Circulation. 2002;105:2012-2018
Published online before print April 15, 2002, doi: 10.1161/01.CIR.0000015982.70785.B7
Published online before print April 15, 2002, doi: 10.1161/01.CIR.0000015982.70785.B7
(Circulation. 2002;105:2012.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Phase 1/2 Placebo-Controlled, Double-Blind, Dose-Escalating Trial of Myocardial Vascular Endothelial Growth Factor 2 Gene Transfer by Catheter Delivery in Patients With Chronic Myocardial Ischemia
From the Divisions of Cardiology (D.W.L., P.R.V., N.C., T.A., J.M.I.) and Cardiovascular Research (D.W.L., P.R.V., J.M.I., C.E.M.) Tufts School of Medicine/St Elizabeth’s Medical Center, Boston, Mass; Division of Cardiology, Rush-Presbyterian–St Luke’s Medical Center (R.C.H.), Chicago, Ill; Department of Cardiology, Scripps Clinic (F.D.F., R.A.S.), La Jolla, Calif; Harvard Medical School Division of Biometrics, Brigham and Women’s Hospital (R.E.K.), Boston, Mass.
Correspondence to Douglas W. Losordo, MD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu
Background— This phase 1/2 study investigated the safety of percutaneous catheter-based gene transfer of naked plasmid DNA encoding for vascular endothelial growth factor 2 (phVEGF2) to left ventricular (LV) myocardium in a prospective, randomized, double-blind, placebo-controlled, dose-escalating study of inoperable patients with class III or IV angina.
Methods and Results— A steerable deflectable 8F catheter with a 27-gauge needle at its distal tip was advanced percutaneously to the endocardial surface of the LV in 19 patients (age, 61±2 years) with chronic myocardial ischemia who were not candidates for conventional revascularization. Patients were randomized in a double-blind fashion to receive 6 injections (total volume, 6.0 mL) of placebo or phVEGF2 in doses of 200 µg (n=9), 800 µg (n=9), or 2000 µg (n=1) guided by LV electromechanical (NOGA) mapping with a gene-to-placebo ratio of 2:1. A total of 114 LV injections were delivered and caused no hemodynamic alterations, sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforation. End-point analysis at 12 weeks disclosed a statistically significant improvement in Canadian Cardiovascular Society (CCS) angina class in phVEGF2-treated versus placebo-treated patients (-1.3 versus -0.1, P=0.04). Remaining efficacy end points—including change in exercise duration (91.8 versus 3.9 seconds), functional improvement by 
2 CCS classes (9 of 12 versus 1 of 6), and Seattle Angina Questionnaire data—all showed strong trends favoring efficacy of phVEGF2 versus placebo treatment.
Conclusions— This phase 1/2, double-blind, randomized trial provides preliminary data that support safety of phVEGF2 catheter-mediated myocardial gene transfer. The statistically significant reduction in anginal class and strong positive trends for remaining end points suggest that a larger phase 2/3 trial is warranted.
Key Words: growth substances • gene therapy • ischemia • angina • angiogenesis
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