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The authors present a case of an acute right middle cerebral artery infarct in a 65-year-old male with a history of diabetes, hypertension, and cardiovascular disease. The timeline of treatment and the evolution of the stroke is described. This case highlights the significant burden of right-sided cerebral artery stroke, even when intervention is swift. [ABSTRACT FROM AUTHOR]

Abstract Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood–brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS.

Acute ischemic stroke (AIS) is a major global health concern due to its high mortality and disability rates. Hemorrhagic transformation, a common complication of AIS, leads to poor prognosis yet lacks effective treatments. Preclinical studies indicate that hyperbaric oxygen (HBO) treatment within 12 h of AIS onset alleviates ischemia/reperfusion injuries, including hemorrhagic transformation. However, clinical trials have yielded conflicting results, suggesting some underlying mechanisms remain unclear. In this study, we confirmed that HBO treatments beginning within 1 h post reperfusion significantly alleviated the haemorrhage and neurological deficits in hyperglycemic transient middle cerebral arterial occlusion (tMCAO) mice, partly due to the inhibition of the NLRP3 inflammasome-mediated pro-inflammatory response in microglia. Notably, reactive oxygen species (ROS) mediate the anti-inflammatory and protective effect of early HBO treatment, as edaravone and N-Acetyl-l-Cysteine (NAC), two commonly used antioxidants, reversed the suppressive effect of HBO treatment on NLRP3 inflammasome-mediated inflammation in microglia. Furthermore, NAC countered the protective effect of early HBO treatment in tMCAO mice with hyperglycemia. These findings support that early HBO treatment is a promising intervention for AIS, however, caution is warranted when combining antioxidants with HBO treatment. Further assessments are needed to clarify the role of antioxidants in HBO therapy for AIS. [ABSTRACT FROM AUTHOR]

Background: Hemorrhagic transformation (HT) is a serious complication of thrombolytic therapy for acute ischemic stroke, limiting its indications and affecting treatment plans and clinical prognosis. Identifying risk factors for HT could help improve the risk–benefit ratio of thrombolytic therapy. We aimed to analyze the predictors of HT after reperfusion therapy with recombinant tissue plasminogen activator (rTPA) in patients with acute ischemic stroke. This study included 115 patients who received rTPA. All patients underwent history taking, clinical examination, neurological examination including Glasgow Coma Scale and National Institutes of Health Stroke Scale scores (NIHSS), radiological investigation, and cardiac investigation. Patients were followed up strictly every 2 h for 1st 24 h then for two weeks clinically using the NIHSS and radiologically using CT or MRI to detect HT. Results: Patients with HT represented 21.7% of all patients receiving rTPA, while symptomatic intracranial hemorrhage (sICH) represented 6.9%. Patients with HT had significantly higher blood pressure, respiratory rate, atrial fibrillation rate, NIHSS score, INR, prothrombin time, neutrophil-to-lymphocyte ratio (NLR), and lower platelet count, LDL level, higher Fazekas score, lower ASPECT score, and prolonged onset-to-needle time. Conclusion: Predicting HT in acute ischemic stroke patients is crucial for optimizing management and potentially improving outcomes. In our study, six predictors were associated with HT: higher respiratory rate, higher atrial fibrillation rate, higher NLR, lower LDL level, higher Fazekas score, lower ASPECT score, and onset-to-needle time greater than 180 min. [ABSTRACT FROM AUTHOR]

Objectives: Blood-brain barrier (BBB) disruption is an important pathological change after cerebral infarction that exacerbates brain injury. We aimed to investigate and compare the predictive utility of pre-treatment BBB permeability (BBBP) and BBBP within 1 h after endovascular treatment (EVT) for hemorrhagic transformation (HT) and 90-day prognosis. Methods: Patients underwent preoperative computed tomography perfusion (CTP) and non-contrast CT (NCCT) within 1 h after EVT. Preoperative BBBP was determined by the relative permeability surface area product (rPS) in the hypoperfusion area. Postoperative BBBP was determined by the post-EVT Alberta Stroke Program Early CT Score (Post-ASPECTS), which is based on brain parenchymal hyperdensity on the postoperative NCCT. Outcomes: We included 100 patients. Univariate logistic regression analysis revealed correlations of preoperative rPS with HT, poor outcomes, and death. However, these correlations were not observed in multivariate logistic regression. A Post-ASPECTS ≤7 and could independently predict poor outcomes, while Post-ASPECTS ≤6 could independently predict death and HT. The baseline National Institutes of Health Stroke Scale (NIHSS) score could independently predict poor outcomes and death but not HT. A combined model using the baseline NIHSS and Post-ASPECTS scores had better predictive performance for poor outcomes and death than baseline NIHSS score alone; however, it was not superior to the predictive performance of the Post-ASPECTS score. Conclusion: The preoperative rPS cannot independently predict clinical outcomes in EVT-treated patients; contrastingly, the Post-ASPECTS score could independently predict poor outcomes, death, and HT. This parameter could inform prompt postoperative treatment decisions. [ABSTRACT FROM AUTHOR]

Purpose: In the treatment of intracranial arterial stenosis (ICAS), controversies remain regarding the optimal treatment strategy. Our study aims to conduct an individual patient-level data meta-analysis of existing RCTs comparing PTAS versus best medical therapy and to identify differences in outcomes such as incidence of ischemic stroke or death. Methods: Randomised controlled trials comparing the outcomes of stenting versus best medical therapy for patients who had symptomatic ICAS of >50%. Excluded studies included case reports, case series, reviews, observational studies, letters or studies evaluating isolated angioplasty techniques without stenting. Data was extracted in accordance with PRISMA guidelines. Results: 7 studies involving 1425 participants were included. There was an increased risk in the incidence of stroke and death within the first 30 days post-procedure for patients treated with PTAS over best medical therapy (RR = 2.22 [1.28–3.86], I² = 0%). Patients who underwent stenting also had a significantly higher risk of intracranial haemorrhage (RR = 12.66 [2.41–66.45], I² = 0%) and death (RR = 5.41 [1.20–24.28], I² = 0%). Under the shared frailty model, stenting when compared to medical therapy has a HR of 1.81 (95% CI:1.25–2.6) of stroke or death across 1 year. Under the parametric Royston-Parmar model, stenting has a significant decrease in the RMST(–0.83 months; 95% CI: –1.30–0.37). Stenting continued to show worse outcomes up to the 3 year mark with a HR of 1.60 (95% CI: 1.11–2.32). Conclusions and Relevance: There is an increased risk of peri- and post-procedural stroke and death over best medical therapy in patients with symptomatic ICAS who undergo PTAS. Further work is required to refine patient selection and mitigate peri-procedural risks. [ABSTRACT FROM AUTHOR]

LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received intravenous injection of 10 mg/kg LT3001 or tPA at 1.5, 3, or 4.5 h after stroke, respectively, and the outcomes were measured at different time points after stroke by performing multi-parametric MRI, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and modified neurological severity score. Lastly, we assessed the effect of LT3001 on the tPA activity in vitro, the international normalized ratio (INR), and the serum levels of active tPA and plasminogen activator inhibitor-1 (PAI-1). LT3001 treated at 1.5 h after stroke is neuroprotective by reducing the CBF lesion size and lowering diffusion and T2 lesion size measured by MRI, which is consistent with the reduction in TTC-stained infarction. When treated at 3 h after stroke, LT3001 had significantly better therapeutic effects regarding reduction of infarct size, swelling rate, and hemorrhagic transformation compared to tPA. When treated at 4.5 h after stroke, tPA, but not LT3001, significantly increased brain swelling and intracerebral hemorrhagic transformation. Lastly, LT3001 did not interfere with tPA activity in vitro, or significantly alter the INR and serum levels of active tPA and PAI-1 in vivo. Our data suggests that LT3001 is neuroprotective in focal embolic stroke rat model. It might have thrombolytic property, not interfere with tPA/PAI-1 activity, and cause less risk of hemorrhagic transformation compared to the conventional tPA. Taken together, LT3001 might be developed as a novel therapy for treating thrombotic ischemic stroke. [ABSTRACT FROM AUTHOR]

