Manuel Rodríguez-Yáñez

Statin treatment withdrawal in ischemic stroke A controlled randomized study

Background: Pretreatment with statins has been shown to reduce brain injury in cerebral ischemia. In this controlled randomized study, we investigated the influence of statin pretreatment and its withdrawal on the outcome of acute ischemic stroke patients. Methods: From 215 patients admitted within 24 hours of a hemispheric ischemic stroke, 89 patients on chronic statin treatment were randomly assigned either to statin withdrawal for the first 3 days after admission (n = 46) or to immediately receive atorvastatin 20 mg/day (n = 43). The primary outcome event was death or dependency (modified Rankin Scale [mRS] score > 2) at 3 months. Early neurologic deterioration (END) and infarct volume at days 4 to 7 were secondary outcome variables. In a secondary analysis, outcome variables were compared with the nonrandomized patients without previous statin therapy (n = 126). Results: Patients with statin withdrawal showed a higher frequency of mRS score > 2 at the end of follow-up (60.0% vs 39.0%; p = 0.043), END (65.2% vs 20.9%; p < 0.0001), and greater infarct volume (74 [45, 126] vs 26 [12, 70] mL; p = 0.002) compared with the non–statin-withdrawal group. Statin withdrawal was associated with a 4.66 (1.46 to 14.91)–fold increase in the risk of death or dependency, a 8.67 (3.05 to 24.63)–fold increase in the risk of END, and an increase in mean infarct volume of 37.63 mL (SE 10.01; p < 0.001) after adjusting for age and baseline stroke severity. Compared with patients without previous treatment with statins, statin withdrawal was associated with a 19.01 (1.96 to 184.09)–fold increase in the risk of END and an increase in mean infarct volume of 43.51 mL (SE 21.91; p = 0.048). Conclusion: Statin withdrawal is associated with increased risk of death or dependency at 90 days. Hence, this treatment should be continued in the acute phase of ischemic stroke.

The Increase of Circulating Endothelial Progenitor Cells After Acute Ischemic Stroke Is Associated With Good Outcome

Background and Purpose— Increased circulating endothelial progenitor cells (EPC) have been associated with a low cardiovascular risk and may be involved in endothelial cell regeneration. The present study was designed to evaluate the prognostic value of EPC in acute ischemic stroke. Methods— Forty-eight patients with a first-ever nonlacunar ischemic stroke were prospectively included in the study within 12 hours of symptoms onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale, and functional outcome was assessed at 3 months by the modified Rankin Scale (mRS). Infarct volume growth between admission and days 4 to 7 was measured on multiparametric MRI. EPC colonies were defined as early outgrowth colony-forming unit-endothelial cell (CFU-EC). The increment of CFU-EC was quantified during the first week and defined as the absolute difference between the number of CFU-EC at day 7 and admission. The influence of CFU-EC increase on good functional outcome (mRS ≤2) and infarct growth was analyzed by logistic regression and linear models. Results— Patients with good outcome (n=25) showed a higher CFU-EC increment during the first week (median [quartiles], 23 [11, 36] versus −3 [−7, 1], P<0.0001) compared with patients with poor outcome. CFU-EC increment ≥4 during the first week was associated with good functional outcome at 3 months (odds ratio, 30.7; 95% CI, 2.4 to 375.7; P=0.004) after adjustment for baseline stroke severity, ischemic volume and thrombolytic treatment. For each unit increase in the CFU-EC the mean reduction in the growth of infarct volume was 0.39 (0.03 to 0.76) mL (P=0.033). Conclusions— The increase of circulating EPC after acute ischemic stroke is associated with good functional outcome and reduced infarct growth. These findings suggest that EPC might participate in neurorepair after ischemic stroke.

