Frequency and Determinants for Hemorrhagic Transformation of Cerebral Infarction

Terruso, Valeria; D’Amelio, Marco; Benedetto, Norma Di; Lupo, I; Saia, Valentina; Famoso, Giorgia; Mazzola, Maria Antonietta; Aridon, Paolo; Sarno, C; Ragonese, Paolo; Savettieri, Giovanni

doi:10.1159/000229781

Cited by 99 publications

(80 citation statements)

References 43 publications

(33 reference statements)

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“…Stroke severity and infarct size is the single factor that best correlates with HT. 1 Other factors include increasing age, baseline systolic blood pressure, hypertension, serum glucose, and antiplatelet use. A meta-analysis of 55 human studies reported factors associated with tPA-related HT including older age, greater stroke severity, higher glucose, atrial fibrillation, congestive heart failure, renal impairment, previous antiplatelet agents, leukoaraiosis, and a visible acute cerebral ischemic lesion on pretreatment brain imaging.…”

Section: Clinical Factors Associated With Hemorrhagic Transformationmentioning

confidence: 99%

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Jickling

Liu

Stamova

et al. 2013

J Cereb Blood Flow Metab

450

369

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Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (o18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood-brain barrier (BBB) disruption. This contrasts to delayed HT (418 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.

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Section: Clinical Factors Associated With Hemorrhagic Transformationmentioning

confidence: 99%

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Jickling

Liu

Stamova

et al. 2013

J Cereb Blood Flow Metab

450

369

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“…4,5 HT occurs in 10% to 40% of patients with ischemic stroke 5 and is predictive of the worst clinical outcomes. 6 Our aim was to test whether LDL-C lowering with chronic PCSK9 inhibition increases the risk of HT in acute ischemic stroke.…”

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confidence: 99%

“…3 A relationship between low LDL-C levels and the risk of hemorrhagic transformation (HT) after ischemic stroke has been suggested. 4,5 HT occurs in 10% to 40% of patients with ischemic stroke 5 and is predictive of the worst clinical outcomes. 6 Our aim was to test whether LDL-C lowering with chronic PCSK9 inhibition increases the risk of HT in acute ischemic stroke.…”

mentioning

confidence: 99%

Low Levels of Low-Density Lipoprotein-C Associated With Proprotein Convertase Subtilisin Kexin 9 Inhibition Do Not Increase the Risk of Hemorrhagic Transformation

Tran-Dinh

Levoye

Lambert

et al. 2014

Stroke

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P roprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the low-density lipoprotein (LDL) receptor pathway. PCSK9 binds to the LDL receptor at the cell surface and targets it for lysosomal degradation after endocytosis.1 As a result, heterozygous carriers of PCSK9 loss-of-function mutations have naturally low LDL-C levels and a reduced incidence of cardiovascular events.2 Pharmacological inhibition of PCSK9, especially when used in combination with statins, reduces LDL-C to low levels (≈0.25g/L).3 A relationship between low LDL-C levels and the risk of hemorrhagic transformation (HT) after ischemic stroke has been suggested. 4,5 HT occurs in 10% to 40% of patients with ischemic stroke 5 and is predictive of the worst clinical outcomes. 6 Our aim was to test whether LDL-C lowering with chronic PCSK9 inhibition increases the risk of HT in acute ischemic stroke. We assessed this risk in a mouse model with low LDL-C levels because of PCSK9 deficiency. MethodsOur in vivo protocol was approved by the Animal Ethics Committee of Inserm/Diderot University-Paris (2012-2015/698-0098). PCSK9-knockout (PCSK9 −/− ) and control mice (PCSK9 +/+ ), purchased from Jackson Laboratory, were fed with a high-fat/high-cholesterol (21%/0.15%) diet for 1 month. Plasma lipids were measured using colorimetric assays on an Olympus AU400 chemistry analyzer.Mice (male; 10 weeks old; 25 g) were anesthetized with isoflurane, and their body temperature was maintained at 37°C with a heating pad. Cerebral ischemia/reperfusion was induced by a 4-hour intraluminal middle cerebral artery occlusion (MCAO) by introducing a 7-0 silicon-coated monofilament (Doccol Corporation) through the right common carotid to decrease cerebral blood flow at the bifurcation of the right MCA and the right internal carotid. After removing the monofilament, reperfusion was allowed for the next 20 hours. Mice Background and Purpose-Low levels of low-density lipoprotein-cholesterol (LDL-C) are suspected to be associated with a risk of hemorrhagic transformation after ischemic stroke. We assessed the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice with low levels of LDL-C resulting from proprotein convertase subtilisin kexin 9 (PCSK9) deficiency. Methods-PCSK9−/− and PCSK9 +/+ mice were fed with a high-fat/high-cholesterol (21%/0.15%) diet for 1 month. Plasma lipids were measured using colorimetric assays. PCSK9 −/− and PCSK9 +/+ mice (n=15 per group) were subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous hemorrhagic transformation was assessed by quantification of hemoglobin in ischemic tissue. In vitro, a cell model of blood-brain barrier was used to test endothelial barrier integrity in response to decreasing concentrations of LDL-C from 1 to 0.25g/L in ischemia/reperfusion conditions. Results-PCSK9−/− mice had lower LDL-C, high-density lipoprotein-cholesterol, and total cholesterol levels than PCSK9 were euthanized, and intravascular washout ...

