabling neurological symptoms, no contraindications for i.v.alteplase and were independent in ADLs prior to the index event. Non-contrast CT brain scan, CT perfusion and CT angiography of head and neck were used to determine the presence of potentially salvageable brain. Results (Table): Mean age was 91 years (range 90 - 98 years). The initial NIHSS was 15.7 ± 6.8. The median NIHSS at hospital discharge was 7.4 ± 8.4 (p <0.001). The median door to needle time was 50.5 minutes (range 36 - 74 minutes). There was no hemorrhagic transformation and no in-hospital mortality. The overall mortality rate at 90 days was 30% (6 of 20 patients) and the rate of good outcome in survivors, defined as mRS ≤ 3 at 90 days was 35.7% (5 of 14 patients). Comment: Intravenous thrombolysis for ischemic stroke in nonagenerians is safe and effective, with good rates of immediate improvement. However, the l90 days mortality rate is high and the long term functional outcome is poor. This data can be useful in helping families make treatment decisions in the most elderly patients with acute ischemic stroke.

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Abstract T P229: Deletion of Voltage Gated Proton Channel in Microglial Cells is Neurovascular Protective After Ischemic Brain Injury

Stroke ◽

10.1161/str.46.suppl_1.tp229 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Weiguo Li ◽

Becca Ward ◽

Mohammed Abdelsaid ◽

Tianzheng Yu ◽

Yisang Yoon ◽

...

Keyword(s):

Ischemic Stroke ◽

Ischemia Reperfusion ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Proton Channel ◽

Ros Generation ◽

Vascular Integrity ◽

Voltage Gated ◽

Underlying Mechanisms ◽

Cerebral Artery Occlusion

Despite the failure of antioxidant treatments in clinical trials, the undoubted role of reactive oxygen species (ROS) in neurovascular damage after ischemic stroke calls for a more targeted approach. ROS production by microglia, the primary resident immune cells in the brain, is a key event of this process in ischemic stroke. Voltage gated proton channel, Hv1, is localized primarily to microglia and sustains NADPH oxidase activity. Deletion of Hv1 is neuroprotective after permanent middle cerebral artery occlusion (MCAO). We hypothesized that Hv1-mediated microglial ROS generation is also critical for vascular integrity and contributes to reperfusion injury after transient ischemic stroke. The wildtype (WT) and Hv1 knockout (KO) rats (n=4) were subjected to permanent or 3/24 h transient MCAO. The neurological deficiency, infarct, hemorrhagic transformation, and edema ratio were assessed. We found that in both permanent and transient MCAO model, KO rats develop smaller infarct, less vascular injury, edema, and hemorrhagic transformation, resulting in better short-term functional outcome. These results suggest that deletion of microglial Hv1 channel is vasculoprotective after ischemia/reperfusion and the underlying mechanisms need to be further studied.

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Association of Matrix Metalloproteinase 9 and Cellular Fibronectin and Outcome in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

Frontiers in Neurology ◽

10.3389/fneur.2020.523506 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lu Wang ◽

Linghui Deng ◽

Ruozhen Yuan ◽

Junfeng Liu ◽

Yuxiao Li ◽

...

Keyword(s):

Ischemic Stroke ◽

Matrix Metalloproteinase ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Brain Edema ◽

Meta Analysis ◽

Hemorrhagic Transformation ◽

Poor Outcome ◽

Metalloproteinase 9 ◽

Cellular Fibronectin

Introduction: The role of matrix metalloproteinase 9 (MMP-9) and cellular fibronectin (c-Fn) in acute ischemic stroke is controversial. We systematically reviewed the literature to investigate the association of circulating MMP-9 and c-Fn levels and MMP-9 rs3918242 polymorphism with the risk of three outcome measures after stroke.Methods: We searched English and Chinese databases to identify eligible studies. Outcomes included severe brain edema, hemorrhagic transformation, and poor outcome (modified Rankin scale score ≥3). We estimated standardized mean differences (SMDs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs).Results: Totally, 28 studies involving 7,239 patients were included in the analysis of circulating MMP-9 and c-Fn levels. Meta-analysis indicated higher levels of MMP-9 in patients with severe brain edema (SMD, 0.76; 95% CI, 0.18–1.35; four studies, 419 patients) and hemorrhagic transformation (SMD, 1.00; 95% CI, 0.41–1.59; 11 studies, 1,709 patients) but not poor outcome (SMD, 0.30; 95% CI, −0.12 to 0.72; four studies, 759 patients). Circulating c-Fn levels were also significantly higher in patients with severe brain edema (SMD, 1.55; 95% CI, 1.18–1.93; four studies, 419 patients), hemorrhagic transformation (SMD, 1.75; 95% CI, 0.72–2.78; four studies, 458 patients), and poor outcome (SMD, 0.46; 95% CI, 0.16–0.76; two studies, 210 patients). Meta-analysis of three studies indicated that the MMP-9 rs3918242 polymorphism may be associated with hemorrhagic transformation susceptibility under the dominant model (TT + CT vs. CC: OR, 0.621; 95% CI, 0.424–0.908; P = 0.014). No studies reported the association between MMP-9 rs3918242 polymorphism and brain edema or functional outcome after acute stroke.Conclusion: Our meta-analysis showed that higher MMP-9 levels were seen in stroke patients with severe brain edema and hemorrhagic transformation but not poor outcome. Circulating c-Fn levels appear to be associated with all three outcomes including severe brain edema, hemorrhagic transformation, and poor functional outcome. The C-to-T transition at the MMP-9 rs3918242 gene appears to reduce the risk of hemorrhagic transformation.

