Marc Ruel1, Vincent Chan1, Erik J. Suuronen1, Fraser D. Rubens1, Frank W. Sellke2, Nancy Camack3, Duncan J. Stewart3, Robert S. Beanlands1, Thierry G. Mesana1; 1University of Ottawa Heart Institute, Ottawa, ON, Canada; 2Beth Israel Deaconess Medical Center - Harvard Medical School, Boston, MA; 3St.Michael's Hospital - University of Toronto, Toronto, ON, Canada
Objective: Recent evidence suggests that the high prevalence of endothelial dysfunction and decreased bioavailable nitric oxide (NO) is a main reason why therapeutic angiogenesis, and more recently cell therapy, have generally failed in humans. Building from preclinical work, the Phase I EMAT study tested the hypothesis that L-arginine, a NO donor, is safe and may potentiate surgical angiogenesis.Methods: Patients (n=19) with surgical triple-vessel disease and a severely diffusely diseased left anterior descending (LAD) artery were randomized in 2x2 factorial fashion to receive ten 200µg injections of VEGF165 plasmid DNA or placebo in the anterior myocardium along the proximal and mid LAD, plus oral L-arginine supplementation at a dose of 6 g/day or placebo for 3 months. The distal LAD and other coronary arteries were grafted using arterial grafts. Primary end-points were 3-month changes in myocardial perfusion and contractility of the anterior myocardium, using 13-N ammonia cardiac positron-emission tomography (PET), radionuclide angiography, and echocardiography. Baseline scans were obtained 3-6 days postop to delineate the effects of CABG against subsequent treatment effects. Analyses were nonparametric. [Registered at ClinicalTrials.gov, NCT00134433]
Results: Preoperative patient characteristics were equivalent between groups. There was no perioperative or late mortality. After adjustment for early post-CABG baseline, patients who received the combination of VEGF165 injections and L-arginine supplementation had improved proximal and mid anterior wall perfusion on 13-N ammonia PET (P=0.08, Kruskall-Wallis), less ischemia, and significantly better contractility (P=0.02, Kruskall-Wallis) of the corresponding myocardial territory at 3 months. This corroborated with a trend towards better 3-month disease perception on the Seattle Angina Questionnaire (score improvement of 47±35, dual treatment group; P=0.1, Kruskall-Wallis).
Conclusion: This study is, to our knowledge, the first to intervene with concomitant substrate modification in patients receiving new biosurgical therapies, here using VEGF165 angiogenesis. Results suggest both safety and efficacy. Concomitant endothelial modulation with L-arginine or equivalent not only has the potential to make angiogenesis effective, but may also be of use in cell therapy trials.
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