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“…Inclusion criteria have been previously reported. 9,10 Briefly, all patients performed a baseline brain computed tomography (CT) scan within 24 hours from symptoms onset and a follow-up CT. Patients with transient ischemic attacks and cerebral hemorrhage were excluded.…”

Section: Methodsmentioning

confidence: 99%

Early and Late Mortality of Spontaneous Hemorrhagic Transformation of Ischemic Stroke

D'Amelio¹,

Terruso²,

Famoso

et al. 2014

Journal of Stroke and Cerebrovascular Diseases

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Background: Hemorrhagic transformation (HT), a complication of ischemic stroke (IS), might influence patient's prognosis. Our aim is to evaluate, in a hospitalbased series of patients not treated with thrombolysis, the relationship between HT and mortality. Methods: We compared mortality of individuals with spontaneous HT with that of individuals without. Medical records of patients diagnosed with anterior IS were retrospectively reviewed. Outcome measures were 30-and 90-day survival after IS onset. Kaplan-Meier estimates were used to construct survival curves. Cox proportional hazards model was used to estimate hazard ratio (HR) for the main outcome measure (death). HT was stratified in hemorrhagic infarction and parenchymal hematoma (PH). We also evaluated the relationship between HT and the main mortality risk factors (gender, age, premorbid status, severity of stroke, and radiological features). Results: Thirty days from stroke onset, 8.1% (19 of 233) of patients died. At multivariate analysis, PH (HR: 7.7, 95% confidence interval [CI]: 2.1, 27.8) and low level of consciousness at admission (HR: 5.0, 95% CI: 1.3, 18.6) were significantly associated with death. At 3-month follow-up, mortality rate was 12.1% (28 of 232). At multivariate analysis, large infarct size (HR: 2.7, 95% CI: 1.2, 6.0) and HT (HR: 2.3, 95% CI: 1.0, 5.4) were independent risk factors for mortality. Parenchymal hematoma was, however, the strongest predictor of late mortality (HR: 7.9, 95% CI: 2.9, 21.4). Conclusions: Neurological status and infarct size play a significant role, respectively, in early and late mortality after IS. Parenchymal hematoma independently predicts both early and late mortality.

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Frequency and Determinants for Hemorrhagic Transformation of Cerebral Infarction

Cited by 99 publications

References 43 publications

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Low Levels of Low-Density Lipoprotein-C Associated With Proprotein Convertase Subtilisin Kexin 9 Inhibition Do Not Increase the Risk of Hemorrhagic Transformation

Early and Late Mortality of Spontaneous Hemorrhagic Transformation of Ischemic Stroke

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