title: Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding.
abstract: Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to increased angiogenesis and higher nonsurgical bleeding.
  
  
  
  Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2-blocking antibody. Ang-2 gene expression was measured by reverse transcription-polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar.
  
  
  
  Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (P=0.001 and P<0.001, respectively). This corresponded to an increased angiogenic potential of serum from patients with LVADs (P<0.001), which was normalized with Ang-2 blockade. Furthermore, plasma from LVAD patients contained higher amounts of thrombin (P=0.003), which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells (P<0.001), which was reduced with thrombin receptor blockade (P=0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more nonsurgical bleeding events compared with patients with Ang-2 levels below the mean (P=0.003).
  
  
  
  Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher nonsurgical bleeding events. Ang-2 therefore may contribute to arteriovenous malformation formation and subsequent bleeding in LVAD patients.
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Corey E
authors.initials: CE
authors.lastname: Tabit
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Phetcharat
authors.initials: P
authors.lastname: Chen
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Gene H
authors.initials: GH
authors.lastname: Kim
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Savitri E
authors.initials: SE
authors.lastname: Fedson
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Gabriel
authors.initials: G
authors.lastname: Sayer
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Coplan
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Valluvan
authors.initials: V
authors.lastname: Jeevanandam
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.).
authors.forename: Nir
authors.initials: N
authors.lastname: Uriel
authors.affiliation: From the Department of Medicine, Section of Cardiology (C.E.T., P.C., G.H.K., G.S., M.J.C., N.U., J.K.L.) and Department of Surgery, Section of Cardiac and Thoracic Surgery (V.T.), University of Chicago, IL; and Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.E.F.). jliao@medicine.bsd.uchicago.edu.
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
mesh_terms: D000368:Aged; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D001165:Arteriovenous Malformations / Q000150:complications; D015415:Biomarkers; D003430:Cross-Sectional Studies; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006353:Heart-Assist Devices; D006470:Hemorrhage / Q000209:etiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D013917:Thrombin / Q000494:pharmacology
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers; D013917:Thrombin
keywords: LVAD; angiogenesis; angiopoietin-2; cardiac transplant; nonsurgical bleeding; thrombin