Cerebral ischemia reperfusion (I/R) is one of the neurovascular diseases which leads to severe brain deterioration. Haemorrhagic transformation (HT) is the main complication of ischemic stroke. It exacerbates by reperfusion, causing a more deleterious effect on the brain and death. The current study explored the protective effect of sertraline (Sert) against cerebral I/R in rats by inhibiting HT, together with the molecular pathways involved in this effect. Forty-eight wister male rats were divided into 4 groups: Sham, Sert + Sham, I/R, and Sert + I/R. The ischemic model was induced by bilateral occlusion of the common carotid artery for 20 min, then reperfusion for 24 h. Sertraline (20 mg/kg, p.o.) was administrated for 14 days before exposure to ischemia. Pre-treatment with Sert led to a significant attenuation of oxidative stress and inflammation. In addition, Sert attenuated phosphorylation of extracellular regulated kinases and nuclear factor kappa—p65 expression, consequently modulating microglial polarisation to M2 phenotype. Moreover, Sert prevented the hemorrhagic transformation of ischemic stroke as indicated by the notable decrease in neuronal expression of CD163, activity of Heme oxygenase-2 and matrix metalloproteinase-2 and 9 levels. In the same context, Sert decreased levels of autophagy and apoptotic markers. Furthermore, histological examination, Toluidine blue, and Prussian blue stain aligned with the results. In conclusion, Sert protected against cerebral I/R damage by attenuating oxidative stress, inflammation, autophagy, and apoptotic process. It is worth mentioning that our study was the first to show that Sert inhibited hemorrhagic transformation. The protective effect of sertraline against injury induced by cerebral ischemia reperfusion via inhibiting Hemorrhagic transformation. [ABSTRACT FROM AUTHOR]

Background: Patients with ischemic stroke and atrial fibrillation (AF) are at high risk of developing hemorrhagic transformation (HT). The aim of the current study is to evaluate the incidence of hemorrhagic transformation and associated risk factors in a hospital-based sample with ischemic stroke and AF patients. A prospective study with a total of 234 stroke patients with AF was consecutively recruited. HT incidence was determined by computed tomography (CT) or magnetic resonance imaging (MRI). Risk factors associated with HT was identified by comparing patients with and without HT. Results: The incidence of HT in ischemic stroke with AF was 22.6%. Univariate analysis established that old age, hypertension, diabetes mellitus, anticoagulant medications, NIHSS, cerebral microbleeds (CMB), superficial siderosis (SS) and size of infarction were significantly more frequent with HT. Multivariable logistic regression analysis demonstrated that old age [odds ratio (OR): 1.05, confidence interval (CI) 1.01–1.09], size of infarction (OR: 2.57, CI 1.06–6.27) and CMB ≥ 10 (OR: 4.68, CI 1.71–12.84) were significantly associated with the risk of HT. Conclusions: Older age, larger infarction size, and CMB ≥ 10 were risk factors significantly associated with HT. [ABSTRACT FROM AUTHOR]

Ischemic stroke is one of the major causes of devastating neurological disabilities and mortality worldwide. Despite extensive research for treatment approaches, there remains limited therapy in the stroke field. Therefore, more research is required for reproducibility to understand stroke pathology in pre-clinical studies. In the current modified method, mice were subjected to photothrombotic stroke (pt-MCA; proximal-middle cerebral artery was exposed with a 532 nm laser beam for 4 min) by retro-orbital injection of photosensitive dye, Rose Bengal (15 mg/kg) before the laser light exposure. Sensorimotor deficits were assessed by rotarod and catwalk test at 72 h following post-pt-MCAO, and brain samples were collected for infarct volume and hemorrhagic transformation (HT) assessments. Cognitive impairments were assessed by a novel objective recognition and Morris's water maze tests at the end of the follow-up. pt-MCAO animals significantly reduced body weight and impaired motor and cognitive functions. Furthermore, pt-MCAO animals showed apparent infarction, brain edema, and increased HT compared to the sham animals. Additionally, this method enables concurrent measurement of short-term and long-term neurological dysfunction with relatively larger cortical and sub-cortical infarct volume following pt-MCAO. With respect to the other models, this modified model offers enhanced reproducibility regarding infarct volume and cognitive/functional outcomes and avoids complications associated with critical surgeries and craniotomy. In conclusion, this modified model helps to understand stroke pathogenesis and minimize the animals' numbers which help to increase the scientific and statistical potential in pre-clinical studies. [ABSTRACT FROM AUTHOR]

Background: Fahr's disease is a very rare inherited neurodegenerative disorder characterized by diffuse and symetric intracranial calcification of the bilateral basal ganglia and cerebellum. Although the disease is slowly progressive, several acute forms have been described. We would like to present a very rare case of Fahr's disease with an ischemic stroke and its hemorrhagic transformation. Case presentation: A 70-year-old woman presented to our emergency department with rapid cognitive decline, dysarthria and right limb weakness. Cranial computed tomography showed diffuse and symmetric hyperdense areas at the level of the bilateral dentate nuclei of cerebellar hemispheres and basal ganglia, suggestive of calcification consistent with Fahr's disease on a background of thyroidectomy history, and effacement in the left caudate region. The patient was admitted to the intensive care unit with suspected left cerebral ischemic stroke. Because of clinical deterioration with increasing drowsiness and right hemiplegia, a control computed tomography scan was performed. Upon detection of a 6 * 8 cm lesion corresponding to an intracerebral hematoma in the left temporoparietal area with intraventricular component, she underwent surgery. The patient did not become hemodynamically stable and died on post-operative day 3. Conclusions: The calcium deposits in the walls of the cerebral vessels in Fahr's disease may exacerbate inflammatory processes leading to disruption of the blood-brain barrier. In addition, peripheral blood extravasation into the disrupted blood brain barrier due to ischemic stroke may lead to hemorrhagic transformation. [ABSTRACT FROM AUTHOR]

Background and purpose: Hemorrhagic transformation (HT) is the most serious complication of intravenous thrombolysis in ischemic stroke patients. Inflammation plays a critical role in the pathological progression of HT. This study was to explore the relationship between fibrinogen-to-albumin ratio (FAR), a novel systemic inflammation biomarker, and HT after intravenous thrombolysis in patients with ischemic stroke. Methods: This retrospective study enrolled ischemic stroke patients who underwent intravenous thrombolysis between Jan 2017 to May 2022. The characteristic data of all patients at admission were retrospectively collected. The univariate and multivariate logistic regression analyses were performed to evaluate the correlation between FAR and HT after intravenous thrombolysis. The optimal cut-off value of FAR for predicting HT was determined by the receiver operating characteristic curve. Results: A total of 363 ischemic stroke patients were enrolled in the present study. Sixty-two patients had HT after intravenous thrombolysis. In multivariate regression analysis, FAR was significantly associated with HT (odds ratio [OR], 1.105; 95% confidential interval [CI], 1.029–1.186, P = 0.006). The receiver operating characteristic curve analysis indicated FAR predicts HT after intravenous thrombolysis with an AUC of 0.613 (95%CI, 0.530–0.695; P = 0.005) and an optimal cut-off value of 0.101. The correlation between FAR and HT after intravenous thrombolysis was still observed when patients were stratified according to FAR levels. A higher FAR level was independently related to the occurrence of HT after adjusting for the potential confounding factors. Conclusion: Higher FAR level was independently associated with HT after intravenous thrombolysis in patients with ischemic stroke. [ABSTRACT FROM AUTHOR]

Objective: To build a clinical–radiomics model based on noncontrast computed tomography images to identify the risk of hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) following intravenous thrombolysis (IVT). Materials and methods: A total of 517 consecutive patients with AIS were screened for inclusion. Datasets from six hospitals were randomly divided into a training cohort and an internal cohort with an 8:2 ratio. The dataset of the seventh hospital was used for an independent external verification. The best dimensionality reduction method to choose features and the best machine learning (ML) algorithm to develop a model were selected. Then, the clinical, radiomics and clinical–radiomics models were developed. Finally, the performance of the models was measured using the area under the receiver operating characteristic curve (AUC). Results: Of 517 from seven hospitals, 249 (48%) had HT. The best method for choosing features was recursive feature elimination, and the best ML algorithm to build models was extreme gradient boosting. In distinguishing patients with HT, the AUC of the clinical model was 0.898 (95% CI 0.873–0.921) in the internal validation cohort, and 0.911 (95% CI 0.891–0.928) in the external validation cohort; the AUC of radiomics model was 0.922 (95% CI 0.896–0.941) and 0.883 (95% CI 0.851–0.902), while the AUC of clinical–radiomics model was 0.950 (95% CI 0.925–0.967) and 0.942 (95% CI 0.927–0.958) respectively. Conclusion: The proposed clinical–radiomics model is a dependable approach that could provide risk assessment of HT for patients who receive IVT after stroke. Key points: Noncontrast computed tomography (NCCT) is valuable for predicting hemorrhagic transformation (HT) after intravenous thrombolysis (IVT) treatment. Machine learning is vital for predicting HT. NCCT radiomics integrated with clinical factors could facilitate predicting HT. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether hyperdense middle cerebral artery sign (HMCAS) on pretreatment no-contrast CT (NCCT) is associated with hemorrhagic transformation (HT) after endovascular thrombectomy (EVT). Methods: Patients with acute middle cerebral artery (MCA) occlusion who received EVT in three comprehensive hospitals were retrospectively evaluated. They were divided into four groups based on the presence or absence of HMCAS and corresponding CTA findings, among whom differences were compared. Univariate and multivariate logistic regression analyses were performed to investigate the association between HMCAS and HT and its subtypes. Results: 318 patients were included, among whom 149 (46.9%) had HMCAS. Patients in the proximal positive HMCAS group had higher National Institute of Health Stroke Scale scores and lower Alberta Stroke Program Early CT Scores (ASPECTS) than those in the proximal negative HMCAS group. The rate of HT was higher in the proximal positive HMCAS group than that in the proximal negative HMCAS group. In multivariate logistic regression analysis, the proximal HMCAS were independently associated with HT (adjusted OR = 2.073, 95% CI 1.211–3.551, p = 0.008) and aHT (adjusted OR = 2.271, 95% CI 1.294–3.986, p = 0.004), but not with sHT. Patients who developed HT, including aHT and sHT, had a lower rate of good outcome. Conclusion: Proximal HMCAS on initial NCCT was independently associated with aHT in patients who received EVT for acute MCA occlusion. Both aHT and sHT had a detrimental effect on clinical outcome. [ABSTRACT FROM AUTHOR]

