title: RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke.
abstract: OBJECTIVE
  Hemorrhagic transformation (HT) is a major complication of ischemic stroke that worsens outcomes and increases mortality. Disruption of the blood-brain barrier is a central feature of HT pathogenesis, and leukocytes may contribute to this process. We sought to determine whether ischemic strokes that develop HT have differences in RNA expression in blood within 3 hours of stroke onset prior to treatment with thrombolytic therapy.
  
  
  METHODS
  Stroke patient blood samples were obtained prior to treatment with thrombolysis, and leukocyte RNA was assessed by microarray analysis. Strokes that developed HT (n = 11) were compared to strokes without HT (n = 33) and controls (n = 14). Genes were identified (corrected p < 0.05, fold change ≥|1.2|), and functional analysis was performed. RNA prediction of HT in stroke was evaluated using cross-validation, and in a second stroke cohort (n = 52).
  
  
  RESULTS
  Ischemic strokes that developed HT had differential expression of 29 genes in circulating leukocytes prior to treatment with thrombolytic therapy. A panel of 6 genes could predict strokes that later developed HT with 80% sensitivity and 70.2% specificity. Key pathways involved in HT of human stroke are described, including amphiregulin, a growth factor that regulates matrix metalloproteinase-9; a shift in transforming growth factor-β signaling involving SMAD4, INPP5D, and IRAK3; and a disruption of coagulation factors V and VIII.
  
  
  CONCLUSIONS
  Identified genes correspond to differences in inflammation and coagulation that may predispose to HT in ischemic stroke. Given the adverse impact of HT on stroke outcomes, further evaluation of the identified genes and pathways is warranted to determine their potential as therapeutic targets to reduce HT and as markers of HT risk.
authors.affiliation: Department of Neurology and the MIND Institute, University of California, Davis, Sacramento, CA.
authors.forename: Glen C
authors.initials: GC
authors.lastname: Jickling
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Ander
authors.forename: Boryana
authors.initials: B
authors.lastname: Stamova
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhan
authors.forename: Dazhi
authors.initials: D
authors.lastname: Liu
authors.forename: Lena
authors.initials: L
authors.lastname: Rothstein
authors.forename: Piero
authors.initials: P
authors.lastname: Verro
authors.forename: Jane
authors.initials: J
authors.lastname: Khoury
authors.forename: Edward C
authors.initials: EC
authors.lastname: Jauch
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Pancioli
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Broderick
authors.forename: Frank R
authors.initials: FR
authors.lastname: Sharp
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000097:blood* / Q000150:complications / Q000235:genetics; D002543:Cerebral Hemorrhage / Q000097:blood / Q000209:etiology / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000097:blood*; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000097:blood* / Q000150:complications / Q000235:genetics; D013997:Time Factors
chemical_list: D012333:RNA, Messenger