Role of inflammatory markers in brain ischemia

Purpose of reviewInflammatory mechanisms play an important role in the risk of stroke and during the acute phase of brain ischemia, which contributes to functional outcome of patients. We review the role of inflammatory markers in these aspects of brain ischemia. Recent findingsSystemic inflammatory mechanisms are associated with higher risk of stroke and vascular recurrences after a first ischemic stroke. Several inflammatory molecules are implicated during the acute phase of ischemic stroke, such as cytokines (interleukin-6, tumor necrosis factor-α), adhesion cell molecules (vascular cell adhesion molecule type 1, intercellular adhesion molecule type 1) and metalloproteinases. Metalloproteinases and vascular cell adhesion molecule levels are useful in the diagnosis of ischemic stroke. Inflammatory cytokines (interleukin-6 and tumor necrosis factor-α) and adhesion cell molecules are related to the presence of early neurological deterioration and infarct volume. Finally, metalloproteinases play an important role in the development of hemorrhagic transformation. SummaryMolecular markers of inflammation can be useful tools for the management of patients with ischemic stroke, both during the acute phase and to predict prognosis and prevent the risk of a new vascular event.

Increased Plasma Levels of 15-Deoxy Δ Prostaglandin J2 Are Associated With Good Outcome in Acute Atherothrombotic Ischemic Stroke

Background and Purpose— The 15-deoxy &Dgr; prostaglandin J2 (15-dPGJ2) is an anti-inflammatory prostaglandin that has been proposed to be the endogenous ligand of peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;), a nuclear receptor that can exert potent anti-inflammatory actions by repressing inflammatory genes when activated. It has been suggested that 15-dPGJ2 could be beneficial in neurological disorders in which inflammation contributes to cell death such as stroke. Methods— We investigated the relationship between plasma levels of 15-dPGJ2 and early neurological deterioration (END), infarct volume, and neurologic outcome in 552 patients with an acute stroke admitted within 24 hours after symptoms onset. Results— Median [quartiles] plasma 15-dPGJ2 levels on admission were significantly higher in patients than in controls (60.5 [11.2 to 109.4] versus 5.0 [3.8 to 7.2] pg/mL; P<0.0001). Levels of this prostaglandin were also significantly higher in patients with vascular risk factors (history of hypertension or diabetes) and with atherothrombotic infarcts (113.9 [81.6 to 139.7] pg/mL), than in those with lacunar (58.7 [32.7 to 86.2] pg/mL), cardioembolic (12.1 [6.5 to 39.2] pg/mL), or undetermined origin infarcts (11.4 [5.6 to 24.3] pg/mL) (P<0.0001). In the subgroup of patients with atherothrombotic infarcts, the adjusted odds ratio of END and poor outcome for 1 pg/mL increase in 15-dPGJ2 were 0.95 (95% CI, 0.94 to 0.97) and 0.97 (95% CI, 0.96 to 0.98), respectively. In a generalized linear model, by 1 U increase in 15-dPGJ2, there was a reduction of 0.47 mL (95% CI, 0.32 to 0.63) in the mean estimated infarct volume. Conclusions— Increased plasma 15-dPGJ2 concentration is associated with good early and late neurological outcome and smaller infarct volume. These findings suggest a neuroprotective effect of 15-dPGJ2 in atherothrombotic ischemic stroke.

High serum levels of leptin are associated with post-stroke depression.

BACKGROUND Depression is a frequent mood disorder that affects around 33% of stroke patients and has been associated with both poorer outcome and increased mortality. Our aim was to test the possible association between inflammatory and neurotrophic molecular markers and the development of post-stroke depression. METHOD We studied 134 patients with a first episode of ischemic stroke without previous history of depression or speech disorders. We screened for the existence of major depression symptoms in accordance with DSM-IV criteria and a Yesavage Geriatric Depression Scale (GDS) score >11 at discharge and 1 month after stroke. At these times, serum levels of molecular markers of inflammation [interleukin (IL)-1beta, IL-6, intracellular adhesion molecule 1 (ICAM-1), tumor necrosis factor (TNF)-alpha, leptin and high-sensitivity C-reactive protein (hs-CRP)] and neurotrophic factors [brain-derived neurotrophic factor (BDNF)] were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Twenty-five patients (18.7%) were diagnosed as having major depression at discharge. Out of 104 patients who completed the follow-up period, 23 were depressed at 1 month (22.1%). Patients with major depression showed higher serum leptin levels at discharge [43.4 (23.4-60.2) v. 6.4 (3.7-16.8) ng/ml, p<0.001] and at 1 month after stroke [46.2 (34.0-117.7) v. 6.4 (3.4-12.2) ng/ml, p<0.001). Serum levels of leptin >20.7 ng/ml were independently associated with post-stroke depression [odds ratio (OR) 16.4, 95% confidence interval (CI) 5.2-51.5, p<0.0001]. Leptin levels were even higher in the eight patients who developed depression after discharge [114.6 (87.6-120.2) v. 7.2 (3.6-13.6) ng/ml, p<0.0001]. CONCLUSIONS Serum leptin levels at discharge are found to be associated with post-stroke depression and may predict its development during the next month.