Hyperglycemia is a risk factor for poor prognosis after acute ischemic stroke and promote the occurrence of hemorrhagic transformation (HT). The activation of P2RX7 play an important role in endotheliocyte damage and BBB disruption. Ferroptosis is a novel pattern of programmed cell death caused by the accumulation of intracellular iron and lipid peroxidation, resulting in ROS production and cell death. This study is to explore the mechanism of P2RX7 in reducing HT pathogenesis after acute ischemic stroke through regulating endotheliocyte ferroptosis. Male SD rats were performed to establish middle cerebral artery occlusion (MCAO) model injected with 50% high glucose (HG) and HUVECs were subjected to OGD/R treated with high glucose (30 mM) for establishing HT model in vivo and in vitro. P2RX7 inhibitor (BBG), and P2RX7 small interfering RNAs (siRNA) were used to investigate the role of P2RX7 in BBB after MCAO in vivo and OGD/R in vitro, respectively. The neurological deficits, infarct volume, degree of intracranial hemorrhage, integrity of the BBB, immunoblotting, and immunofluorescence were evaluated at 24 h after MCAO. Our study found that the level of P2RX7 was gradually increased after MCAO and/or treated with HG. Our results showed that treatment with HG after MCAO can aggravate neurological deficits, infarct volume, oxidative stress, iron accumulation, and BBB injury in HT model, and HG-induced HUVECs damage. The inhibition of P2RX7 reversed the damage effect of HG, significantly downregulated the expression level of P53, HO-1, and p-ERK1/2 and upregulated the level of SLC7A11 and GPX4, which implicated that P2RX7 inhibition could attenuate oxidative stress and ferroptosis of endothelium in vivo and in vitro. Our data provided evidence that the P2RX7 play an important role in HG-associated oxidative stress, endothelial damage, and BBB disruption, which regulates HG-induced HT by ERK1/2 and P53 signaling pathways after MCAO. [ABSTRACT FROM AUTHOR]

Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is frequently observed in patients with acute ischemic stroke (AIS). FVH is associated with functional outcome at 3 months in AIS patients receiving endovascular thrombectomy. In the present study, we assessed whether FVH predicted early neurological deterioration (END) and hemorrhagic transformation (HT) within 72 h in AIS patients receiving endovascular thrombectomy. We retrospectively analyzed 104 patients with acute internal-carotid-artery or proximal middle-cerebral-artery occlusion within 16 h after symptom onset. Before thrombectomy, all patients underwent brain magnetic resonance imaging. END was defined as an increase of 4 points or more from baseline National Institutes of Health Stroke Scale (NIHSS) during 72 h following onset. HT was assessed by brain computed tomography. Statistical analyses were performed to predict END and HT. The proportion of high FVH score, high American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grade in non-END group was higher than that in END group (p < 0.001, p < 0.001, respectively). FVH score was positively correlated with ASITN/SIR grade (r = 0.461, p < 0.001). FVH score was a predictor factor for END (adjusted OR, 13.552; 95% CI, 2.408–76.260; p = 0.003), while FVH score was not a predictor factor for HT. Furthermore, NIHSS at admission (adjusted OR, 1.112; 95% CI, 1.006–1.228; p = 0.038) and high-density lipoprotein cholesterol (adjusted OR, 18.865; 95% CI, 2.998–118.683; p = 0.002) were predictor factors for HT. To assess FVH score before thrombectomy might be useful for predicting END in AIS patients receiving endovascular thrombectomy. [ABSTRACT FROM AUTHOR]

Tissue plasminogen activator (tPA) is recommended by the FDA to dissolve intravascular clots after acute ischemic stroke (AIS). However, it may contribute to hemorrhagic transformation (HT). The Wnt/β-catenin signaling pathway plays an important role in regulating the blood–brain barrier (BBB) formation in the central nervous system. We explored whether glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) reduces the risk of HT after rtPA treatment via the Wnt/β-catenin pathway by using a rat transient middle cerebral artery occlusion (MCAO) model in vivo and an oxygen–glucose deprivation plus reoxygenation (OGD/R) model in vitro. Our results showed that EX-4 attenuated neurological deficits, brain edema, infarct volume, BBB disruption, and rtPA-induced HT in ischemic stroke. EX-4 suppressed the production of ROS and the activation of MMP-9 to protect the integrity of the BBB by activating the Wnt/β-catenin signaling pathway. PRI-724, a selective inhibitor of β-catenin, was able to reverse the therapeutic effect of EX-4 in vivo and in vitro. Therefore, our results indicate that the GLP-1R agonist may be a potential therapeutic agent to decrease the risk of rtPA-induced HT after ischemic stroke via the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: Hemorrhagic transformation (HT) following cerebral endovascular thrombectomy (EVT) for large vessel occlusion (LVO) in acute ischemic stroke is associated with poor outcome. Recent studies have shown that EVT can be efficacious in imaging-selected patients as late as 6–24 h from onset (late time window; LTW). We sought to determine predictors and prognostic implications of HT following EVT in LTW. Methods: Consecutive patients undergoing EVT for LVO were recruited into a prospective multicenter database. HT was divided into petechial hemorrhagic-infarction and parenchymal hematoma (PH) type 1 or 2 defined as confluent hemorrhage covering < or > than 1/3 of the infarct volume, respectively. Multivariate analyses were performed to determine variables associated with HT subtypes. Results: Among 611 patients included (mean age 70.5 ± 12.5 years; median NIHSS 16), 115 (18.8%) had HT and 33 of them (5.4%) had PH2. Independent PH2 predictors included failed recanalization (OR 7.0, 95% CI 2.3–21.6), longer time from symptom onset to admission (OR 1.002 per minute 95% CI 1.001–1.003) and hyperlipidemia (OR 3.12; 95%CI 1.12–8.7). HT was not associated with outcome. In contrast, PH2 patients had lower favorable outcome rates (14.3 vs 41.6%, p = 0.004) and higher mortality rates (39 vs 17%, p = 0.001). Patients who underwent EVT in the late versus early window had similar PH2 rates (4.5 vs 6.7%, p = 0.27). In multivariate models, PH2 tripled the odds of both 90-day poor outcome (OR 3.1, 95% CI 1.01–9.5) and 90-day mortality (OR 3.2, 95% CI 1.4–7.3). Conclusions: PH2 following EVT is associated with increased mortality and unfavorable outcome rates. Rates of PH2 are not different between LTW patients and those treated < 6 h from symptom onset. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that uric acid (UA) is a powerful water-soluble antioxidant and free radical scavenger for humans. However, the relationship between serum uric acid (SUA) and hemorrhagic transformation (HT) is still controversial. To address this challenge, we aimed to explore the association between serum UA and HT in patients with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). Methods: A retrospective analysis was conducted in patients with anterior circulation AIS who underwent IVT at Affiliated Hospital of Qingdao University from 2016 to 2021. HT was evaluated by CT or MRI within 7 days after admission. Baseline demographic, clinical, and laboratory data were compared between the HT and non-HT groups, and between different types of HT groups which were documented according to the European Cooperative Acute Stroke Study III Classification (ECASS III). Results: A total of 727 AIS patients were enrolled, including 112 patients who experienced HT (HT group) and 615 patients who did not experience HT (non-HT group). Patients with HT had significantly lower UA levels compared to those without HT (253.65 ± 97.75 vs 315.97 ± 96.42, p < 0.001); however, there was no significant difference for UA levels in different types of HT (p = 0.907). After adjusting confounders, patients in the fourth UA quartile showed a significant decrease in HT compared with those in the first quartile (OR 0.266, 95% CI 0.107–0.661, p = 0.006). The best cutoff value was identified as 218.5 μmol/L after analysis. Conclusions: These findings suggest that low levels of UA may be associated with HT after IVT. [ABSTRACT FROM AUTHOR]

