title: Gene transfer of hepatocyte growth factor attenuates postinfarction heart failure.
abstract: BACKGROUND
  Despite advances in surgical and percutaneous coronary revascularization, ongoing ischemia that is not amenable to standard revascularization techniques is a major cause of morbidity and mortality. Hepatocyte Growth Factor (HGF) has potent angiogenic and anti-apoptotic activities, and this study evaluated the functional and biochemical effects of HGF gene transfer in a rat model of postinfarction heart failure.
  
  
  RESULTS
  Lewis rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient recombinant adenovirus encoding HGF (n=10) or empty null virus as control (n=9), and animals were analyzed after six weeks. Pressure-volume conductance catheter measurements demonstrated significantly preserved contractile function in the HGF group compared with Null control animals as measured by maximum developed LV pressure (79+/-5 versus 56+/-4 mm Hg, P<0.001) and maximum dP/dt (2890+/-326 versus 1622+/-159 mm Hg/sec, P<0.01). Significant preservation of LV geometry was associated with HGF treatment (LV Diameter HGF 13.1+/-0.54 versus Null 14.4+/-0.15 mm P<0.01; LV wall thickness 1.73+/-0.10 versus 1.28+/-0.07 mm P<0.01). Angiogenesis was significantly enhanced in HGF treated animals as measured by both Von Willebrand's Factor immunohistochemical staining and a microsphere assay. TUNEL analysis revealed a significant reduction in apoptosis in the HGF group (3.42+/-0.83% versus 8.36+/-1.16%, P<0.01), which correlated with increased Bcl-2 and Bcl-xL expression in the HGF animals.
  
  
  CONCLUSIONS
  Hepatocyte Growth Factor gene transfer following a large myocardial infarction results in significantly preserved myocardial function and geometry, and is associated with significant angiogenesis and a reduction in apoptosis. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure.
authors.affiliation: Department of Cardiothoracic Surgery, University of Pennsylvania School of Medicine, Pliladelphia, PA 19104, USA.
authors.forename: Vasant
authors.initials: V
authors.lastname: Jayasankar
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Bish
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Pirolli
authors.forename: Subhasis
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Mark F
authors.initials: MF
authors.lastname: Berry
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burdick
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Gardner
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D005822:Genetic Vectors; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D017228:Hepatocyte Growth Factor / Q000032:analysis / Q000235:genetics*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008863:Microspheres; D009203:Myocardial Infarction / Q000150:complications*; D018919:Neovascularization, Physiologic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014841:von Willebrand Factor / Q000032:analysis / Q000276:immunology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D014841:von Willebrand Factor; D017228:Hepatocyte Growth Factor