title: Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial 'delivery-efficacy' mismatch.
abstract: The aim of this study was to determine the effects of direct intramyocardial pVEGF165 gene transfer on regional myocardial blood flow in a porcine model of chronic myocardial ischaemia. Pigs underwent placement of an ameroid constrictor around the left circumflex coronary artery. After 3 weeks, animals received direct intramyocardial injections of pVEGF165 (20 x 50 microl at 1 microg/microl, n=11) or a plasmid vector encoding chloramphenicol acetyltransferase (20 x 50 microl at 1 microg/microl, n=11) into a specified target area (TA) of the left lateral wall. At 3 weeks after gene transfer, animals underwent final evaluation including a systematic assessment of regional myocardial blood flow (MBF) under resting and stress conditions. In all, 20 animals (10 per group) reached final studies. There was no change in mean arterial blood pressure or Rentrop collateral score from gene delivery to final studies in either group, nor were there differences between study groups. MBF was significantly higher in the areas adjacent to the TA in the VEGF group under resting (P<0.001) and stress conditions (P<0.05). In addition, pVEGF165 gene transfer abolished flow differences between the adjacent areas and the septum. MBF was not different between study groups in the TA, the anterior wall, or the septum. In conclusion, direct intramyocardial pVEGF165 gene transfer significantly improves myocardial blood flow. However, this effect is limited to the myocardial segments adjacent to the area of gene delivery. These data, therefore, demonstrate a spatial 'delivery-efficacy' mismatch with implications for myocardial gene delivery sites and detection of treatment effects in vivo.
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, UK.
authors.forename: P W
authors.initials: PW
authors.lastname: Radke
authors.forename: A
authors.initials: A
authors.lastname: Heinl-Green
authors.forename: O M
authors.initials: OM
authors.lastname: Frass
authors.forename: U
authors.initials: U
authors.lastname: Griesenbach
authors.forename: S
authors.initials: S
authors.lastname: Ferrari
authors.forename: D M
authors.initials: DM
authors.lastname: Geddes
authors.forename: E W F W
authors.initials: EW
authors.lastname: Alton
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D002908:Chronic Disease; D003326:Coronary Circulation / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006339:Heart Rate / Q000502:physiology; D017202:Myocardial Ischemia / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013552:Swine; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015500:Chloramphenicol O-Acetyltransferase