Hemorrhagic transformation (HT) is a common complication after thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in ischemic stroke. In this article, recent research progress of HT in vivo and in vitro studies was reviewed. We have discussed new potential mechanisms and possible experimental models of HT development, as well as possible biomarkers and treatment methods. Meanwhile, we compared and analyzed rodent models, large animal models and in vitro BBB models of HT, and the limitations of these models were discussed. The molecular mechanism of HT was investigated in terms of BBB disruption, rt-PA neurotoxicity and the effect of neuroinflammation, matrix metalloproteinases, reactive oxygen species. The clinical features to predict HT were represented including blood biomarkers and clinical factors. Recent progress in neuroprotective strategies to improve HT after stroke treated with rt-PA is outlined. Further efforts need to be made to reduce the risk of HT after rt-PA therapy and improve the clinical prognosis of patients with ischemic stroke. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to analyze the multimodal score of the regional pial collateral in predicting hemorrhagic transformation (HT) after mechanical thrombectomy in acute ischemic stroke (AIS). Methods: On the basis of different brain regions and multiphase computed tomography angiography (mCTA), we evaluated the pial arterial filling status in extent, delay, and contrast washout. The prediction models of HT and symptomatic intracerebral hemorrhage (sICH) were established using mCTA (model-H1 and model-S1), CT perfusion (CTP, model-H2 and model-S2), and comprehensive parameters (model-H3 and model-S3). The receiver operating characteristic curve was used to analyze the prediction performance of each model. Results: Among the 102 patients with AIS who received thrombectomy, 36 (35.3%) developed HT, and 15 (14.7%) of whom had sICH. In model-H1 and model-S1, washout independently influenced HT (OR, 95%CI 0.398, 0.249–0.634) and sICH (OR, 95%CI 0.552, 0.342–0.892). In model-H2, the relative surface permeability independently influenced HT (OR, 95%CI 1.217, 1.082–1.370). Model-H3 and model-S3 improved the prediction performance (areas under the curve: HT, 0.957; sICH, 0.938). The correlation coefficients between relative cerebral blood volume and the three modes of pial arterial filling status were higher than those of other CTP parameters. The 90-day modified Rankin scale score in the sICH group was significantly increased (P < 0.05). Conclusion: The multimodal regional pial collateral score has good value in the risk assessment of HT and sICH in patients with AIS after mechanical thrombectomy. The combination of multiple parameters can improve diagnostic performance. [ABSTRACT FROM AUTHOR]

Atrial fibrillation causes a fivefold increase of stroke risk. CHA2DS2-VASC is widely used to evaluate the risk of cardiac embolism in patients with non-valvular atrial fibrillation (NVAF) and identify the patients eligible for anticoagulation therapy. This study aimed to identify the significance of CHA2DS2-VASC score on the severity and hemorrhagic transformation (HT) in patients with NVAF-induced acute ischemic stroke (NVAF-AIS). Total 113 patients diagnosed as NVAF-AIS were included in this study. Patients were categorized into severe stroke group (NIHSS > 10) and non-severe group (NIHSS ≤ 10), and the risk factors for severe stroke were investigated. Based on the results of repeated brain CT/MRI examination performed within 14 days from stroke onset or immediately in case of clinical worsening, patients were divided into HT group and non-HT group, and the predictors for HT were then analyzed. CHA2DS2-VASC score [median (interquartile range) 5 (3–5) vs. 3 (2–4); p = 0.002] in severe stroke group was significantly higher than that in non-severe group. The severe stroke group showed significantly increased prevalence of heart failure (20% vs. 48.5%, p = 0.002) and decreased hemoglobin (136.4 ± 18.0 vs.143.6 ± 15.6 g/L, p = 0.031) compared with non-severe group. Multivariate regression analysis revealed that CHA2DS2-VASc score was a powerful predictor for the severity of NVAF-AIS. Forty-seven of total recruited patients (43.2%) developed HT within 14 days after the onset of NVAF-AIS. CHA2DS2-VASc score as well as elevated glycated hemoglobin and intravenous rt-PA were the independent risk factors of HT. CHA2DS2-VASC score was closely associated with the severity of NVAF-AIS. Patients with higher CHA2DS2-VASC score were more likely to develop HT after NVAF-AIS. [ABSTRACT FROM AUTHOR]

It is a clinically well-established fact that patients with diabetes have very poor stroke outcomes. Yet, the underlying mechanisms remain largely unknown. Our previous studies showed that male diabetic animals show greater hemorrhagic transformation (HT), profound loss of cerebral vasculature in the recovery period, and poor sensorimotor and cognitive outcomes after ischemic stroke. This study aimed to determine the impact of iron chelation with deferoxamine (DFX) on (1) cerebral vascularization patterns and (2) functional outcomes after stroke in control and diabetic rats. After 8 weeks of type 2 diabetes induced by a combination of high-fat diet and low-dose streptozotocin, male control and diabetic animals were subjected to thromboembolic middle cerebral artery occlusion (MCAO) and randomized to vehicle, DFX, or tPA/DFX and followed for 14 days with behavioral tests. Vascular indices (vascular volume and surface area), neurovascular remodeling (AQP4 polarity), and microglia activation were measured. Brain microvascular endothelial cells (BMVEC) from control and diabetic animals were evaluated for the impact of DFX on ferroptotic cell death. DFX treatment prevented vasoregression and microglia activation while improving AQP4 polarity as well as blood-brain barrier permeability by day 14 in diabetic rats. These pathological changes were associated with improvement of functional outcomes. In control rats, DFX did not have an effect. Iron increased markers of ferroptosis and lipid reactive oxygen species (ROS) to a greater extent in BMVECs from diabetic animals, and this was prevented by DFX. These results strongly suggest that (1) HT impacts post-stroke vascularization patterns and recovery responses in diabetes, (2) treatment of bleeding with iron chelation has differential effects on outcomes in comorbid disease conditions, and (3) iron chelation and possibly inhibition of ferroptosis may provide a novel disease-modifying therapeutic strategy in the prevention of post-stroke cognitive impairment in diabetes. [ABSTRACT FROM AUTHOR]

Background: The optimal timing of anticoagulation after stroke in patients with atrial fibrillation (AF) is unknown. We aimed to objectively assess the rate of radiological hemorrhagic transformation (HT) associated with early anticoagulation. Patients and methods: A prospective, open label study (NCT04435418) of patients with AF treated with apixaban within 14 days of ischemic stroke/TIA onset was conducted. Baseline and follow-up CT scans were assessed for HT and graded using European Cooperative Acute Stroke Study (ECASS) criteria. The primary endpoint was symptomatic HT. Incident HT rates were assessed as Objective Performance Criteria. Results: One-hundred AF stroke patients, with a mean age of 79 ± 11 years were enrolled. Median infarct volume was 4 (0.5–10.75) ml. Median time from index event onset to apixaban initiation was 2 (1–6) days, and median baseline NIHSS was 4 (1–9). Asymptomatic HT on baseline imaging was present in 15 patients. Infarct volume (OR = 1.1, [1.02–1.12], p < 0.0001) and NIHSS (OR = 1.11, [1.03–1.20], p = 0.007) were both associated with baseline HT. No patients developed symptomatic HT or systemic hemorrhage. Incident asymptomatic HT was seen on follow-up CT scan in 3 patients. Patients with incident HT were functionally independent (mRS = 0–2) at 90 days. Recurrent ischemic events occurred within 90 days in 13 patients, 4 of which were associated with severe disability (mRS 3–5) and 4 with death. Discussion: Early apixaban treatment did not precipitate symptomatic HT after stroke. All HT was asymptomatic identified on imaging. Recurrent ischemic events were common and clinically symptomatic. Conclusions: Symptomatic HT rates are likely to be low in randomized trials of DOAC initiation post-stroke. Recurrent ischemic stroke may be the major clinical outcome. These data may be used as expected event rates when calculating sample size requirements for future safety/efficacy trials of early versus late DOAC initiation after AF-related stroke. [ABSTRACT FROM AUTHOR]