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Acute Hyperglycemia Is Associated with Immediate Brain Swelling and Hemorrhagic Transformation After Middle Cerebral Artery Occlusion in Rats

Acta Neurochirurgica Supplement - Brain Edema XVI ◽

10.1007/978-3-319-18497-5_42 ◽

2016 ◽

pp. 237-241 ◽

Cited By ~ 11

Author(s):

Devin W. McBride ◽

Julia Legrand ◽

Paul R. Krafft ◽

Jerry Flores ◽

Damon Klebe ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Brain Swelling ◽

Acute Hyperglycemia ◽

Cerebral Artery Occlusion

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The effect of repeated remote ischemic postconditioning on infarct size in patients with an ischemic stroke (REPOST): study protocol for a randomized clinical trial

Trials ◽

10.1186/s13063-019-3264-0 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Thijs Landman ◽

Yvonne Schoon ◽

Michiel Warlé ◽

Frank-Erik De Leeuw ◽

Dick Thijssen

Keyword(s):

Clinical Trial ◽

Ischemic Stroke ◽

Infarct Size ◽

Randomized Clinical Trial ◽

Study Protocol ◽

Ischemic Postconditioning ◽

Remote Ischemic Postconditioning

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Abstract TP33: Ischemic Stroke Outcomes in Medical vs Endovascular Treatment of Proximal Carotid Artery Occlusion

Stroke ◽

10.1161/str.47.suppl_1.tp33 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Yamin Shwe ◽

Chunyan Cai ◽

Anjail Z Sharrief ◽

Amrou Sarrraj

Keyword(s):

Ischemic Stroke ◽

Carotid Artery ◽

Endovascular Treatment ◽

Small Sample Size ◽

Retrospective Chart Review ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Carotid Artery Occlusion ◽

Small Sample ◽

Neurological Deficits

Background: Acute ischemic stroke (AIS) due to proximal carotid artery occlusion (pCAO) can be associated with significant neurological deficits and poor outcome without timely intervention and successful reperfusion. Intravenous thrombolytics (IT) have low recanalization rates in pCAO and these patients were excluded from recent randomized controlled trials which showed superiority of endovascular therapy (EVT) over IT. Purpose: The purpose of this study is to investigate clinical outcomes in AIS due to pCAO treated with medical vs. endovascular treatment. Methods: We conducted a retrospective chart review of patients who underwent IT or EVT±IT for all types of pCAO from January 2008 to June 2015. Our primary outcome was the functional outcome at discharge measured by modified Rankin score (mRS) 0-3. The secondary outcomes were hemorrhagic transformation (HT), neurological worsening (NW), symptomatic hemorrhage (sICH) and death. Logistic regression analysis was used to compare outcomes between the two groups. Results: A total of 133 patients were included in the study. Baseline characteristics are depicted in table 1. There were no significant differences between the two groups. IV tPA was given in 56% IT vs. 72% EVT (p=0.14). While there was a shift towards better outcomes in the mRS distribution in EVT group (22% vs. 16%) as shown in Figure 1, the treatment effect did not reach significance (OR 1.71, 95% CI (0.55, 5.34), p=0.35). There was also no difference in HT (26% vs. 14%, p=0.14), or NW (26% vs. 21%, p=0.6). However, sICH was higher in EVT (3.7% vs. 0%, p=0.2). Conclusion: Our study did not show difference in discharge functional outcomes between EVT and IT in AIS with pCAO. Our results are limited by small sample size and retrospective nature. Future prospective studies randomizing patients to medical vs. endovascular treatments are warranted to guide management.

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