Severity Of Hemorrhagic Transformation Research Articles

Higher blood glucose is associated with the severity of hemorrhagic transformation after endovascular therapy for stroke

ObjectivesHyperglycemia is associated with poor outcome in large vessel occlusion (LVO) stroke, with mechanism for this effect unknown. Materials and methodsWe used our prospective, multicenter, observational study, Blood Pressure After Endovascular Stroke Therapy (BEST), of anterior circulation LVO stroke undergoing endovascular therapy (EVT) from 11/2017-7/2018 to determine association between increasing blood glucose (BG) and intracerebral hemorrhage (ICH). Our primary outcome was degree of ICH, classified as none, asymptomatic ICH, or symptomatic ICH (≥4-point increase in National Institutes of Health Stroke Scale [NIHSS] at 24 h with any hemorrhage on imaging). Secondary outcomes included 24 h NIHSS, early neurologic recovery (ENR, NIHSS 0-1 or NIHSS reduction by ≥8 within 24 h), and 90-day modified Rankin Scale (mRS) using univariate and multivariable regression. ResultsOf 485 enrolled patients, increasing BG was associated with increasing severity of ICH (adjusted OR, aOR 1.06, 95 % CI 1.02-1.1, p < 0.001), higher 24 h NIHSS (aOR 1.22, 95 % CI 1.11-1.34, p < 0.001), ENR (aOR 0.90, 95 % CI 0.82-1.00, p < 0.002), and 90-day mRS (aOR 1.06, 95 % CI 1.03-1.09, p < 0.001) when adjusted for age, presenting NIHSS, ASPECTS, 24-hour peak systolic blood pressure, time from last known well, and successful recanalization. ConclusionsIn the BEST study, increasing BG was associated with greater odds of increasing ICH severity. Further study is warranted to determine whether treatment of will decrease ICH severity following EVT.

Frequency, Severity, Risk Factors, and Outcome of Hemorrhagic Transformation in Anterior and Posterior Stroke.

Background: There are few data on hemorrhagic transformation in posterior circulation strokes (PCS) compared to anterior circulation strokes (ACS). The aim of this study was to retrospectively analyze the incidence of hemorrhagic transformation, its different subtypes, the associations with different risk factors, and the outcome of ACS and PCS patients. Methods: A retrospective analysis of consecutive ischemic stroke patients with hemorrhagic transformation was performed. Clinical and demographic data were collected from electronic patient records. Results: Included were 186 ACS patients and 67 PCS patients. The median age was 77 years, with PCS patients being slightly younger than ACS patients. ACS patients were more likely to be treated with acetylsalicylic acid before stroke. ACS and PCS patients had comparable frequencies and severity of hemorrhagic transformation. After excluding ACS patients who received thrombectomy, PCS patients developed hemorrhagic transformation more frequently compared to ACS patients. Risk factors for hemorrhagic transformation did not differ between ACS and PCS patients and included vitamin K antagonist use before stroke and thrombectomy in ACS patients. There was no correlation between hemorrhagic transformation and stroke outcome. Conclusions: Hemorrhagic transformation occurs with similar frequency in PCS and ACS patients but is more common in PCS patients after the exclusion of ACS patients undergoing thrombectomy.

Post-acute ischemic stroke hyperglycemia aggravates destruction of the blood-brain barrier.

Abstract JOURNAL/nrgr/04.03/01300535-202406000-00039/inline-graphic1/v/2023-10-24T010719Z/r/image-tiff Post-acute ischemic stroke hyperglycemia increases the risk of hemorrhagic transformation, which is associated with blood-brain barrier disruption. Brain microvascular endothelial cells are a major component of the blood-brain barrier. Intercellular mitochondrial transfer has emerged as a novel paradigm for repairing cells with mitochondrial dysfunction. In this study, we first investigated whether mitochondrial transfer exists between brain microvascular endothelial cells, and then investigated the effects of post-acute ischemic stroke hyperglycemia on mitochondrial transfer between brain microvascular endothelial cells. We found that healthy brain microvascular endothelial cells can transfer intact mitochondria to oxygen glucose deprivation-injured brain microvascular endothelial cells. However, post-oxygen glucose deprivation hyperglycemia hindered mitochondrial transfer and exacerbated mitochondrial dysfunction. We established an in vitro brain microvascular endothelial cell model of the blood-brain barrier. We found that post-acute ischemic stroke hyperglycemia reduced the overall energy metabolism levels of brain microvascular endothelial cells and increased permeability of the blood-brain barrier. In a clinical study, we retrospectively analyzed the relationship between post-acute ischemic stroke hyperglycemia and the severity of hemorrhagic transformation. We found that post-acute ischemic stroke hyperglycemia serves as an independent predictor of severe hemorrhagic transformation. These findings suggest that post-acute ischemic stroke hyperglycemia can aggravate disruption of the blood-brain barrier by inhibiting mitochondrial transfer.