Blood–brain barrier (BBB) dysfunction underlies the pathogenesis of many neurological diseases. Platelet-derived growth factor receptor-alpha (PDGFRα) induces hemorrhagic transformation (HT) downstream of tissue plasminogen activator in thrombolytic therapy of acute stroke. Thus, PDGFs are attractive therapeutic targets for BBB dysfunction. In the present study, we examined the role of PDGF signaling in the process of tissue remodeling after middle cerebral arterial occlusion (MCAO) in mice. Firstly, we found that imatinib increased lesion size after permanent MCAO in wild-type mice. Moreover, imatinib-induced HT only when administrated in the subacute phase of MCAO, but not in the acute phase. Secondly, we generated genetically mutated mice (C-KO mice) that showed decreased expression of perivascular PDGFRα. Additionally, transient MCAO experiments were performed in these mice. We found that the ischemic lesion size was not affected; however, the recruitment of PDGFRα/type I collagen-expressing perivascular cells was significantly downregulated, and HT and IgG leakage was augmented only in the subacute phase of stroke in C-KO mice. In both experiments, we found that the expression of tight junction proteins and PDGFRβ-expressing pericyte coverage was not significantly affected in imatinib-treated mice and in C-KO mice. The specific implication of PDGFRα signaling was suggestive of protective effects against BBB dysfunction during the subacute phase of stroke. Vascular TGF-β1 expression was downregulated in both imatinib-treated and C-KO mice, along with sustained levels of MMP9. Therefore, PDGFRα effects may be mediated by TGF-β1 which exerts potent protective effects in the BBB. [ABSTRACT FROM AUTHOR]

To determine the correlation of uric acid (UA) with hemorrhagic transformation (HT) and poor short-term functional outcomes in anterior circulation acute ischemic stroke (AIS) patients after endovascular thrombectomy (EVT). A retrospective analysis was conducted for anterior circulation AIS patients who underwent EVT at our hospital from 2015 to 2019. HT within 72 h was documented according to the European Cooperative Acute Stroke Study II Classification. Baseline demographic, clinical and laboratory data were compared between the HT and non-HT groups, and between patients with favorable and unfavorable outcomes on 90-day. A total of 247 AIS patients were enrolled, of which 92 (37.2%) and 85 (34.4%) experienced HT and had favorable functional outcomes at 3 months respectively. Patients with HT had significantly lower UA levels compared to those without HT (322.60 ± 94.49 vs. 350.25 ± 99.28 μmol /L, P = 0.032). In contrast, UA levels were similar in patients with good or poor outcomes (345.67 ± 103.55 vs. 336.95 ± 95.5 μmol /L, P = 0.509). Compared to the patients with UA levels in the first quartile, those in the fourth quartile were at a higher risk of HT in univariate logistic regression analysis (OR = 0.383, 95% CI = 0.173–0.848, P = 0.018). The association remained significant after multivariable adjustment for potential confounders. A lower UA level is an independent risk factor of HT post-EVT in anterior circulation AIS patients, but is not associated with the short-term functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Hemorrhagic transformation (HT) is a common complication of acute ischemic stroke (AIS), and inflammation has been found to play an important role in the occurrence of HT. We aimed to investigate the impact of lymphocyte-to-monocyte ratio (LMR), a maker of inflammatory status, on HT in patients with AIS. Methods: Consecutive AIS patients within 7 days from stroke onset were enrolled between January 2016 and October 2017. LMR was calculated according to lymphocyte and monocyte counts obtained within 24 h on admission. Patients were categorized into three groups according to LMR tertiles. HT was detected by follow-up computed tomography (CT) or magnetic resonance imaging (MRI) during hospitalization. The multivariate logistic analysis was used to evaluate the independent relationship between LMR and HT. Results: A total of 1005 patients were finally included. HT was observed in 99 (9.9%) patients, with 51 (5.1%) hemorrhagic infarction (HI) and 48 (4.8%) parenchymal hematoma (PH). After adjustment for potential confounders, the odds ratio (OR) of HT was 0.523 (95% confidence interval [CI] 0.293–0.936, P = 0.029) for the highest LMR tertile compared with the lowest tertile. Multiple-adjusted spline regression model showed a nonlinear approximately L-shaped relationship between LMR levels and HT (P for nonlinear trend = 0.030). There was no significant association of baseline LMR with PH (OR 0.562, 95% CI 0.249–1.268, P = 0.165). Conclusion: Lower LMR was independently related to higher risk of HT in patients with AIS. Admission LMR may be used as one of the predictors for HT. Further prospective multicenter studies are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous heparin at a prophylactic dose (SHPD) is a rather common treatment in ischemic stroke, but whether it confers an increased risk of hemorrhagic transformation of cerebral infarct (HT) and whether its reduction or discontinuation favors HT regression are presently poorly understood.Methods: Two samples of ischemic stroke patients with a cerebral lesion diameter ≥ 3 cm on brain CT scan, admitted over 7 years to our stroke unit, were retrospectively examined: (1) patients treated or not treated with SHPD (enoxaparin 4000 U/day), with subsequent assessment of possible HT appearance (N = 267, mean age 75.9 ± 12.8 years) and (2) patients treated with SHPD, with HT and subsequent reduction/discontinuation or maintenance of the initial dose, and subsequent assessment of HT evolution (N = 116, mean age 75.7 ± 11.1 years). HT severity was quantified according to the ECASS study (HT score).Results: In the first sample, after adjustment for age, sex, stroke severity, cerebral lesion diameter, and other possible confounders, SHPD was inversely associated with HT appearance (hazard ratio 0.62, 95% CI 0.39-0.98, P = 0.04). In the second sample, after adjustment for age, sex, stroke severity, cerebral lesion diameter, and initial HT severity, SHPD reduction/discontinuation had an inverse effect on both HT score improvement (odds ratio 0.42, 95% CI 0.18-0.99, P = 0.049) and HT improvement according to neuroradiological reports (odds ratio 0.34, 95% CI 0.14-0.82, P = 0.015).Conclusions: This retrospective study suggests that SHPD may play a protective role in HT appearance and evolution, which requires verification by a randomized clinical trial. [ABSTRACT FROM AUTHOR]

Objective: To determine the correlation of thyroid hormone status with hemorrhagic transformation (HT) and short-term clinical outcomes in patients with acute ischemic stroke (AIS) after endovascular thrombectomy (EVT) Methods: A retrospective analysis was conducted on AIS patients who underwent EVT at our hospital from 2016 to 2019. Thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), and free thyroxine (FT4) levels were assessed, and logistic regression analyses were performed with HT incidence and functional outcome at 3 months. Results: A total of 199 patients (148 males; mean age 62.9 ± 13.1 years) were included in the study. The number of patients with HT and unfavorable functional outcomes at 3 months were 74 (37.2%) and 129 (64.8%), respectively. Multiple logistic regression analysis showed that low TSH level (OR = 0.609; 95% CI 0.402–0.920, 푃 = 0.019) was an independent risk factor of poor functional outcome, while none of the thyroid hormones were significantly associated with HT risk. The optimal cutoff value of TSH that best distinguished both unfavorable outcome (sensitivity 31%, specificity 88.6%, area under the curve (AUC) 0.586) and mortality at 3 months (sensitivity 47.4%, specificity 78.3%, AUC 0.606) was 0.485 uIU/ml. Conclusion: A lower TSH value upon admission may predict an unfavorable functional outcome in AIS patients after EVT, but thyroid hormone levels have no bearing on the risk of HT. [ABSTRACT FROM AUTHOR]

Background and Purpose: The role of bilirubin in patients treated with mechanical thrombectomy (MT) is unknown. We investigated the relationship between admission bilirubin levels and hemorrhagic complication in acute ischemic stroke (AIS) patients treated with MT and detailed the roles of direct bilirubin (DB), indirect bilirubin (IDB), and total bilirubin (TB).Methods: Consecutive AIS patients treated with MT were enrolled from two stroke centers. Outcome measures included hemorrhagic transformation (HT) and symptomatic intracranial hemorrhage (sICH) within 48 h. An independent association of bilirubin with outcomes was identified by multivariate logistic regression analysis. The accuracies of bilirubin in predicting outcome were evaluated using receiver operating characteristic curve analysis.Results: Of the 153 enrolled patients, 64 (41.8%) were diagnosed with HT, of which 28 (18.3%) had sICH. In univariate analyses, DB, IDB, and TB were higher in patients with HT and sICH than in patients without. After adjustment for potential confounders, DB (odds ratio [OR], 1.364; 95% confidence interval [CI], 1.133-1.641; p = 0.001), IDB (OR, 1.143; 95% CI, 1.052-1.242; p = 0.002), and TB (OR, 1.106; 95% CI, 1.041-1.175; p = 0.001) were independently associated with HT. IDB (OR, 1.177; 95% CI, 1.064-1.303; p = 0.002) and TB (OR, 1.102; 95% CI, 1.027-1.182; p = 0.007) were independently associated with sICH. Receiver operating characteristic curve analysis showed no significant difference between the three indicators of predicting HT and sICH.Conclusions: Elevated admission bilirubin is an independent predictor of HT and sICH in AIS patients treated with MT. [ABSTRACT FROM AUTHOR]

