Teresa García-Berrocoso

B-type natriuretic peptides and mortality after stroke A systematic review and meta-analysis

Objective: To measure the association of B-type natriuretic peptide (BNP) and N-terminal fragment of BNP (NT-proBNP) with all-cause mortality after stroke, and to evaluate the additional predictive value of BNP/NT-proBNP over clinical information. Methods: Suitable studies for meta-analysis were found by searching MEDLINE and EMBASE databases until October 26, 2012. Weighted mean differences measured effect size; meta-regression and publication bias were assessed. Individual participant data were used to estimate effects by logistic regression and to evaluate BNP/NT-proBNP additional predictive value by area under the receiver operating characteristic curves, and integrated discrimination improvement and categorical net reclassification improvement indexes. Results: Literature-based meta-analysis included 3,498 stroke patients from 16 studies and revealed that BNP/NT-proBNP levels were 255.78 pg/mL (95% confidence interval [CI] 105.10–406.47, p = 0.001) higher in patients who died; publication bias entailed the loss of this association. Individual participant data analysis comprised 2,258 stroke patients. After normalization of the data, patients in the highest quartile had double the risk of death after adjustment for clinical variables (NIH Stroke Scale score, age, sex) (odds ratio 2.30, 95% CI 1.32–4.01 for BNP; and odds ratio 2.63, 95% CI 1.75–3.94 for NT-proBNP). Only NT-proBNP showed a slight added value to clinical prognostic variables, increasing discrimination by 0.028 points (integrated discrimination improvement index; p < 0.001) and reclassifying 8.1% of patients into correct risk mortality categories (net reclassification improvement index; p = 0.003). Neither etiology nor time from onset to death affected the association of BNP/NT-proBNP with mortality. Conclusion: BNPs are associated with poststroke mortality independent of NIH Stroke Scale score, age, and sex. However, their translation to clinical practice seems difficult because BNP/NT-proBNP add only minor predictive value to clinical information.

B-Type Natriuretic Peptides Help in Cardioembolic Stroke Diagnosis Pooled Data Meta-Analysis

Background and Purpose— Determining the underlying cause of stroke is important to optimize secondary prevention treatment. Increased blood levels of natriuretic peptides (B-type natriuretic peptide/N-terminal pro-BNP [BNP/NT-proBNP]) have been repeatedly associated with cardioembolic stroke. Here, we evaluate their clinical value as pathogenic biomarkers for stroke through a literature systematic review and individual participants’ data meta-analysis. Methods— We searched publications in PubMed database until November 2013 that compared BNP and NT-proBNP circulating levels among stroke causes. Standardized individual participants’ data were collected to estimate predictive values of BNP/NT-proBNP for cardioembolic stroke. Dichotomized BNP/NT-proBNP levels were included in logistic regression models together with clinical variables to assess the sensitivity and specificity to identify cardioembolic strokes and the additional value of biomarkers using area under the curve and integrated discrimination improvement index. Results— From 23 selected articles, we collected information of 2834 patients with a defined cause. BNP/NT-proBNP levels were significantly elevated in cardioembolic stroke until 72 hours from symptoms onset. Predictive models showed a sensitivity >90% and specificity >80% when BNP/NT-proBNP were added considering the lowest and the highest quartile, respectively. Both peptides also increased significantly the area under the curve and integrated discrimination improvement index compared with clinical models. Sensitivity, specificity, and precision of the models were validated in 197 patients with initially undetermined stroke with final pathogenic diagnosis after ancillary follow-up. Conclusions— Natriuretic peptides are strongly increased in cardioembolic strokes. Future multicentre prospective studies comparing BNP and NT-proBNP might aid in finding the optimal biomarker, the best time point, and the optimal cutoff points for cardioembolic stroke identification.

Differentiating ischemic from hemorrhagic stroke using plasma biomarkers: The S100B/RAGE pathway

Although neuroimaging is useful in differentiating ischemic (IS) from hemorrhagic (ICH) stroke in the Emergency Department, a wide-available rapid biochemical test would add advantages in the pre-hospital triage and management of stroke patients. Our aim was to examine the predictive value of a panel of blood-borne biomarkers to differentiate IS from ICH. Admission blood samples obtained within 24h from stroke symptoms onset were tested by ELISA for CRP, D-dimer, sRAGE, MMP9, S100B, BNP, NT-3, caspase-3, chimerin-II, secretagogin, cerebellin and NPY. The complete protocol was achieved in 915 patients (776 IS, 139 ICH). Among blood samples obtained <6 h from symptoms onset (n=337), S100B levels were increased in ICH (107.58 vs 58.70 pg/mL; p<0.001) whereas sRAGE levels were decreased (0.77 vs 1.02 ng/mL; p=0.009) as compared to IS. In this subset of patients S100B (OR 3.97 95% CI 1.82-8.68; p=0.001) and sRAGE (OR 0.22 95% CI 0.10-0.52; p<0.001) were independently associated with ICH. A regression tree was created by CART method showing good classification ability (AUC=0.762). Similar results were found for samples obtained within 3 h. In conclusion, a combination of biomarkers including those of the S100B/RAGE pathway seems promising to achieve a rapid biochemical diagnosis of IS versus ICH in the first hours from symptoms onset. This article is part of a Special Issue entitled: Translational Proteomics.

Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation

Cerebral stroke induces massive Th1-shifted inflammation both in the brain and the periphery, contributing to the outcome of stroke. A Th1-type response is neurotoxic whereas a Th2-type response is accompanied by secretion of anti-inflammatory cytokines, such as interleukin-4 (IL-4). Interleukin-33 (IL-33) is a cytokine known to induce a shift towards the Th2-type immune response, polarize macrophages/microglia towards the M2-type, and induce production of anti-inflammatory cytokines. We found that the plasma levels of the inhibitory IL-33 receptor, sST2, are increased in human stroke and correlate with a worsened stroke outcome, suggesting an insufficient IL-33-driven Th2-type response. In mouse, peripheral administration of IL-33 reduced stroke-induced cell death and improved the sensitivity of the contralateral front paw at 5days post injury. The IL-33-treated mice had increased levels of IL-4 in the spleen and in the peri-ischemic area of the cortex. Neutralization of IL-4 by administration of an IL-4 antibody partially prevented the IL-33-mediated protection. IL-33 treatment also reduced astrocytic activation in the peri-ischemic area and increased the number of Arginase-1 immunopositive microglia/macrophages at the lesion site. In human T-cells, IL-33 treatment induced IL-4 secretion, and the conditioned media from IL-33-exposed T-cells reduced astrocytic activation. This study demonstrates that IL-33 is protective against ischemic insult by induction of IL-4 secretion and may represent a novel therapeutic approach for the treatment of stroke.

Prognostic value of blood interleukin-6 in the prediction of functional outcome after stroke: A systematic review and meta-analysis

We aimed to quantify the association of blood interleukin-6 (IL-6) concentrations with poor outcome after stroke and its added predictive value over clinical information. Meta-analysis of 24 studies confirmed this association with a weighted mean difference of 3.443 (1.592-5.294) pg/mL, despite high heterogeneity and publication bias. Individual participant data including 4112 stroke patients showed standardized IL-6 levels in the 4th quartile were independently associated with poor outcome (OR=2.346 (1.814-3.033), p<0.0001). However, the additional predictive value of IL-6 was moderate (IDI=1.5%, NRI=5.35%). Overall these results indicate an unlikely translation of IL-6 into clinical practice for this purpose.

Brain Perihematoma Genomic Profile Following Spontaneous Human Intracerebral Hemorrhage

Background Spontaneous intracerebral hemorrhage (ICH) represents about 15% of all strokes and is associated with high mortality rates. Our aim was to identify the gene expression changes and biological pathways altered in the brain following ICH. Methodology/Principal Findings Twelve brain samples were obtained from four deceased patients who suffered an ICH including perihematomal tissue (PH) and the corresponding contralateral white (CW) and grey (CG) matter. Affymetrix GeneChip platform for analysis of over 47,000 transcripts was conducted. Microarray Analysis Suite 5.0 was used to process array images and the Ingenuity Pathway Analysis System was used to analyze biological mechanisms and functions of the genes. We identified 468 genes in the PH areas displaying a different expression pattern with a fold change between −3.74 and +5.16 when compared to the contralateral areas (291 overexpressed and 177 underexpressed). The top genes which appeared most significantly overexpressed in the PH areas codify for cytokines, chemokines, coagulation factors, cell growth and proliferation factors while the underexpressed codify for proteins involved in cell cycle or neurotrophins. Validation and replication studies at gene and protein level in brain samples confirmed microarray results. Conclusions The genomic responses identified in this study provide valuable information about potential biomarkers and target molecules altered in the perihematomal regions.

The proteome of human brain after ischemic stroke.

Although stroke is among the most common causes of death and chronic disability worldwide, the proteome of the ischemic human brain remains unknown. Only a few studies have investigated the ischemic brain proteome in rodent stroke models. We performed aproteomic study of the human brain after ischemic stroke usinga 2-dimensional differential gel electrophoresis-based proteomic approach. In brain samples from 6 deceased stroke patients and 3 control subjects, there was an average of 1,442 ± 231 protein spots in the gels. Changes of at least 1.5-fold in the relative expression of 132 protein spots between different cerebral areas (infarct core, peri-infarct, and contralateral tissue) were identified (p < 0.05); 39 of these were successfully identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Among the identified protein spots, we validated the results of 10 proteins by Western blot and determined the cellular localization in brain parenchyma for 3 of the identified proteins: dihydropyrimidinase-related protein 2, vesicle-fusing ATPase, and Rho dissociation inhibitor 1. These results contribute to understanding the processes that follow cerebral ischemia; moreover, some of the identified proteins may be therapeutic targets or biologic markers for determining the diagnosis and prognosis of stroke.