Plasma osteoprotegerin level is associated with hemorrhagic transformation in stroke patients who underwent endovascular thrombectomy

ObjectiveOsteoprotegerin (OPG) is a component of the tumor necrosis factor receptor superfamily. Several studies have shown a relationship between OPG and cardiovascular disease. We investigated the association between plasma OPG levels and hemorrhagic transformation in stroke patients who received endovascular thrombectomy (EVT). MethodsWe prospectively enrolled 360 patients diagnosed with acute ischemic stroke and performed EVT from April 2014 to December 2020. Blood sampling for plasma OPG was performed after fasting for 12 h after EVT. Hemorrhagic transformation was defined using the definition and classification of the European Cooperative Acute Stroke Study-3 trial. ResultsOf all the included patients, 130 (36.1%) experienced hemorrhagic transformation. The mean ± standard deviation of the plasma OPG concentrations was 200.2 ± 74.4 pg/mL. In multivariable analysis, after adjusting for age, sex, body mass index (BMI), and variables with p < 0.1 in univariable analysis (diabetes mellitus, atrial fibrillation, coronary artery disease, alcohol intake, current smoking, NIHSS, ASPECT score, mass effect, hemoglobin, vitamin D 25(OH)D), increased plasma OPG concentration was independently related to any hemorrhagic transformation (highest tertile vs. lowest tertile of OPG; odds ratio [OR] 2.31, 95% confidence interval [CI] (1.29–4.14), p = 0.005) and severity of hemorrhagic transformation (OR 2.92, 95% CI (1.66–5.12), p = 0.001). ConclusionsOur results demonstrate that increased plasma OPG level is related to the occurrence and severity of hemorrhagic transformation in patients with cerebral infarction who receive EVT.

Abstract 56: Diabetic Stroke Promotes a Sexual Dimorphic Expansion of Circulating and Cerebrovascular Th17 Cells in Female Rats

Diabetes increases the risk &amp; severity of hemorrhagic transformation (HT) after ischemic stroke, worsening the functional outcomes &amp; recovery. Women experience more severe strokes and suffer from a higher rate of stroke &amp; diabetic-related complications including cognitive impairment. Yet, experimental data on sex differences in cerebrovascular complications of stroke &amp; diabetes is limited. We recently showed that diabetes negates neurovascular protection even in young females &amp; amplifies HT. We hypothesized that 1) circulating &amp;/or cerebrovascular Th17 is elevated in high fat diet (HFD)-induced diabetic females rats that develop greater HT &amp; 2) that ischemic stroke further promotes the expansion of Th17 cells. Methods: Diabetes was induced in male &amp; Female WWistar rats by a HFD and&amp; low dose streptozotocin combination. At 12-14 weeks of age control and&amp; diabetic rats were subjected to 1 hr middle cerebral artery occlusion (MCAO) or ShamSham surgery. Cell suspensions prepared from freshly harvested blood, brain &amp; small intestine specimens were analyzed by flow cytometry using antibodies against cell surface markers (CD3, CD4, γδTCR) &amp; intracellular markers (IL4, IL10, IL17, IFNγ &amp; FOXP3) of T cells. Results (Table): HFD differentially increased circulating &amp; cerebral Th17 cells in females, but not males. Non-diabetic females also had significantly more circulating &amp; cerebral inflammatory cells than males, which was further expanded by diabetes. Stroke increased cerebral Th17 cells in the presence &amp; absence of HFD-induced diabetes in both sexes. However, stroke in the absence of diabetes differentially increased circulating Th17 cells only in males, yet in females only after compounded with diabetes. Conclusion: Expansion of Th17 cells may contribute to the sexual dimorphic differences that exists in stroke &amp; diabetes-related complications. Whether this contributes to cerebrovascular &amp; cognitive dysfunction in females remain to be determined.

Aggravation of hemorrhagic transformation by early intraarterial infusion of low-dose vascular endothelial growth factor after transient focal cerebral ischemia in rats

Vascular endothelial growth factor (VEGF) is a unique growth factor associated with angiogenesis, vascular permeability, and neuroprotection. The aim of this study was to observe the effects of early intraarterial infusion of low-dose VEGF on ischemia/reperfusion injury after transient focal cerebral ischemia in rats. Male Sprague–Dawley rats were subjected to 2 h of focal ischemia by middle cerebral artery occlusion. After the 2 h ischemia, the rats were infused with 0.3 μg/kg of VEGF ( n = 15), or the vehicle as a control ( n = 15), via the reperfused internal carotid artery. The brains were collected after a 1 h, 6 h, or 72 h reperfused period. Severity of ischemic cellular injury, serum extravasation, hemorrhagic transformation, and matrix metalloproteinase (MMP)-2 and -9 expressions were compared between the VEGF-treated and control groups. No significant difference in the extent of ischemic cellular injury and serum extravasation was observed between the two groups. However, vessel numbers with hemorrhagic transformation were significantly greater in the VEGF-treated group than in the control group after the 72 h reperfusion (9.4 ± 1.6 versus 2.6 ± 1.5; P = 0.028). The severity of hemorrhagic transformation was not correlated with the extent of ischemic cellular injury or serum extravasation. MMP-2 and -9 expressions were not enhanced in the VEGF-treated group compared with the control group. These results suggest that exogenous VEGF administered intravascularly at a very early point in reperfusion aggravates hemorrhagic transformation. The aggravated hemorrhagic transformation does not seem to depend on the enlargement of ischemic cellular injury, serum extravasation, or overexpressions of MMP-2 and -9.

