Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: An association between high blood pressure (BP) in acute intracerebral hemorrhage (ICH) and hematoma growth (HG) has not been clearly demonstrated. Therefore, the impact of BP changes and course on HG and clinical outcome in patients with acute ICH was determined. METHODS: In total, 117 consecutive patients with acute (<6 h) supratentorial ICH underwent baseline and 24-h CT scans, CT angiography for the detection of the spot sign and non-invasive BP monitoring at 15-min intervals over the first 24 h. Maximum and minimum BP, maximum BP increase and drop from baseline, and BP variability values from systolic BP (SBP), diastolic BP and mean arterial pressure (MAP) were calculated. SBP and MAP loads were defined as the proportion of readings >180 and >130 mmHg, respectively. HG (>33% or >6 ml), early neurological deterioration (END) and 3-month mortality were recorded. RESULTS: Baseline BP variables were unrelated to either HG or clinical outcome. Conversely, SBP 180-load independently predicted HG (odds ratio 1.05, 95% CI 1.010-1.097, P = 0.016), whilst both SBP 180-load (odds ratio 1.04, 95% CI 1.001-1.076, P = 0.042) and SBP variability (odds ratio 1.2, 95% CI 1.047-1.380, P = 0.009) independently predicted END. Although none of the BP monitoring variables was associated with HG in the spot-sign-positive group, higher maximum BP increases from baseline and higher SBP and MAP loads were significantly related to HG in the spot-sign-negative group. CONCLUSIONS: In patients with acute supratentorial ICH, SBP 180-load independently predicts HG, whilst both SBP 180-load and SBP variability predict END.

Ultraearly hematoma growth predicts poor outcome after acute intracerebral hemorrhage.

OBJECTIVE: To investigate the impact of the adjustment of initial intracerebral hemorrhage (ICH) volume by onset-to-imaging time (ultraearly hematoma growth [uHG]) on further hematoma enlargement and outcome in patients with acute ICH. METHODS: We studied 133 patients with acute (<6 hours) supratentorial ICH. Patients underwent baseline and 24-hour CT scans for ICH volume measurement, and a CT angiography (CTA) for the detection of the spot sign. We defined uHG as the relation between baseline ICH volume/onset-to-imaging time, hematoma growth (HG) as hematoma enlargement >33% or >6 mL at 24 hours, early neurologic deterioration (END) as increase ≥4 points in the NIH Stroke Scale score or death at 24 hours, and poor long-term outcome as modified Rankin Scale score >2 at 3 months. RESULTS: The uHG was significantly faster in spot sign patients (p < 0.001), as well as in patients who experienced HG (p = 0.021), END (p < 0.001), 3-month mortality (p < 0.001), and poor long-term outcome (p < 0.001). The uHG improved the accuracy of baseline ICH volume in the prediction of END (sensitivity 93.1% vs 82.8%, specificity 85.3% vs 82.4%) and 3-month mortality (sensitivity 77.5% vs 70%, specificity 87.9% vs 84.6%). A uHG >10.2 mL/hour emerged as the most powerful predictor of HG (odds ratio [OR] 3.55, 95% confidence interval [CI] 1.39-9.07, p = 0.008), END (OR 70.22, 95% CI 14.63-337.03, p < 0.001), 3-month mortality (OR 16.96, 95% CI 5.32-54.03, p < 0.001), and poor long-term outcome (OR 6.19, 95% CI 1.32-28.98, p = 0.021). CONCLUSIONS: The uHG represents a powerful and easy-to-use tool for improving the prediction of HG and outcome in patients with acute ICH.

Update on the Serum Biomarkers and Genetic Factors Associated with Safety and Efficacy of rt-PA Treatment in Acute Stroke Patients.

An accurate understanding of the mechanisms underlying an individual's response to rt-PA treatment is critical to improve stroke patients' management. We thus reviewed the literature in order to identify biochemical and genetic factors that have been associated with safety and efficacy of rt-PA administration after stroke.

