title: Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis.
  
  
  OBJECTIVE
  This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy.
  
  
  METHODS
  Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated virus serotype 9 viral vectors carrying VEGF-B167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B167 transgene controlled by the atrial natriuretic factor promoter.
  
  
  RESULTS
  Compared with control subjects, VEGF-B167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B167 expression was low in normally functioning hearts and stimulated by cardiac pacing; it thus functioned as an ideal therapeutic transgene, active only under pathological conditions.
  
  
  CONCLUSIONS
  Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B167 gene transfer as an affordable and effective new therapy for nonischemic heart failure.
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; University of Leipzig-Heart Center, Department of Cardiology/Internal Medicine, Leipzig, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Woitek
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jeffery C
authors.initials: JC
authors.lastname: Powers
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; University of Leipzig-Heart Center, Department of Cardiology/Internal Medicine, Leipzig, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ottiger
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Suraj
authors.initials: S
authors.lastname: Parikh
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kulczycki
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Marykathryn
authors.initials: M
authors.lastname: Hurst
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Nadja
authors.initials: N
authors.lastname: Ring
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Farah
authors.initials: F
authors.lastname: Shaikh
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Polina
authors.initials: P
authors.lastname: Gross
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kolpakov
authors.affiliation: University of Leipzig-Heart Center, Department of Cardiology/Internal Medicine, Leipzig, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Linke
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Victor
authors.initials: V
authors.lastname: Rizzo
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Abdelkarim
authors.initials: A
authors.lastname: Sabri
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy. Electronic address: fabio.recchia@temple.edu.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000628:therapy*; D003331:Coronary Vessels; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D007261:Infusions, Intra-Arterial; D008297:Male; D019076:Transgenes; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics*
chemical_list: D042561:Vascular Endothelial Growth Factor B
keywords: gene therapy; heart failure; translational approach