Victor Llombart

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.

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.

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.

Plasmatic retinol-binding protein 4 and glial fibrillary acidic protein as biomarkers to differentiate ischemic stroke and intracerebral hemorrhage

A rapid differentiation of acute ischemic stroke and intracerebral hemorrhage (ICH) is essential for an adequate treatment and to promote a better outcome. Our aim was to identify new plasma biomarkers to differentiate stroke subtypes and to combine their diagnostic ability with other biomarkers already described for this clinical indication.

Cardioembolic stroke diagnosis using blood biomarkers.

Stroke is one of the main causes of death and disability in the world. Cardioembolic etiology accounts for approximately one fifth of all ischemic strokes whereas 25-30% remains undetermined even after an advanced diagnostic workup. Despite there is not any biomarker currently approved to distinguish cardioembolic stroke among other etiologies in clinical practice the use of biomarkers represents a promising valuable complement to determine stroke etiology reducing the number of cryptogenic strokes and aiding in the prescription of the most appropriated primary and secondary treatments in order to minimize therapeutic risks and to avoid recurrences. In this review we present an update about specific cardioembolic stroke-related biomarkers at a protein, transcriptomic and genetic level. Finally, we also focused on reported biomarkers associated with atrial fibrillation (a cardiac illness strongly related with cardioembolic stroke subtype) thus with a potential to become biomarkers to detect cardioembolic stroke in the future.

Fluorescent Molecular Peroxidation Products A Prognostic Biomarker of Early Neurologic Deterioration After Thrombolysis

Background and Purpose— Fluorescent molecular peroxidation products (FMPPs) are considered potential markers of molecular oxidative damage and may provoke increased permeability and disruption of the blood–brain barrier. This study aimed to determine the value of FMPPs as a biomarker to predict neurological worsening related to early hemorrhagic transformation. Methods— Baseline FMPP levels were measured in 186 consecutive acute ischemic stroke patients before tissue plasminogen activator treatment was administered. A serial FMPP profile (baseline before tissue plasminogen activator treatment, and 1, 2, 12, and 24 hours from treatment) was determined in a subset of 100 patients. Computed tomographic scans were performed at admission and repeated at 24 to 48 hours or after neurological worsening occurred. Symptomatic intracranial hemorrhage was defined as blood at any site in the brain associated with neurological deterioration. Results— Patients who worsened had higher median FMPP levels compared with those who did not (59.68 [48.63–85.73] versus 44.87 [36.37–58.90] Uf/mL; P=0.035) at baseline. After logistic regression multivariate analysis, FMPP >48.2 Uf/mL together with age, hypertension, and systolic blood pressure remained baseline predictors of worsening at 48 hours. Moreover, baseline FMPP determination helped to distinguish between patients who worsened and those who did not (Integrated Discrimination Improvement index, 5.7%; P=0.0004). Finally, within patients who had worsened at 48 hours, those with symptomatic intracranial hemorrhage had higher FMPP levels (P=0.038). Conclusions— FMPPs might be a valuable biomarker of poor early neurological outcome and be related to the appearance of symptomatic intracranial hemorrhage in tissue plasminogen activator–treated patients, one of the most feared neurological complications after thrombolytic treatment of acute ischemic stroke.

Role of beta-defensin 2 and interleukin-4 receptor as stroke outcome biomarkers.