Uric acid (UA) is an antioxidant with neuroprotective effects in experimental stroke models. Whether serum UA plays a role in hemorrhagic transformation (HT) remains unclear. We aimed to explore the association between serum UA and HT in patients with acute ischemic stroke (AIS). AIS patients within 7 days after stroke onset were consecutively enrolled between January 2016 and October 2017. Patients were categorized into three groups according to serum UA tertiles by sex. HT was detected by follow-up CT or MRI within 7 days after admission. The multivariate logistic analysis was performed to assess the association of serum UA with HT. We included 1230 patients (mean age 64.1 years, 63.5% males) and 133 (10.8%) patients experienced HT. After adjusting confounders, patients in the second and third UA tertiles showed a significant decrease in HT compared with those in the lowest tertile (OR 0.432, 95% CI 0.266–0.702; OR 0.033, 95% CI 0.013–0.086, respectively). Similar results were observed for sex-based subgroups. Males with higher UA had lower risk of HT compared with the lowest UA tertile (OR 0.332, 95% CI 0.170–0.651; OR 0.008, 95% CI 0.001–0.070, respectively). In females, the highest UA tertile was inversely associated with HT (OR 0.148, 95% CI 0.058–0.376). Multiple-adjusted spline regression analyses further confirmed the dose-response relationship between UA levels and HT. Higher serum UA is independently associated with lower HT following stroke. More studies are needed to elucidate the potential neuroprotective mechanism of serum UA and its link to HT. [ABSTRACT FROM AUTHOR]

Background and purpose: Data on procedure time (PT) for mechanical thrombectomy (MT) are scarce. Moreover, the relationship among PT, postprocedural hemorrhagic transformation (HT), and functional outcomes in MT patients remains unclear. We investigated whether postprocedural HT mediated the relationship between PT and functional outcomes in patients with stent-retriever thrombectomy. Methods: We retrospectively analyzed consecutive patients who underwent MT at two comprehensive stroke centers. PT was defined as the time from puncture to first successful recanalization or to abortion of the procedure if successful recanalization was not achieved. A favorable outcome was defined as a 90-day modified Rankin Scale score of 0–2. HT was classified using the European Cooperative Acute Stroke Study definition. Results: Among 283 patients (mean age, 67.2 ± 11.9 years; male, 53.7%), 124 (43.8%) patients had a favorable outcome and 27 (9.5%) patients experienced symptomatic intracranial hemorrhage (sICH). Whether in the overall cohort or in the successful recanalization cohort, extended PT was an independent predictor for a poor outcome (per 30 min: OR 1.433, 95% CI 1.062–1.865, p = 0.019; OR 1.522, 95% CI 1.062–2.159, p = 0.020, respectively) and sICH (per 30 min: OR 1.391, 95% CI 1.030–1.865, p = 0.029; OR 1.716, 95% CI 1.161–2.648, p = 0.009, respectively). Moreover, postprocedural HT might partially explain the worse function outcomes in patients with an extended PT (the regression coefficient was changed by 28.2% and 28.1%, respectively). Conclusions: The PT is an independent predictor for 90-day outcomes in stent-retriever thrombectomy patients. Postprocedural HT was partially responsible for the worse outcome in patients who experienced a longer PT. [ABSTRACT FROM AUTHOR]

Stroke induces blood-brain barrier (BBB) breakdown, which promotes complications like oedema and hemorrhagic transformation. Administration of recombinant tissue plasminogen activator (rtPA) within a therapeutic time window of 4.5 h after stroke onset constitutes the only existing treatment. Beyond this time window, rtPA worsens BBB breakdown. Canonical Wnt pathway induces BBB formation and maturation during ontogeny. We hypothesized that the pathway is required to maintain BBB functions after stroke; thus, its activation might improve rtPA therapy. Therefore, we first assessed pathway activity in the brain of mice subjected to transient middle cerebral artery occlusion (MCAo). Next, we evaluated the effect of pathway deactivation early after stroke onset on BBB functions. Finally, we assessed the impact of pathway activation on BBB breakdown associated to delayed administration of rtPA. Our results show that pathway activity is induced predominately in endothelial cells early after ischemic stroke. Early deactivation of the pathway using a potent inhibitor, XAV939, aggravates BBB breakdown and increases hemorrhagic transformation incidence. On the other hand, pathway activation using a potent activator, 6-bromoindirubin-3′-oxime (6-BIO), reduces the incidence of hemorrhagic transformation associated to delayed rtPA administration by attenuating BBB breakdown via promotion of tight junction formation and repressing endothelial basal permeability independently of rtPA proteolytic activity. BBB preservation upon pathway activation limited the deleterious effects of delayed rtPA administration. Our study demonstrates that activation of the canonical Wnt pathway constitutes a clinically relevant strategy to extend the therapeutic time window of rtPA by attenuating BBB breakdown via regulation of BBB-specific mechanisms. [ABSTRACT FROM AUTHOR]

The goal of this paper is to review literature on the topic of anticoagulation resumption after stroke from atrial fibrillation. Following ischemic stroke, the average annual risk of recurrent stroke in a patient with a CHADS2 score of 9 is 12.2%%, translating to an average daily risk of 0.03%%. Oral anticoagulant therapy provides a 75% relative risk reduction. However, in the 2-week period immediately following an acute stroke, this daily risk appears to be elevated. The same period is associated with an increased risk of hemorrhagic transformation of ischemic stroke due to reperfusion, impaired autoregulation, and disruption of the blood-brain barrier. Use of thrombolytics and anticoagulants, baseline infarct size, presence of microhemorrhages, and evidence of hemorrhagic transformation further increases the risk of symptomatic hemorrhagic. The decision to resume anticoagulation early after ischemic stroke from atrial fibrillation must carefully balance the risks of hemorrhagic transformation with the risk of recurrent stroke. There are currently 4 trials in progress at present (OPTIMAS, ELAN, TIMING, and START) comparing different anticoagulant resumption protocols after stroke in patients on non–vitamin K oral anticoagulants. There are a number of major limitations of the studies to date on the timing of anticoagulation resumption on stroke in atrial fibrillation. For instance, they do not explicitly account for infarct size, presence/absence of hemorrhagic transformation, recanalization via mechanical thrombectomy, and bleeding diatheses such as liver synthetic dysfunction or thrombocytopenia. These factors are crucial in personalizing a treatment decision to an individual patient. [ABSTRACT FROM AUTHOR]

Purpose: Intracranial hemorrhage (ICH) is a potentially severe complication after mechanical thrombectomy (MT). Here, we investigated risk factors for the occurrence of any and symptomatic ICH after MT due to large-vessel occlusion of the anterior circulation.Methods: Consecutive patients with acute ischemic anterior circulation stroke with large-vessel occlusion undergoing MT were analyzed. ICH was categorized according to the Heidelberg Bleeding Classification. Forty-three procedural and clinical parameters were analyzed using univariate tests and multivariate logistic regressions.Results: Of 612 patients, any ICH was detected in 195 (31.9%), while 27 (4.4%) developed a symptomatic ICH. Infarct size > 1/3 of vascular territory in control imaging (OR 2.18, 95% CI 1.45-3.21), higher serum glucose levels (OR 1.23 for change of 15 units mg/dL, 95% CI 1.10-1.39), and higher thrombectomy maneuver count (OR 1.21, 95% CI 1.11-1.32) were significantly associated with a higher risk of developing any ICH compared to no ICH. Wake-up strokes (OR 3.99, 95% CI 1.38-11.60), transfer from an external clinic (OR 3.04, 95% CI 1.24-7.48), and higher serum glucose levels (OR 1.22 for change of 15 units mg/dL, 95% CI 1.05-1.42) were revealed as independent risk factors for development of symptomatic ICH compared to no symptomatic ICH. Patients with no infarct demarcation (OR 0.10, 95% CI 0.01-0.80) and complete recanalization (OR 0.57, 95% CI 0.37-0.86) showed a lower risk of developing any ICH.Conclusion: Wake-up strokes and patients who are treated within a drip-and-ship concept are especially vulnerable for symptomatic ICH, while complete recanalization, contrary to subtotal recanalization only, was revealed as a protective factor against ICH. [ABSTRACT FROM AUTHOR]

