This Article Full Text Full Text (PDF) All Versions of this Article: 39/7/2006    most recent STROKEAHA.107.495044v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Moldes, O. Articles by Castillo, J. Search for Related Content PubMed PubMed Citation Articles by Moldes, O. Articles by Castillo, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Stroke Related Collections Acute Cerebral Infarction Computerized tomography and Magnetic Resonance Imaging Thrombolysis Other Vascular biology

(Stroke. 2008;39:2006.)
© 2008 American Heart Association, Inc.

Original Contributions

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

Octavio Moldes, BSc; Tomás Sobrino, PhD; Mónica Millán, MD; Mar Castellanos, MD, PhD; Natalia Pérez de la Ossa, MD; Rogelio Leira, MD, PhD; Joaquín Serena, MD, PhD; José Vivancos, MD, PhD; Antonio Dávalos, MD, PhD José Castillo, MD, PhD

From the Department of Neurology (O.M., T.S., R.L., J.C.), Clinical Neuroscience Research Laboratory, Hospital Clínico Universitario, University of Santiago de Compostela, Santiago de Compostela; the Department of Neurosciences (M.M., N.P.d.l.O., A.D.), Hospital Universitari Germans Trias i Pujol, Badalona; the Department of Neurology (M.C., J.S.), Hospital Universitari Doctor Josep Trueta, Girona; and the Department of Neurology (J.V.), Hospital Universitario de La Princesa, Madrid, Spain.

Correspondence to Prof José Castillo, Servicio de Neurología, Hospital Clínico Universitario, 15706 Santiago de Compostela, Spain. E-mail mecasti{at}usc.es

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).

Results— Nineteen patients (14.2%) developed severe brain edema. Median ET-1 (8.4 [6.7, 9.6] versus 1.9 [1.6, 3.2] fmol/mL, P<0.0001) and c-Fn (6.0 [4.1, 6.7] versus 3.2 [2.1, 4.6] mg/L, P<0.0001) 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 >5.5 fmol/mL before t-PA treatment were independently associated with development of severe brain edema (OR, 139.7; CI95%, 19.3 to 1012.2; P<0.0001), after adjustment for baseline stroke severity, early CT signs of infarction, serum levels of cFn >4.5 mg/L, and cardioembolic stroke subtype.

Conclusions— ET-1 serum levels >5.5 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.

Key Words: endothelin-1 • thrombolytic therapy • ischemic stroke • cerebral edema