Lipoprotein-associated phospholipase A(2) activity is associated with large-artery atherosclerotic etiology and recurrent stroke in TIA patients.

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has emerged as a novel biomarker in cardiovascular diseases due to its ability to predict stroke in population-based studies. We aimed to investigate Lp-PLA2 levels in transient ischemic attack (TIA) patients and to study their relationship with stroke recurrence. Methods: Lp-PLA2 mass and activity were measured by means of the PLAC test with an automated Olympus analyzer and by a colorimetric activity method (diaDexus) in 166 TIA patients and 144 healthy controls. Vascular risk factors and stroke etiology were assessed. Outcome was defined as the presence of recurrent stroke/TIA within 7 and 30 days after the index TIA. Multivariate analyses were performed to identify potential predictors of recurrence. Results: Both Lp-PLA2 mass and activity (p < 0.05) were higher in TIA than in controls. Several risk factors or previous treatments were associated with Lp-PLA2 mass and activity level. During follow-up, 20 strokes/TIA (12%) occurred within the first 30 days and the presence of a large-artery atherosclerosis etiology of stroke (HR 3.28, p = 0.011), together with the past medical history of hyperlipidemia (HR 3.68, p = 0.008) and Lp-PLA2 activity of >207 nmol/ml/min (HR 2.7, p = 0.042) were all significant predictors for recurrent stroke/TIA. Conclusions: Lp-PLA2 activity might add significant prognostic information in the early evaluation of TIA patients.

Ischemic stroke outcome: A review of the influence of post-stroke complications within the different scenarios of stroke care

Stroke remains one of the main causes of death and disability worldwide. The challenge of predicting stroke outcome has been traditionally assessed from a general point of view, where baseline non-modifiable factors such as age or stroke severity are considered the most relevant factors. However, after stroke occurrence, some specific complications such as hemorrhagic transformations or post stroke infections, which lead to a poor outcome, could be developed. An early prediction or identification of these circumstances, based on predictive models including clinical information, could be useful for physicians to individualize and improve stroke care. Furthermore, the addition of biological information such as blood biomarkers or genetic polymorphisms over these predictive models could improve their prognostic value. In this review, we focus on describing the different post-stroke complications that have an impact in short and long-term outcome across different time points in its natural history and on the clinical-biological information that might be useful in their prediction.

Brain Natriuretic Peptide Is Associated with Worsening and Mortality in Acute Stroke Patients but Adds No Prognostic Value to Clinical Predictors of Outcome

Background: At the present time, the determination of the outcome of stroke patients is based on the analysis of clinical and neuroimaging data. The use of prognostic blood biomarkers could aid in decision-making processes, e.g. admitting patients to specialized stroke units. Although the prognostic role of natriuretic peptides has been studied in heart failure and coronary diseases, the value of brain natriuretic peptide (BNP) is less known within the field of strokes. Objective: We aimed to study the relationship between plasma levels of BNP and acute neurological worsening or mortality after stroke in a large cohort of patients (investigating both ischemic and hemorrhagic disease). Methods: Consecutive stroke patients (ischemic and hemorrhagic) admitted to the Stroke Unit of our University Hospital within 24 h of the onset of symptoms were included. Stroke severity was assessed according to the National Institutes of Health Stroke Scale (NIHSS) at admission and at discharge. Neurological worsening was defined as an increase of 4 or more points in the NIHSS score or death during the patient’s stay at the Stroke Unit. Blood samples were drawn upon admission to measure plasma levels of BNP (Biosite Inc., San Diego, Calif., USA). Statistical analysis was performed using SPSS 15.0 and R software. Results: Altogether, 896 patients were included in the study. BNP plasma levels were higher among patients who deteriorated the most over time (n = 112; 90.5 vs. 61.2 ng/l; p = 0.006) or died (n = 83; 118.2 vs. 60.9 ng/l; p < 0.001). Multivariate logistic regression analysis indicated that plasma BNP level was an independent predictor of neurological worsening [BNP >56.7 ng/l; odds ratio (OR) = 1.64; p = 0.04] and death after stroke (BNP >65.3 ng/l; OR = 1.97; p = 0.034). Adding BNP level to other well-known clinical predictors of bad outcome did not significantly increase the predictive value. Conclusions: Plasma levels of BNP measured during the acute phase of stroke are associated both with early neurological worsening and mortality. However, this biological information does not supply prognostic information which would add to clinical variables, which limits its use as a biomarker. Further investigation and systematic reviews are needed to clarify the role of natriuretic peptides in stroke outcome.