Diabetes increases the risk of occurrence and poor functional recovery after ischemic stroke injury. Previously, we have demonstrated greater hemorrhagic transformation (HT), edema, and more severe functional deficits after stroke in diabetic animals that also presented with cerebral vasoregression and endothelial cell death in the recovery period. Given that Toll-like receptor 4 (TLR-4) activation in microvascular endothelial cells triggers a robust inflammatory response, we hypothesized that inhibition of TLR-4 signaling prevents endothelial cell death and improves outcomes after stroke. Animals were treated with vehicle or TLR-4 inhibitor TAK242 (3 mg/kg; i.p.) following middle cerebral artery occlusion (MCAO). Neurobehavioral deficits were measured at baseline and day 3 after ischemic stroke. Primary brain microvascular endothelial cells (BMVECs) from diabetic animals were subjected to oxygen glucose deprivation re-oxygenation (OGDR) and treated with 0.1 mM iron(III)sulfate hydrate (iron) (to mimic the post-stroke bleeding) and TLR-4 inhibitors. Ischemic stroke increased the expression of TLR-4 in both hemispheres and in the microvasculature of diabetic animals. Cerebral infarct, edema, HT, and functional deficits were greater in diabetic compared to control animals. Inhibition of TLR-4 significantly reduced the neurovascular injury and improved functional outcomes. OGDR and iron reduced the cell viability and increased the expression of TLR-4 associated proteins (RIP3, MyD88, phospho-NF-kB, and release of IL-6) in BMVECs from diabetic animals. In conclusion, TLR-4 is highly upregulated in the microvasculature and that beneficial effects of TLR-4 inhibition are more profound in diabetes. This suggests that inhibition of vascular TLR-4 may provide therapeutic benefits for stroke recovery in diabetes. [ABSTRACT FROM AUTHOR]

Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation. [ABSTRACT FROM AUTHOR]

Hemorrhagic transformation (HT) is one of the most feared complications of acute recanalization therapies. The aim of this study was to evaluate whether blood-brain barrier permeability (BBBP) imaging can predict HT in the setting of acute recanalization therapy and to determine the sensitivity and specificity of BBBP for the prediction of HT according to the type of reperfusion therapy. We assessed a total of 46 patients who received recanalization therapy (intravenous (IV) recombinant tissue plasminogen activator (tPA), mechanical thrombectomy with a stent retriever or both) for acute ischemic stroke within the internal carotid artery or middle cerebral artery. BBBP above the threshold was significantly associated with HT after adjustment for confounding factors in all patients (OR 45.4, 95% CI 2.9~711.2, p = 0.007), patients who received IV tPA (OR 20.1, 95% CI 1.2-336.7, p = 0.037), and patients who received endovascular therapy (OR 47.2, 95% CI 1.9-1252.5, p = 0.022). The sensitivity and specificity of the initial BBBP measurement as a predictor of HT in the overall 46 patients were 80 and 71%, respectively. These values were 75 and 64% in only IV tPA group, 100 and 80% in only endovascular group, 77 and 67% in IV tPA with or without endovascular therapy group, and 86 and 76% in endovascular therapy with or without bridging IV tPA therapy group. Increased pretreatment BBBP values were significantly associated with HT after acute recanalization therapy. This correlation with HT was stronger in patients receiving endovascular mechanical thrombectomy than in patients receiving IV rtPA. [ABSTRACT FROM AUTHOR]

Association between serum calcium and magnesium versus hemorrhagic transformation (HT) remains to be identified. A total of 1212 non-thrombolysis patients with serum calcium and magnesium collected within 24 h from stroke onset were enrolled. Backward stepwise multivariate logistic regression analysis was conducted to investigate association between calcium and magnesium versus HT. Calcium and magnesium were entered into logistic regression analysis in two models, separately: model 1, as continuous variable (per 1-mmol/L increase), and model 2, as four-categorized variable (being collapsed into quartiles). HT occurred in 140 patients (11.6%). Serum calcium was slightly lower in patients with HT than in patient without HT (P = 0.273). But serum magnesium was significantly lower in patients with HT than in patients without HT (P = 0.007). In logistic regression analysis, calcium displayed no association with HT. Magnesium, as either continuous or four-categorized variable, was independently and inversely associated with HT in stroke overall and stroke of large-artery atherosclerosis (LAA). The results demonstrated that serum calcium had no association with HT in patients without thrombolysis after acute ischemic stroke. Serum magnesium in low level was independently associated with increasing HT in stroke overall and particularly in stroke of LAA. [ABSTRACT FROM AUTHOR]

Background: Many patients who receive intravenous (i.v.) recombinant tissue-plasminogen activator (rt-PA) for acute cerebral ischemia were under angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) at stroke onset. ACE-Is and ARBs have neuroprotective properties in animal models.Objective: To evaluate whether the 3-month outcome of patients treated with i.v. rt-PA for cerebral ischemia was influenced by on-going therapy with ACE-Is or ARBs.Method: This study was observational, conducted in two prospective registries of stroke patients treated with i.v. rt-PA. We evaluated outcomes with the modified Rankin scale and symptomatic intracranial hemorrhages (s-ICH) according to the ECASS2 criteria. We compared outcomes between patients with and without ACE-Is/ARBs according to the modified Rankin scale (mRS) at month 3, using logistic regression analyses adjusted on propensity scores, and propensity-matched analyses.Results: Of 1803 patients, 455 (25.2%) were under ACE-Is (259), ARBs (188) or both (8). At 3 months, patients under ACE-Is or ARBs were more likely to have an mRS 0-1, but did not differ for mRS 0-2, s-ICH and death. After adjustment on propensity scores, the association between ACE-Is/ARBs and mRS 0-1 disappeared. The propensity-matched analysis, performed in 397 pairs of patients, found no difference in outcomes between patients with and without ACE-Is or ARBs.Conclusion: In patients treated by intravenous thrombolytic therapy for ischemic stroke, on-going treatment with ACE-Is or ARBs does not influence on outcomes after adjustment on baseline characteristics and propensity scores. [ABSTRACT FROM AUTHOR]

Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke but poses risk for hemorrhagic transformation (HT). Cell therapy has been investigated as a potential therapy to improve recovery after stroke by the modulation of inflammatory responses and the improvement of blood-brain barrier (BBB) integrity, both of which are associated with HT after t-PA. In our present study, we studied the effect of autologous bone marrow mononuclear cells (MNCs) in an embolic stroke model. We administered MNCs in a rat embolic stroke 2 h after administering t-PA. We observed that even though autologous MNCs did not alter the incidence of HT, they decreased the severity of HT and reduced BBB permeability. One possible mechanism could be through the inhibition of MMP3 released by astrocytes via JAK/STAT pathway as shown by our in vitro cell interaction studies. [ABSTRACT FROM AUTHOR]

Matrix metalloprotease-3 (MMP3) activation mediates the tissue plasminogen activator (tPA)-induced hemorrhagic transformation after stroke. Hyperglycemia (HG) further exacerbates this outcome. We have recently shown that HG increases MMP3 activity in the brain after stroke. However, the combined HG-tPA effect on MMP3 activation, and the mechanisms through which MMP3 is activated were not previously reported. Accordingly, this study tested the hypothesis that tPA and HG increases MMP3 activity in the brain after stroke through peroxynitrite induced tyrosine nitration. Normoglycemic and mildly hyperglycemic male Wistar rats were subjected to middle cerebral artery suture occlusion for 90 min or thromboembolic occlusion, and up to 24 h reperfusion, with and without tPA. MMP3 activity and tyrosine nitration were evaluated in brain homogenates at 24 h. Brain microvascular endothelial cells (BMVEC) were subjected to either 3 h hypoxia or 6 h OGD under either normal or high glucose conditions with or without tPA, with or without peroxynitrite scavenger, FeTPPs. MMP3 activity and MMP3 tyrosine nitration were assessed at 24 h. HG and tPA significantly increased activity and tyrosine nitration of MMP3 in the brain. In BMVECs, tPA but not HG increased MMP3 activity. Treating BMVEC with FeTPPs significantly reduced the tPA-induced increase in MMP3 activity and nitration. Augmented oxidative and nitrative stress may be potential mechanisms contributing to MMP3 activation in hyperglycemic stroke, especially with tPA administration. Peroxynitrite may be playing a critical role in mediating MMP3 activation through tyrosine nitration in hyperglycemic stroke. [ABSTRACT FROM AUTHOR]

Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tissue plasminogen activator (tPA) treatment. The widespread use of tPA is still limited by the fear of hemorrhagic transformation (HT), and underlying mechanisms are actively being pursued in preclinical studies. However, experimental models use a 10 times higher dose of tPA than the clinical dose (10 mg/kg) and mostly employ only male animals. In this translational study, we hypothesized that low-dose tPA will improve the functional recovery after the embolic stroke in both control and diabetic male and female animals. 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 clot occlusion of the middle cerebral artery (MCA). The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. An additional set of animals were subjected to 90 min MCAO with suture. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. In the control groups, female rats had smaller infarcts and better functional outcomes. tPA decreased infarct size in both sexes with a greater effect in males. While there was no difference in HT between males and females without tPA, HT was less in the female + tPA group. In the diabetic groups, neuronal injury increased in females reaching that of the infarct sizes seen in male rats. tPA decreased infarct size in females but not males. HT was greater in female rats than in males and was not further increased with tPA. Diabetes worsened neurological deficits in both sexes. Male animals showed improved sensorimotor skills, especially with tPA treatment, but there was no improvement in females. These data suggest that diabetes amplifies neurovascular injury and neurological deficits in both sexes. Human dose tPA offers some degree of protection in male but not female rats. Given that control female animals experience less injury compared to male rats, the diabetes effect is more profound in females. [ABSTRACT FROM AUTHOR]