Use of diffusion weighted MRI to predict the occurrence and severity of hemorrhagic transformation in a rabbit model of embolic stroke

Severe hemorrhagic transformation (HT) is an important complication of thrombolytic therapy. A method to identify stroke victims destined to severe HT could improve the patient selection and thus the safety of such treatment. In this study, we investigated whether very early serial diffusion weighted magnetic resonance imaging (DWI) could predict the occurrence of HT in an embolic model of experimental stroke. We tested the hypothesis that the ischemic brains with very low initial apparent diffusion coefficients (ADC) are destined to severe early (≤5.5 h) HT. We retrospectively analyzed DWI scans of 45 New Zealand white rabbits subjected to thromboembolic stroke and treated with thrombolysis. DWI was obtained 0.5, 2, 3 and 5 h after embolization. Various thrombolytics were administered 1 h post embolization. The percentage of pixels within the ischemic hemisphere with ADC values below 550×10 −6 mm 2/s was calculated and then compared to the severity of HT observed on gross brain sections at 5.5 h. As early as 30 min after embolization, ischemic brains destined to severe HT exhibited a significantly greater percentage of pixels below the cut-off value compared to those without HT: severe HT: 25%, 18.75–37.25% vs. no HT: 12%, 5.00–16.00% (median, 25th–75th %, P<0.001). Petechial HT when percentages were in the intermediate range. Quantitative analysis of initial ADC value might identify individual stroke patients at risk of severe HT.

Acute Hypertension, but Not Thrombolysis, Increases the Incidence and Severity of Hemorrhagic Transformation Following Experimental Stroke in Rabbits

Hemorrhagic transformation (HT) is a poorly understood yet frequent complication of stroke. A transient increase in blood pressure (BP) occurs immediately after experimental embolization in rabbits and we evaluated the relationship between this acute hypertensive response and subsequent hemorrhagic transformation, as well as the attenuation of this hypertensive response with an anesthetic dose of halothane. We also examined embolism-induced HT during infusion of the thrombolytic agents tissue plasminogen activator and streptokinase. A blood clot embolus was injected into the internal carotid artery and flushed into the middle cerebral artery. In the first experiment, BP was monitored in anesthetized or unanesthetized rabbits for 20 min prior to and up to 1 h after embolization. In the second experiment, animals were embolized half-way through an infusion of tPA (3.0 mg/kg; 20% administered as an iv bolus, with the remainder infused over 30 min) or streptokinase (30,000 U/kg iv infused over 30 min). In unanesthetized animals, the HT score (number of brain sections displaying visible HT) was significantly correlated with the peak mean arterial pressure recorded at embolization (r=0.60,n=24,P<0.01). No relationship was observed between BP and HT score in animals anesthetized with halothane. Although HT incidence and extent were significantly related to elevated BP in the unanesthetized animals, halothane administration actually increased HT incidence. Embolization during thrombolytic infusion did not increase the occurrence or severity of HT. These data suggest that acute hypertension, but not ongoing thrombolysis, is a significant risk factor for HT following cerebral embolization.

Hemorrhagic transformation following tissue plasminogen activator in experimental cerebral infarction.

The effect of an intravenous infusion of recombinant tissue plasminogen activator on hemorrhagic transformation early after middle cerebral artery territory ischemia was studied in an established awake nonhuman primate (baboon) model. Following 3 hours' occlusion of the middle cerebral artery and 30 minutes' reperfusion in each of 30 baboons, a 60-minute infusion of recombinant tissue plasminogen activator (at three doses: Group A, 0.3 mg/kg, n = 6; Group B, 1.5 mg/kg, n = 6; Group C, 10 mg/kg, n = 6) or normal saline (n = 12) was undertaken. The frequency and volume of intracerebral hemorrhage, the volume of infarction, and clinical alterations were determined by computed tomography at 24 hours and 10 days, neuropathology at 14 days, and serial daily neurologic evaluations, respectively. Peripheral (nonintracranial) hemorrhage (Group A, p = 0.46; Group B, p = 0.015; Group C, p = 0.002) and peak plasma tissue plasminogen activator levels varied directly with the dose of recombinant tissue plasminogen activator. Petechial hemorrhagic infarction was a common finding among the 30 baboons. No significant differences in the incidences or volumes of infarction-related hemorrhage were apparent in any group compared with the respective saline-treated baboons. In pooled data, no significant relation between the volume of hemorrhage and the volume of infarction could be established. We conclude that the incidence and severity of hemorrhagic transformation are not related to infarction size and that recombinant tissue plasminogen activator does not increase the incidence or severity (volume) of hemorrhage when given early (less than or equal to 3.5 hours) after the onset of focal cerebral ischemia in this model.