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CLINICAL RESEARCH: CLINICAL TRIAL

A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina

Cindy L. Grines, MD, FACC^*,*, Matthew W. Watkins, MD, FACC, John J. Mahmarian, MD, FACC, Ami E. Iskandrian, MD, FACC, Jeffrey J. Rade, MD, FACC^||, Pran Marrott, MRCP, MSc^¶, Craig Pratt, MD, FACC, Neal Kleiman, MD, FACC for the Angiogenic GENe Therapy (AGENT-2) Study Group

^* Department of Medicine, Section of Cardiology, William Beaumont Hospital, Royal Oak, Michigan, USA
Department of Medicine, University of Vermont, Burlington, Vermont, USA
Department of Medicine, Section of Cardiology, The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA
Department of Medicine/Section of Cardiology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
^|| John Hopkins, Baltimore, Maryland, USA
^¶ Berlex Laboratories, Montville, New Jersey, USA

^* Reprint requests and correspondence: Dr. Cindy L. Grines, Division of Cardiology/3rd Floor Heart Center, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073-6769, USA.
cgrines{at}beaumonthospitals.com

OBJECTIVES: 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 10¹⁰ 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.

Abbreviations and Acronyms   ANOVA = analysis of variance   CABG = coronary artery bypass graft   CK = creatine kinase   FGF = fibroblast growth factor   HIV = human immunodeficiency virus   RPDS = reversible perfusion defect size   SGOT = serum glutamic-oxaloacetic transaminase   SGPT = serum glutamic-pyruvic transaminase   SPECT = single-photon emission computed tomography   99mTc = technetium-99m

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