title: Gene therapy with adenovirus-mediated myocardial transfer of vascular endothelial growth factor 121 improves cardiac performance in a pacing model of congestive heart failure.
abstract: BACKGROUND
  Myocardial ischemia is the most common cause of congestive heart failure. Angiogenic therapy has recently been demonstrated to enhance myocardial perfusion in the ischemic setting. We therefore hypothesized that administration of adenovirus encoding for vascular endothelial growth factor could be used to enhance myocardial function in a pacing-induced model of heart failure.
  
  
  METHODS
  Yorkshire swine underwent a left thoracotomy with placement of a ventricular epicardial pacing system. Animals received adenovirus coding either for the 121-amino-acid isoform of vascular endothelial growth factor (Ad(CU)VEGF121.1 group, n = 8) or a null vector coding for no genes (AdNull group, n = 8). The adenovirus was administered in the left ventricular free wall as 10 transepicardial injections of 100 microL each (total dose of 10(11) particle units). After a 1-week recovery period, animals were paced at a rate of 230 beats/min for 7 days to induce heart failure. Transthoracic echocardiographic and sonomicrometric measurements were performed before pacing (baseline), on termination of pacing (day 0), and then weekly for 3 weeks.
  
  
  RESULTS
  The fractional area change was significantly decreased in AdNull animals at day 0 after pacing compared with the Ad(CU)VEGF121.1 animals (29% +/- 14% vs 46% +/- 8%, P =.02). The fractional area change recovered to baseline values within 7 days in the Ad(CU)VEGF121.1 animals (62% +/- 7%) but remained significantly impaired in the AdNull group compared with that in the Ad(CU)VEGF121.1 animals up to day 21 (P =.04). Similarly, fractional wall thickening demonstrated a decrease at day 0 after pacing that was greater (P <.05) in the AdNull group compared with that in the Ad(CU)VEGF121.1 group in 5 of 6 segments. Fractional wall thickening returned to levels approximating prepacing values in all segments within 7 days in the Ad(CU)VEGF121.1 group but remained significantly impaired compared with prepacing fractional wall thickening (P <.05) in the AdNull group in 5 of 6 segments up to day 21 after pacing. Segmental shortening, as measured by sonomicrometry, also was significantly decreased at day 7 in the AdNull group compared with that in the Ad(CU)VEGF121.1 group (10% +/- 4% vs 16% +/- 3%, P =.004) and remained significantly impaired (P <.05) in the AdNull group at day 14 and 21 when compared with baseline values.
  
  
  CONCLUSIONS
  Preservation of cardiac performance and a more rapid recovery of myocardial function can be achieved in a model of pacing-induced cardiomyopathy with adenovirus-mediated administration of vascular endothelial growth factor compared with that seen in a null virus control group. These data suggest that angiogenic therapy may be useful clinically in treating cardiomyopathy.
authors.affiliation: Evanston Northwestern Healthcare, Evanston, IL 60201, USA.
authors.forename: Eros
authors.initials: E
authors.lastname: Leotta
authors.forename: Gerald
authors.initials: G
authors.lastname: Patejunas
authors.forename: Glenn
authors.initials: G
authors.lastname: Murphy
authors.forename: Joseph
authors.initials: J
authors.lastname: Szokol
authors.forename: Leslie
authors.initials: L
authors.lastname: McGregor
authors.forename: JoAnn
authors.initials: J
authors.lastname: Carbray
authors.forename: Adam
authors.initials: A
authors.lastname: Hamawy
authors.forename: David
authors.initials: D
authors.lastname: Winchester
authors.forename: Neil
authors.initials: N
authors.lastname: Hackett
authors.forename: Ronald
authors.initials: R
authors.lastname: Crystal
authors.forename: Todd
authors.initials: T
authors.lastname: Rosengart
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006333:Heart Failure / Q000235:genetics / Q000628:therapy*; D007091:Image Processing, Computer-Assisted; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D020033:Protein Isoforms; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors