Concomitant treatment with oral L-arginine improves the efficacy of surgical angiogenesis in patients with severe diffuse coronary artery disease: the Endothelial Modulation in Angiogenic Therapy randomized controlled trial.
OBJECTIVE
Endothelial dysfunction and decreased nitric oxide bioavailability may explain why therapeutic angiogenesis and cell therapy have mostly failed in humans. Building from previous large animal work, the Phase I Endothelial Modulation in Angiogenic Therapy trial tested the hypothesis that L-arginine, a nitric oxide donor, may be safe and effective in potentiating surgical angiogenesis in humans.


METHODS
Patients with surgical triple-vessel coronary disease and a severely diffusely diseased left anterior descending artery were randomized in 2 x 2 factorial fashion to receive ten 200-microg injections of vascular endothelial growth factor-165 plasmid DNA or placebo in the anterior myocardium along the proximal and mid-left anterior descending arteries, plus oral L-arginine supplementation at a dose of 6 g per day or placebo for 3 months. The distal left anterior descending artery and other coronary arteries were grafted. End points included 3-month changes in myocardial perfusion and contractility of the anterior myocardium, using (13)N-ammonia positron emission tomography and echocardiography. Baseline scans were obtained 3 to 7 days postoperatively to delineate treatment effects from the effects of coronary artery bypass grafting.


RESULTS
Patient (N = 19) characteristics were equivalent between groups. There was no perioperative or late mortality. Patients who received the combination of vascular endothelial growth factor and L-arginine had improved anterior wall perfusion on positron emission tomography (P = .02), a trend toward smaller perfusion defects (P = .10), and better anterior wall contractility (P = .02, Kruskal-Wallis) at 3 months versus baseline. This was corroborated by a trend toward better disease perception at 3 months versus baseline on the Seattle Angina Questionnaire (score improvement of 47 +/- 35, combination treatment group; P = .1, Kruskal-Wallis).


CONCLUSIONS
To our knowledge, this is the first study to examine concomitant substrate modification in patients undergoing new biosurgical therapies by using vascular endothelial growth factor angiogenesis. The results suggest safety and efficacy. Concomitant endothelial modulation with L-arginine not only has the potential to make angiogenesis effective but also may have implications for cell therapy trials.
Ruel
Marc
M
Division of Cardiac Surgery, University of Ottawa, Ottawa, Ontario, Canada. mruel@ottawaheart.ca
Beanlands
Robert S
RS
Lortie
Mireille
M
Chan
Vincent
V
Camack
Nancy
N
deKemp
Robert A
RA
Suuronen
Erik J
EJ
Rubens
Fraser D
FD
DaSilva
Jean N
JN
Sellke
Frank W
FW
Stewart
Duncan J
DJ
Mesana
Thierry G
TG
D000284:Administration, Oral; D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage*; D001120:Arginine / Q000008:administration & dosage*; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000601:surgery; D003326:Coronary Circulation / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D049268:Positron-Emission Tomography; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
D043925:Angiogenesis Inducing Agents; D020030:Nitric Oxide Donors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D001120:Arginine