A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina.
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.
Grines
Cindy L
CL
Department of Medicine, William Beaumont Hospital, Royal Oak, Michigan, 48073-6967 USA. cgrines@baeumonthhospitals.com
Watkins
Matthew W
MW
Mahmarian
John J
JJ
Iskandrian
Ami E
AE
Rade
Jeffrey J
JJ
Marrott
Pran
P
Pratt
Craig
C
Kleiman
Neal
N
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
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