Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production

BACKGROUND: As critical mediators of local and systemic inflammatory responses, cytokines are produced in the brain following ischaemic stroke. Some have been detected in the circulation of stroke patients, but their role and source is unclear. Focusing primarily on interleukin(IL)-1-related mechanisms, we serially measured plasma inflammatory markers, and the production of cytokines by whole blood, from 36 patients recruited within 12 h and followed up to 1 year after acute ischaemic stroke (AIS). RESULTS: Admission plasma IL-1 receptor antagonist (IL-1ra) concentration was elevated, relative to age-, sex-, and atherosclerosis-matched controls. IL-1β, soluble IL-1 receptor type II, tumour necrosis factor (TNF)-α, TNF-RII, IL-10 and leptin concentrations did not significantly differ from controls, but peak soluble TNF receptor type I (sTNF-RI) in the first week correlated strongly with computed tomography infarct volume at 5–7 days, mRS and BI at 3 and 12 months. Neopterin was raised in patients at 5–7 d, relative to controls, and in subjects with significant atherosclerosis. Spontaneous IL-1β, TNF-α and IL-6 gene and protein expression by blood cells was minimal, and induction of these cytokines by lipopolysaccharide (LPS) was significantly lower in patients than in controls during the first week. Minimum LPS-induced cytokine production correlated strongly with mRS and BI, and also with plasma cortisol. CONCLUSION: Absence of spontaneous whole blood gene activation or cytokine production suggests that peripheral blood cells are not the source of cytokines measured in plasma after AIS. Increased plasma IL-1ra within 12 h of AIS onset, the relationship between sTNF-RI and stroke severity, and suppressed cytokine induction suggests early activation of endogenous immunosuppressive mechanisms after AIS

Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume

There is increasing evidence that inflammation plays an important role in the progression of acute ischemic stroke (AIS). The primary aims of this study were to examine the serum levels of 13 cytokines, C-reactive protein (CRP), glucose, and hemoglobin in AIS patients, and their relationship to stroke lateralization, type, and infarct volume. Forty-five patients with AIS were evaluated. Blood samples were taken within 72 h, and volumetric analyses performed within 1–7 days after AIS onset. Cytokines were measured in serum from all patients and from 40 control subjects using Luminex Bio-Plex XMap technology. The levels of interleukin (IL)-1ra (p < 0.001), IL-6 (p < 0.001), IL-8 (p < 0.001), IL-9 (p = 0.038), IL-10 (p = 0.001), IL-12 (p = 0.001), IL-18 (p < 0.001), and GRO-α (CXCL1) (p = 0.017) were significantly higher in the AIS patients than in the controls. The IL-8 level was significantly correlated with age in the patient group (r = 0.52, p < 0.001). None of the variables were found to be associated with stroke lateralization. Infarct volume was significantly positively correlated with CRP level (r = 0.47, p = 0.005). Patients with radiologically confirmed infarctions had significantly elevated serum levels of GRO-α (p = 0.023). The cytokine profile of the AIS patients supports not only earlier findings of a proinflammatory response but also early activation of endogenous immunosuppressive mechanisms. Novel findings of this study are elevated serum levels of IL-9 and GRO-α. Elevated GRO-α in AIS patients with radiologically confirmed infarctions suggests that GRO-α is specific for stroke of known etiology. Our results indicate that CRP plays an important role in the progression of cerebral tissue injury

Microalbuminuria indicates long-term vascular risk in patients after acute stroke undergoing in-patient rehabilitation

<p>Abstract</p> <p>Background</p> <p>Patients in neurologic in-patient rehabilitation are at risk of cardio- and cerebrovascular events. Microalbuminuria (MAU) is frequent and an important risk predictor but has not been validated in in-patient rehabilitation. We therefore aimed to examine MAU as an indicator of risk and predictor of vascular events in a prospective study.</p> <p>Methods</p> <p>The INSIGHT (<b>IN</b>vestigation of patients with ischemic <b>S</b>troke <b>I</b>n neurolo<b>G</b>ic re<b>H</b>abili<b>T</b>ation) registry is the first to provide large scale data on 1,167 patients with acute stroke (< 3 months) that survived the initial phase of high risk and were undergoing neurologic in-patient rehabilitation. MAU was determined by dipstick-testing and correlated to baseline clinical variables (stroke-origin, functional impairment, co-morbidity, ankle-brachial-index, intima-media-thickeness) as well as vascular events after one year of follow-up. Comparisons were made with the <it>χ</it>² or Mann–Whitney-<it>U</it> Test. Relative risks (RR) with 95% confidence intervals (CI) were estimated using log-binominal models. To evaluate the association between MAU and new vascular events as well as mortality, we calculated hazard ratios (HR) using Cox proportional hazard regression.</p> <p>Results</p> <p>A substantial proportion of patients was MAU positive at baseline (33.1%). Upon univariate analysis these patients were about 4 years older (69 vs. 65 years; p < 0.0001), had a slightly higher body mass index (27.8 vs. 27.1 kg/m²; p = 0.03) and increased waist circumference (79.5 vs. 50.4% for women [p < 0.0001] and 46.8 vs. 43.2% for men [p = 0.04]) and twice as often had diabetes mellitus (41.8 vs. 20.1%; p < 0.0001). Patients with MAU had a similar NIH stroke scale score (median 3 vs. 3; p = 0.379) but had lower values on the Barthel Index (median 75 vs. 90; p < 0.001). They had higher rates of atrial fibrillation (RR 1.38; 95% CI 1.09-1.75), coronary artery disease (RR 1.54; 95% CI 1.18-2.00), heart failure (RR 1.70; 95% CI 1.10-2.60) symptomatic peripheral artery disease (RR 2.30; 95% CI 1.40-3.80) and atherosclerotic stroke etiology (53.7 vs. 35.4%; p < 0.0001). MAU was associated with an increased intima-media-thickness, decreased ankle-brachial-index and polyvascular disease (RR 1.56; 95%CI 1.31-1.99). The event rate after a median follow-up of 13 months was 6.7% for fatal or nonfatal stroke, 4.7% for death, and 10.9% for combined vascular events (stroke, MI, vascular death). The presence of MAU was predictive for vascular events during the following year (HR for total mortality 2.2; 95% CI 1.3-3.7; HR for cardiovascular events 2.3; 95% 1.2 - 4.4).</p> <p>Conclusions</p> <p>INSIGHT demonstrated a significant association between MAU and polyvascular disease and further supports previous findings that MAU predicts cardio-/cerebrovascular events in patients recovering from ischemic stroke. This biomarker may also be used in patients during neurologic in-patient rehabilitation, opening a window of opportunity for early intervention in this patient group at increased risk for recurrent events.</p