MMP‐9 Immunoreactivity in Acute Migraine

Objective.—To examine the role of matrix metalloproteinase 9 (MMP‐9) in migraine during headache and asymptomatic periods.

Micro- and macroalbuminuria predict hemorrhagic transformation in acute ischemic stroke

Background: Hemorrhagic transformation (HT) after cerebral ischemia seems to be related to the endothelial disruption secondary to the ischemic process. Albuminuria has recently been found to be a marker of chronic endothelial damage. Objective: To investigate the relationship between albuminuria and HT in patients with acute ischemic stroke. Methods: We studied 200 patients (51.5% men, age 72.5 ± 8.5 years) with ischemic stroke within the first 24 hours of evolution. HT development was assessed on CT performed between days 4 and 7 of evolution and classified according to the ECASS II criteria. Urinary samples were collected within the first 3 hours after admission and the presence of albuminuria, which was considered to be present when the ratio albumin-to-creatinine was ≥30 mg/g creatinine, was determined by nephelometry within the first 24 hours of evolution. Results: Forty-nine patients (24.5%) had albuminuria and 36 (18%) had HT on the second CT scan. After adjusting for potential confounders including a previous history of diabetes mellitus, hypertension and atrial fibrillation, stroke severity, the presence of early signs of ischemia and leukoaraiosis on the baseline CT scan, and IV anticoagulant treatment, logistic regression analysis showed that albuminuria was independently associated with HT (OR, 7.45; 95% CI 2.30 to 24.16). Moreover, albuminuria was also a significant and independent predictor of parenchymal hemorrhage type 1 and 2 (OR, 8.30; 95% CI 1.77 to 38.89). Conclusion: Albuminuria is an independent predictor of hemorrhagic transformation, and particularly of the most severe bleedings, in patients with acute ischemic stroke. Due to the small number of events, the predictive capacity of albuminuria should be confirmed in larger studies.

Toll-like receptors 7 and 8 expression is associated with poor outcome and greater inflammatory response in acute ischemic stroke

Toll-like receptors are innate immunity receptors that activate inflammation and adaptive immunity. Our objectives were to analyze the association between TLR3, 7, 8 and 9 expressions and clinical outcome in patients with ischemic stroke and the expression of inflammatory molecules. One hundred-ten patients with ischemic stroke were included within 12h of symptoms onset. Stroke severity was evaluated by the NIHSS, and functional outcome was assessed at 3 months by the modified Rankin Scale. Infarct volume at 4-7 days was measured on Computed Tomography imaging. TLR7 and TLR8 at different time points were independently associated with poor outcome. TLR8 was also correlated with infarct volumes. Furthermore, TLR7 and TLR8 on admission were correlated with levels of IL6 and IL1β at 24h, 72 h and 7 days. In conclusion, TLR 7 and TLR8 expressions are associated with poor outcome and greater inflammatory response in acute ischemic stroke.

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.

High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke

The capacity of the blood enzyme glutamate oxaloacetate transaminase (GOT) to remove glutamate from the brain by means of blood glutamate degradation has been shown in experimental models to be an efficient and novel neuroprotective tool against ischemic stroke; however, the beneficial effects of this enzyme should be tested in patients with stroke to validate these results. This study aims to investigate the association of GOT levels in blood with clinical outcome in patients with acute ischemic stroke. In two clinical independent studies, we found that patients with poor outcome show higher glutamate and lower GOT levels in blood at the time of admission. Lower GOT levels and higher glutamate levels were independently associated with poorer functional outcome at 3 months and higher infarct volume. These findings show a clear association between high blood glutamate levels and worse outcome and vice versa for GOT, presumably explained by the capacity of this enzyme to metabolize blood glutamate.