The Temporal Profile of Inflammatory Markers and Mediators in Blood after Acute Ischemic Stroke Differs Depending on Stroke Outcome

Worthmann, Hans; Tryc, Anita Blanka; Goldbecker, Annemarie; T, Y; Tountopoulou, Argyro; Hahn, Andreas; Dengler, Reinhard; Lichtinghagen, Ralf; Weißenborn, Karin

doi:10.1159/000314624

Cited by 114 publications

(80 citation statements)

References 60 publications

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“…Increased circulating levels of inflammatory biomarkers are associated with an adverse neurological outcome in patients with ischemic stroke [37,38,39], suggesting that the link between GDF-15 and inflammation may also contribute some of the prognostic information provided by GDF-15. In patients with acute coronary syndrome, similar associations between GDF-15 and inflammatory biomarkers, including IL-6 and CRP, have been observed [9,10].…”

Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Plasma Levels and Outcome after Ischemic Stroke

Worthmann¹,

Kempf²,

Widera³

et al. 2011

Cerebrovasc Dis

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Background: Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that is induced after experimental brain injury. We hypothesized that the circulating levels of GDF-15 are increased and associated with neurological outcome in patients with ischemic stroke. Methods: Serial blood samples were obtained between 6 h and 7 days after symptom onset in 57 consecutive patients with acute ischemic stroke (n = 51) or transient ischemic attack (n = 6). GDF-15 was measured by immunoradiometric assay. Neurological outcome using the modified Rankin Scale (mRS) at 7 and 90 days was classified as favorable (mRS 0 or 1) or unfavorable (mRS >1). Results: Six hours after symptom onset, GDF-15 levels were abnormally high (>1,200 ng/l) in 68% of the patients. They declined by 8% over the course of 7 days (p < 0.001). GDF-15 levels were correlated with the circulating levels of the inflammatory marker interleukin-6 and the glial protein S100 calcium binding protein B, and with carotid intima-media thickness. Ischemic stroke patients with an mRS score >1 at 7 or 90 days had higher circulating levels of GDF-15 at all preceding sampling time points compared to patients with an mRS score of 0 or 1 (p ≤ 0.002). Similarly, in a logistic regression analysis, GDF-15 levels measured between 6 h and 7 days after symptom onset were associated with mRS at 7 and 90 days. Conclusions: These data show for the first time that the circulating levels of GDF-15 are elevated and associated with neurological outcome in patients with ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Plasma Levels and Outcome after Ischemic Stroke

Worthmann¹,

Kempf²,

Widera³

et al. 2011

Cerebrovasc Dis

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“…Early initiation of treatment has shown a clear benefit, as demonstrated in the recently published EARLY trial, which compared early (within 24 h after the event) initiation of treatment with ER-DP plus ASA (control group received ASA) with initiation after 7 days’ standard ASA treatment [21]. The benefit of the treatment with DP plus ASA was correlated with a significant reduction in innate inflammation [22], which was shown the highest immediately after stroke [23]. …”

Section: Discussionmentioning

confidence: 99%

The Japanese Aggrenox (Extended-Release Dipyridamole plus Aspirin) Stroke Prevention versus Aspirin Programme (JASAP) Study: A Randomized, Double-Blind, Controlled Trial

et al. 2011

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Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93–2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).

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“…A neuroprotective role for TIMP-1 in excitotoxic damage and ischemia has been previously proposed (10,11,22). In addition, TIMP-1 levels have recently been shown to be correlated with stroke outcome in adult humans (23).…”

Section: Mmp-9/timp-1 In Perinatal Brain Injurymentioning

confidence: 97%

Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia–ischemia: a potential marker of neonatal encephalopathy

et al. 2011

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ArticlesTranslational Investigation nature publishing group INTRODUCTION:To implement neuroprotective strategies in newborns, sensitive and specific biomarkers are needed for identifying those who are at risk for brain damage. We evaluated the effectiveness of matrix metalloproteinases (MMPs) and their naturally occurring tissue inhibitors of metalloproteinases (TIMPs) in predicting neonatal encephalopathy (Ne) damage in newborns. RESULTS: Plasma MMP-9 and TIMP-1 levels were upregulated as early as 1 h after the hI insult but not did not show such elevations after other types of injury (ibotenate-induced excitotoxicity, hypoxia, lipopolysaccharide-induced inflammation), and brain levels reflected this increase soon thereafter. We confirmed these results by carrying out plasma MMP-9 and TIMP-1 measurements in human newborns with Ne. In these infants, protein levels of MMP-9 and TIMP-1 were found to be elevated during a short window up to 6 h after birth. DISCUSSION: This feature is particularly useful in identifying newborns in need of neuroprotection. a second peak observed 72 h after birth is possibly related to the second phase of energy failure after a hI insult. Our data, although preliminary, support the use of MMP-9 and TIMP-1 as early biomarkers for the presence and extent of perinatal brain injury in human term newborns. METHODS: We first used a mouse model of neonatal hI injury to explore mechanistic aspects such as the time course of these markers after the hypoxia-ischemia event, and the correlation between the levels of these candidate markers in brain and plasma.T he major perinatal brain lesions associated with cerebral palsy and cognitive impairment are periventricular white matter damage and cortical-subcortical lesions, observed mainly in preterm and term infants, respectively (1,2). A crucial step for the implementation of neuroprotective therapies is the rapid detection of neonates at risk. Despite this urgent need, no appropriate and easily detectable biomarkers for perinatal injury are currently available.Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in multiple processes during development and in adulthood (3-5), including perinatal hypoxia-ischemia (HI) and white matter damage in human neonates. Recent studies in adult MMP-9 knockout mice have demonstrated the key role played by this metalloproteinase in the pathophysiology of traumatic and hypoxic-ischemic (HI) brain injury (6). Concordantly, MMP-9 has been shown to have deleterious effects in the immature brain after HI injury (7). Several of these studies demonstrated a significant increase in MMP-9 expression in the central nervous system within the first 24 h after the insult. MMP-9 also has long-term beneficial effects on neurovascular remodeling and behavioral recovery after stroke in adult rats (8,9). In the adult rat central nervous system, elevated TIMP-1 expression levels may play a neuroprotective role after kainate-induced excitotoxic seizures (10), and gene transfer of TIMP-...

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The Temporal Profile of Inflammatory Markers and Mediators in Blood after Acute Ischemic Stroke Differs Depending on Stroke Outcome

Cited by 114 publications

References 60 publications

Growth Differentiation Factor 15 Plasma Levels and Outcome after Ischemic Stroke

Growth Differentiation Factor 15 Plasma Levels and Outcome after Ischemic Stroke

The Japanese Aggrenox (Extended-Release Dipyridamole plus Aspirin) Stroke Prevention versus Aspirin Programme (JASAP) Study: A Randomized, Double-Blind, Controlled Trial

Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia–ischemia: a potential marker of neonatal encephalopathy

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