Acute ischemic stroke is a complex disease with huge interindividual evolution variability that makes challenging the prediction of an adverse outcome. Our aim was to study the association of bloodstream signatures to early neurological outcome after stroke, by combining a subpooling of samples strategy with protein array discovery approach. Plasma samples from 36 acute stroke patients (< 4.5 h from onset) were equally pooled within outcome groups: worsening, stability, and improvement (n = 3 pools of four patients each, for each outcome group). These nine pools were screened using a 177 antibodies library, and 35 proteins were found altered regarding outcome classification (p < 0.1). Processes of inflammation, immune response, coagulation, and apoptosis were regulated by these proteins. Ten representative candidates, mainly cytokines and chemokines, were assayed for replication in individual baseline plasma samples from 80 new stroke patients: β‐defensin2, MIP‐3b, plasminogen activator inhibitor 1 active, β‐cell‐attracting chemokine 1, Exodus‐2, interleukin‐4 receptor (IL‐4R), IL‐12p40, leukemia inhibitor factor, MIP‐1b, and tumor necrosis factor‐related weak inducer of apoptosis. Multivariate logistic regression analysis showed β‐defensin 2 (ORadj 4.87 [1.13–20.91] p = 0.033) and IL‐4R (ORadj 3.52 [1.03–12.08] p = 0.045) as independent predictors of worsening at 24 h after adjustment by clinical variables. Both biomarkers improve the prediction by 19% as compared to clinical information, suggesting a potential role for risk stratification in acute thrombolyzed stroke patients.

Neuroendocrine hormones as prognostic biomarkers in the setting of acute stroke: overcoming the major hurdles.

Stroke represents one of the major causes of disability and mortality worldwide and prediction of outcome represents a challenge for both clinicians and researchers. In the past years, many blood markers have been associated with stroke outcome but despite this evidence, no biomarker is routinely used in stroke management. In this review, we focus on markers of the neuroendocrine system, which represent potential candidates to be implemented in clinical practice. Moreover, we present a systematic review and literature-based meta-analysis for copeptin, a new biomarker of the hypothalamo–pituitary–adrenal axis that has shown additional predictive value over clinical information in a large prospective study. The meta-analysis of the included 7 studies, with more than 2000 patients, reinforced its association with poor outcome (pooled odds ratio: 2.474 [1.678–3.268]) and mortality (pooled OR: 2.569 [1.642–3.495]). We further review the current situation of the topic and next steps to implement these tools by clinicians.

Profiling and identification of new proteins involved in brain ischemia using MALDI-imaging-mass-spectrometry

The identification of proteins involved in brain ischemia might allow the discovery of putative biomarkers or therapeutic targets for ischemic stroke. Our aim is to study the distribution of proteins within mouse brain after an ischemic insult using MALDI imaging-mass-spectrometry and to identify relevant proteins involved in brain damage. We occluded the middle cerebral artery of C57BL/6J mice. Brain slices were analyzed by MALDI-TOF and infarct (IC) and contralateral (CL) regions were compared using ClinProTools. The ion distribution maps of relevant m/z values were obtained by FlexImagin3.0. Protein identification was conducted through a bottom-up approach consisting on complementary sample fractionation methods. Some identifications were confirmed by immunohistochemistry and western blot. We identified 102 m/z values with different abundances between IC and CL (p<0.05), from which 21 m/z peaks were selected as more relevant. Thirteen of them were found increased in the infarct region and 4 m/z values showed AUC>90% between IC and CL. Identification analyses confirmed altered expressions of ATP5i, COX6C and UMP-CMP kinase in IC compared to CL. BIOLOGICAL SIGNIFICANCE Using MALDI-IMS we identified for the first time new proteins that might be involved in brain ischemia representing potential diagnostic biomarkers or target molecules for neurological recovery.

Blood Markers of Inflammation and Endothelial Dysfunction in Cardioembolic Stroke: Systematic Review and Meta-analysis

Abstract Context: Various processes including inflammation and endothelial dysfunction have been implicated in the pathogenesis of cardioembolic (CE) strokes. Objective: To review the evidence and investigate the association between immune-inflammatory biomarkers and CE strokes versus other stroke subtypes. Methods: We systematically reviewed the literature (sources: MEDLINE, web-based register http://stroke-biomarkers.com, reference lists) with quality assessment and meta-analysis of selected articles. Results: The most consistent association was found between C-reactive protein (CRP) and CE strokes when compared to other stroke subtypes (standardized mean difference 0.223 (0.116, 0.343); p < 0.001) Conclusions: Our findings confirm a possible association between selected inflammatory biomarkers and CE stroke.