title: A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina.
abstract: OBJECTIVE
  The primary objective of this study was to determine whether intracoronary administration of the adenoviral gene for fibroblast growth factor (Ad5FGF-4) can improve myocardial perfusion compared with placebo.
  
  
  BACKGROUND
  Animal studies and observational clinical studies have shown improvement in perfusion of the ischemic myocardium using genes encoding angiogenic growth factors; however, randomized, double-blind data in humans are lacking.
  
  
  METHODS
  We performed a randomized, double-blind, placebo-controlled trial of intracoronary injection of 10(10) adenoviral particles containing a gene encoding fibroblast growth factor (Ad5FGF-4) to determine the effect on myocardial perfusion. Fifty-two patients with stable angina and reversible ischemia comprising >9% of the left ventricle on adenosine single-photon emission computed tomography (SPECT) imaging were randomized to gene therapy (n = 35) or placebo (n = 17). Clinical follow-up was performed, and 51 (98%) patients underwent a second adenosine SPECT scan after 8 weeks.
  
  
  RESULTS
  Overall (n = 52), the mean total perfusion defect size at baseline was 32.4% of the left ventricle, with 20% reversible ischemia and 12.5% scar. At eight weeks, Ad5FGF-4 injection resulted in a significant reduction of ischemic defect size (4.2% absolute, 21% relative; p < 0.001) and placebo-treated patients had no improvement (p = 0.32). Although the change in reversible perfusion defect size between Ad5FGF-4 and placebo was not significant (4.2% vs. 1.6%, p = 0.14), when a single outlier was excluded a significant difference was observed (4.2% vs. 0.8%, p < 0.05). Ad5FGF-4 was well tolerated and did not result in any permanent adverse sequelae.
  
  
  CONCLUSIONS
  Intracoronary injection of Ad5FGF-4 showed an encouraging trend for improved myocardial perfusion; however, further studies of therapeutic angiogenesis with Ad5FGF-4 will be necessary.
authors.affiliation: Department of Medicine, William Beaumont Hospital, Royal Oak, Michigan, 48073-6967 USA. cgrines@baeumonthhospitals.com
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Grines
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Watkins
authors.forename: John J
authors.initials: JJ
authors.lastname: Mahmarian
authors.forename: Ami E
authors.initials: AE
authors.lastname: Iskandrian
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rade
authors.forename: Pran
authors.initials: P
authors.lastname: Marrott
authors.forename: Craig
authors.initials: C
authors.lastname: Pratt
authors.forename: Neal
authors.initials: N
authors.lastname: Kleiman
mesh_terms: D000241:Adenosine; D000256:Adenoviridae / Q000235:genetics*; D000787:Angina Pectoris / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D003326:Coronary Circulation / Q000502:physiology*; D004311:Double-Blind Method; D005260:Female; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D019275:Radiopharmaceuticals; D005346:Fibroblast Growth Factors; D017256:Technetium Tc 99m Sestamibi; D000241:Adenosine