No evidence of APP point mutation and locus duplication in individuals with cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a well-established cause of lobar intracerebral hemorrhage (ICH). Familial forms of CAA are because of mutations in the gene encoding the beta-amyloid precursor protein (APP) and duplications of this gene can cause early-onset Alzheimer's disease associated with CAA. However, the contribution of APP genetic variants in the development of sporadic CAA remains unknown. METHODS: The presence of genetic variants in the APP was examined in 78 patients with CAA-related ICH by sequencing exons 16 and 17 coding the ß-amyloid protein and analyzing the presence of possible duplications of APP by microsatellite analysis and quantitative PCR. RESULTS: We did not identify any pathogenic mutation or chromosomal duplication of APP. CONCLUSIONS: Our results suggest that APP genetic variants, point mutations and locus duplication, are not a common cause of CAA-related ICH in the Spanish population.

Leukoaraiosis is associated with genes regulating blood-brain barrier homeostasis in ischaemic stroke patients.

BACKGROUND: The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis. METHODS: We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30,104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa) was used to examine the role of the identified genes. RESULTS: Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34-17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15-0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38-11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25-0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36-4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212-AA of ITGB6 and rs2290608-GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10(-4) ) and (ii) Fazekas (P = 4.5 × 10(-5) ). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis. CONCLUSIONS: Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.

PAI-1 4G/5G polymorphism is associated with brain vessel reocclusion after successful fibrinolytic therapy in ischemic stroke patients.

BACKGROUND: Despite t-PA proven benefits related to vessel reopening, up to 13% of stroke patients suffer reocclusions after t-PA. We aimed to analyze whether a functional polymorphism in a fibrinolysis inhibitor gene [plasminogen activator inhibitor-1 (PAI-1)] might be associated with reocclusion rates after stroke thrombolytic therapy. METHODS: 165 patients with ischemic stroke who received t-PA < 3 h were studied. Reocclusion and recanalization was diagnosed by transcranial Doppler. PAI-1 4G/5G polymorphism determination was performed by sequencing. PAI-1 mRNA was studied by real-time PCR analysis. National institutes of health stroke scale (NIHSS) was serially measured since patients arrival to assess the neurological outcome, and modified ranking scale (mRS) at 3rd month was used to evaluate functional outcome following stroke. RESULTS: PAI-1 4G/4G patients had higher reocclusion rates (4G/4G = 12.5% versus other genotypes = 2.7%, p = 0.025). . In a logistic regression, the 4G/4G genotype was the only factor associated with reocclusion (OR = 15.16 95%, CI = 1.4-163.4, p = 0.025). 4G/4G genotype was also associated with poor functional outcome at 3rd month (4G/4G = 4 versus others genotypes = 3, p = 0.017) and with mRNA levels at 12 h post stroke symptoms onset (4G/4G patients = 2.01% versus other genotypes = 0.68%, p = 0.034). CONCLUSIONS: PAI-1 4G/4G genotype is associated with reocclusion rates and poor functional outcome among stroke patients treated with t-PA.

Caspase-3 is related to infarct growth after human ischemic stroke.

Our aim was to investigate caspase-3 plasma levels after stroke, its correlation with infarct expansion and neurological outcome. Caspase-3 plasma levels were determined by ELISA at different time points after stroke in 116 t-PA-treated patients and a control group of 40 healthy controls. Neurological status was evaluated by NIHSS scores and functional outcome by modified Rankin Scale. To assess brain infarct growth, serial brain magnetic resonance imaging scans including diffusion- (DWI) and perfusion-weighted (PWI) images were performed in a subgroup of 58 patients. Plasma caspase-3 levels were higher in stroke patients versus the control group throughout the acute phase of stroke. Furthermore, caspase-3 level at 24h was associated with poorer short- and long-term neurological outcome and positively correlated with infarct growth assessed by diffusion-weighted images. Our data suggest that caspase-3 could be involved in recruitment of ischemic brain tissue being a marker of infarct growth.

[The therapeutic potential of endothelial progenitor cells in ischaemic stroke]. / Potencial terapéutico de las células progenitoras endoteliales en el ictus isquémico.

AIM: To review the present knowledge about endothelial progenitor cells (EPCs), their relationship with stroke and their possible therapeutic potential. DEVELOPMENT: Activation of angiogenesis and vasculogenesis after cerebral ischemia is an attempt to recover damaged cerebral tissue. The role of EPCs in angiogenesis/vasculogenesis after brain ischemia remains unknown. Many studies have been published about the isolation, phenotyping and function of EPCs. However, there is not a unique definition for these cells; their origin and function are still an issue of controversy between different research groups. In this review, we summarize the currently used techniques and the most relevant publications about EPCs in experimental models of cerebral ischemia and their role in stroke. CONCLUSIONS: The identification of EPCs in peripheral blood as hematopoietic cells with the ability to differentiate into endothelial cells, broke the paradigm that vasculogenesis was only an embryogenic process. However, better knowledge about the origin and function of EPCs in cerebral ischemia is required. Stimulation of these cells opens a wide new field of cell-based angiogenic therapy that could improve the current stroke treatment.

Potencial terapéutico de las células progenitoras endoteliales en el ictus isquémico / The therapeutic potencial of endothelial progenitor cells in ischaemic stroke

Revisar el conocimiento actual sobre células progenitoras endoteliales (CPE), su relación con el ictus y su posible uso terapéutico. Desarrollo. La activación de la angiogénesis y la vasculogénesis tras la isquemia supone un intento de recuperación del tejido cerebral. El papel que pueden tener las CPE en estos procesos tras la isquemia cerebral es aúndesconocido. Son muchos los trabajos que aparecen en la bibliografía sobre el aislamiento, fenotipo y estudio de la funcionalidad de las CPE, pero no existe aún una definición única para estas células, y su origen y función son aún motivo de controversia.En esta revisión se resumen las técnicas utilizadas actualmente para su estudio y se revisan las publicaciones más relevantes en modelos experimentales de isquemia cerebral y de su papel en el ictus isquémico. Conclusiones. La identificaciónde las CPE en sangre periférica como células hematopoyéticas, con capacidad de diferenciarse en células con un fenotipo endotelial, rompió la visión clásica de la vasculogénesis como un proceso exclusivamente embriogénico. Una década después,sólo encontramos tres trabajos publicados en relación con el papel de las CPE tras la isquemia cerebral en humanos. A pesar de que es necesario un mayor conocimiento de la naturaleza y funcionalidad de las CPE en la isquemia cerebral, la potenciaciónde estas células para su uso como terapia celular podría ser una buena herramienta terapéutica basada en la angiogénesis tras la isquemia cerebral

To review the present knowledge about endothelial progenitor cells (EPCs), their relationship with stroke and their possible therapeutic potential. Development. Activation of angiogenesis and vasculogenesis after cerebral ischemia is an attempt to recover damaged cerebral tissue. The role of EPCs in angiogenesis/vasculogenesis after brain ischemia remainsunknown. Many studies have been published about the isolation, phenotyping and function of EPCs. However, there is not a unique definition for these cells; their origin and function are still an issue of controversy between different research groups.In this review, we summarize the currently used techniques and the most relevant publications about EPCs in experimental models of cerebral ischemia and their role in stroke. Conclusions. The identification of EPCs in peripheral blood as hematopoietic cells with the ability to differentiate into endothelial cells, broke the paradigm that vasculogenesis was only anembryogenic process. However, better knowledge about the origin and function of EPCs in cerebral ischemia is required.Stimulation of these cells opens a wide new field of cell-based angiogenic therapy that could improve the current stroke treatment