Ischemic stroke accounts for approximately 85% of all strokes. Although severe strokes constitute a minority of cases, they are associated with a majority of the subsequent disability and death. Reperfusion therapy with intravenous tissue plasminogen activator (tPA) and/or endovascular thrombectomy is a mainstay of acute stroke management. Intensive care management of stroke is focused on reducing complications of reperfusion, such as hemorrhagic transformation, and minimizing secondary brain injury, including brain edema and progressive stroke. Additionally, severe stroke patients frequently need ventilatory or hemodynamic support provided in an intensive care unit (ICU) setting. Here, we discuss the current medical and surgical ICU management aspects of acute ischemic stroke and identify areas where ongoing studies may reveal new treatments to improve neurological recovery. [ABSTRACT FROM AUTHOR]

Hemorrhagic transformation occurs in about 10-15% of patients with acute ischemic stroke. The treatment of hemorrhagic conversion is complex and includes blood pressure management, reversing coagulopathy, and managing its complications including increased intracranial pressure. Future research should be directed on identifying indications to treat and use of appropriate homeostatic regimens to effectively reverse the different anticoagulants and thrombolytic agents in an attempt to improve outcomes of patients with hemorrhagic transformation. [ABSTRACT FROM AUTHOR]

Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke who are treated with tissue plasminogen activator (tPA). It is associated with high morbidity and mortality, but no effective treatments are currently available to reduce HT risk. Therefore, methods to prevent HT are urgently needed. In this study, we used TWS119, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt/β-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague-Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke and then were administered rtPA, rtPA combined with TWS119, or vehicle at 4 h. The animals were sacrificed 24 h after infarct induction. Rats treated with rtPA showed evident HT, had more severe neurologic deficit, brain edema, and blood-brain barrier breakdown, and had larger infarction volume than did the vehicle group. Rats treated with TWS119 had significantly improved outcomes compared with those of rats treated with rtPA alone. In addition, Western blot analysis showed that TWS119 increased the protein expression of β-catenin, claudin-3, and ZO-1 while suppressing the expression of GSK-3β. These results suggest that TWS119 reduces rtPA-induced HT and attenuates blood-brain barrier disruption, possibly through activation of the Wnt/β-catenin signaling pathway. This study provides a potential therapeutic strategy to prevent tPA-induced HT after acute ischemic stroke. [ABSTRACT FROM AUTHOR]

To determine the clinical implications of hemorrhagic transformation (HT) after thrombolysis, 241 eligible patients receiving alteplase for acute ischemic stroke were studied. HT was classified, according to the European Cooperative Acute Stroke Study criteria, as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH). Symptomatic intracranial hemorrhage (SICH) was defined according to the National Institute of Neurological Disorders and Stroke study. A novel classification, clinically significant intracranial hemorrhage (CSICH) was defined as HTs associated with an unfavorable clinical outcome (modified Rankin Scale 5-6) at 3 months. For all subtypes of HT, we found that patients receiving alteplase were more often in the standard-dose group (0.90 ± 0.02 mg/kg) than in the lower dose group (0.72 ± 0.07 mg/kg). PH and SICH were related to an unfavorable clinical outcome, while HI was not. There was a positive trend between age and CSICH in patients receiving the standard dose (P = 0.0101), and between alteplase dose and CSICH in patients ≥70 years old (P = 0.0228). All PHs (including asymptomatic PHs) and symptomatic HIs have been found to be associated with unfavorable outcome, and for this reason defined as CSICH. Independent predictors of CSICH were age ≥70 years and the standard dose of alteplase. Further studies of thrombolysis for ischemic stroke with different doses of alteplase are warranted. [ABSTRACT FROM AUTHOR]

Numerous preclinical studies indicate that sustained endothelial activation significantly contributes to tissue edema, perpetuates the inflammatory response, and exacerbates tissue injury ultimately resulting in organ failure. However, no specific therapies aimed at restoring endothelial function are available as yet. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of endothelial function and endothelial responses to injury. Recent studies indicate that S1PR are attractive targets to treat not only disorders of the arterial endothelium but also microvascular dysfunction caused by ischemic or inflammatory injury. In this article, we will review the current knowledge of the role of S1P and its receptors in endothelial function in health and disease, and we will discuss the therapeutic potential of targeting S1PR not only for disorders of the arterial endothelium but also the microvasculature. The therapeutic targeting of S1PR in the endothelium could help to bridge the gap between biomedical research in vascular biology and clinical practice. [ABSTRACT FROM AUTHOR]

The present study investigates the association between hour-to-hour blood pressure (BP) variability and severe hemorrhagic transformation (HT) after intravenous thrombolysis (IVT) during hyperacute stage. We analyzed hour-to-hour BP measurement within 24 h after IVT in patients with acute ischemic stroke. We calculated the maximum, minimum, and average (mean) of 24-h BP values, and BP variability profiles including standard deviation (SD), average squared difference between successive measurements (SV), average squared difference between rise and drop successive measurements (SV rise and SV drop), and maximum of SV rise and SV drop (SVrisemax and SVdropmax) after quartering 0-to-24 h BP course. HT was classified as hemorrhagic infarction (HI) or parenchymal hematoma (PH). Symptomatic intracerebral hemorrhage (sICH) was defined as HT with worsening of the National Institute of Health Stroke Scale score by ≥4 points or leading to death. Severe HT was defined as either PH or sICH. Totally, 461 patients were included. We observed HT in 142 (30.8 %), PH in 43 (9.3 %), and sICH in 12 (2.6 %) patients. Binary logistic regression indicated that SBP and SBP within the first 24 h were associated with sICH (OR, 4.538; 95 % CI, 1.834-11.230; p = 0.001 and OR, 6.117; 95 % CI, 2.000-18.711; p = 0.002) and PH (OR, 2.146; 95 % CI, 1.106-4.165; p = 0.024 and OR, 2.202; 95 % CI, 1.046-4.633; p = 0.038). For the SBP SV parameters among four periods of the initial 24 h, only SV, SVrise, and SVrisemax during the first 6 h were significantly associated with sICH (OR, 2.785; 95 % CI, 1.294-5.994; p = 0.009; OR, 1.825; 95 % CI, 1.110-3.002; p = 0.018 and OR, 1.495; 95 % CI, 1.039-2.149; p = 0.030) and PH (OR, 2.088; 95 % CI, 1.287-3.387; p = 0.003; OR, 1.501; 95 % CI, 1.044-2.156; p = 0.028 and OR, 1.334; 95 % CI, 1.023-1.739; p = 0.033). High systolic BP variability during the first 6 h after IVT was related with severe HTs, which highlights the potential predictability to severe HTs. [ABSTRACT FROM AUTHOR]

Introduction: Intravenous recombinant tissue plasminogen activator (IV-rtPA) is given in acute ischemic stroke patients to achieve reperfusion. Hemorrhagic transformation (HT) is a serious complication of IV-rtPA treatment and related to blood-brain barrier (BBB) injury. It is unclear whether HT occurs secondary to reperfusion in combination with ischemic BBB injury or is caused by the negative effect of IV-rtPA on BBB integrity. The aim of this study was to establish the association between reperfusion and the occurrence of HT. Methods: From the DUST study, patients were selected with admission and follow-up non-contrast CT (NCCT) and CT perfusion (CTP) imaging, and a perfusion deficit in the middle cerebral artery territory on admission. Reperfusion was categorized qualitatively as reperfusion or no-reperfusion by visual comparison of admission and follow-up CTP. Occurrence of HT was assessed on follow-up NCCT. The association between reperfusion and occurrence of HT on follow-up was estimated by calculating odds ratios (ORs) and 95 % confidence intervals (CIs) with additional stratification for IV-rtPA treatment. Results: Inclusion criteria were met in 299 patients. There was no significant association between reperfusion and HT (OR 1.2 95%CI 0.5-3.1). In patients treated with IV-rtPA ( n = 203), the OR was 1.3 (95%CI 0.4-4.0), and in patients not treated with IV-rtPA ( n = 96), the OR was 0.8 (95%CI 0.1-4.5). HT occurred in 14 % of the IV-rtPA patients and in 7 % of patients without IV-rtPA (95%CI of difference −1 to 14 %). Conclusion: Our results suggest that the increased risk of HT after acute ischemic stroke treatment is not dependent on the reperfusion status. [ABSTRACT FROM AUTHOR]