High Serum Levels of Endothelin-1 Predict Severe Cerebral Edema in Patients With Acute Ischemic Stroke Treated With t-PA

Abstract

Background and Purpose-Severe cerebral edema is associated with poor outcome in patients with acute stroke.Experimental studies suggest that astrocytic endothelin-1 (ET-1) has deleterious effects on water homeostasis, cerebral edema, and blood brain barrier (BBB) integrity, which contribute to more severe ischemic brain injury. In this study we analyze the association between high serum levels of ET-1 and the development of severe cerebral edema in patients treated with t-PA. Methods-One hundred thirty-four patients treated with t-PA according SITS-MOST (Safe Implementation of Thrombolysis in Stroke Monitoring Study) criteria were prospectively studied. Serum levels of ET-1, matrix metalloproteinase-9 (MMP-9), and cellular fibronectin (c-Fn) were determined by ELISA in serum samples obtained on admission, before t-PA bolus. Severe brain edema was diagnosed if extensive swelling caused any shifting of the structures of the midline was detected on the cranial CT performed at 24 to 36 hours. Stroke severity was evaluated before t-PA administration and at 24 hours by NIHSS. Functional outcome at 3 months was evaluated by the modified Rankin Scale (mRS). .6] mg/L, PϽ0.0001) serum levels were significantly higher in patients with severe cerebral edema. The best cut-off values for ET-1 and c-Fn serum levels for the prediction of severe brain edema were 5.5 fmol/mL (sensitivity 95% and specificity 94%) and 4.5 mg/L (sensitivity 73% and specificity 77%) respectively. ET-1 serum levels Ͼ5.5 fmol/mL before t-PA treatment were independently associated with development of severe brain edema (OR, 139.7; CI95%, 19.3 to 1012.2; PϽ0.0001), after adjustment for baseline stroke severity, early CT signs of infarction, serum levels of cFn Ͼ4.5 mg/L, and cardioembolic stroke subtype. Conclusions-ET-1 serum levels Ͼ5.5 fmol/mL are associated with severe brain edema in acute stroke patients treated with t-PA. These results suggest that ET-1 may be a new diagnostic marker for development of severe brain edema in patients with acute ischemic stroke treated with t-PA.

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

“…All of these effects could be blocked by treatment with a CRFR1 antagonist, suggesting that CRF and its receptor CRFR1 have a key role in hypoxic cerebral edema and apoptosis. In humans, ET-1 levels >5.5 fmol/mL in serum are linked to severe brain edema in acute stroke patients (35). ET-1 A plays a protective role during brain edema (36), but ET-1 B receptors also regulate astrocytic function (31); in an experimental rat model of stroke, an ET-1 B antagonist could reduce brain edema, serum ET-1, and astrocyte swelling (37).…”

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

“…47 Moreover, the pharmacologic blockade of the endothelin type A receptor attenuated ischemic brain injury, edema formation, and blood-brain barrier disruption in rats, 48 and high serum levels of endothelin-1 have been shown to predict malignant edema in patients with acute ischemic stroke who are receiving recombinant tissue plasminogen activator. 49 Only a few immune cells such as neutrophils invaded the brains of KNG-deficient mice after tMCAO. Neutrophils have been shown to be involved in stroke development by producing free radicals and other neurotoxic factors.…”

Blockade of Bradykinin Receptor B1 but Not Bradykinin Receptor B2 Provides Protection From Cerebral Infarction and Brain Edema

“…40,45 Most interestingly, high serum levels of endothelin-1 have very recently been shown to predict severe cerebral edema in patients with acute ischemic stroke after recombinant tissue plasminogen activator treatment. 46 The molecular pathways that link the kallikrein-kinin system and endothelin-1-driven mechanism in ischemic stroke need to be further established.…”