Endothelial Modulation for Angiogenic Therapy

The EMAT trial tests the hypothesis that the concomitant treatment of chronic endothelial dysfunction in patients undergoing angiogenic therapy can make angiogenesis clinically effective. This is achieved with a 2x2 factorial, double-blind, placebo-controlled randomized trial of intramyocardial vascular endothelial growth factor (VEGF) angiogenesis at a dose of 2 mg and of adjunct endothelial modulation therapy using oral L-arginine supplementation at a dose of 6 g/day in patients undergoing surgical perivascular angiogenic therapy. The study involves surgical angiogenesis techniques similar to those previously used and reported to be clinically safe by the principal investigator and collaborators. Patients with a diffusely disease left anterior descending (LAD) coronary artery have this artery grafted with an internal thoracic artery in either its proximal or distal portion (according to what is felt by the surgeon to be most optimal as per usual practice). The segment of the LAD that is not directly bypassed (i.e. either the proximal portion if a distal bypass is performed by the surgeon or the distal portion if a proximal bypass is performed) is treated by the surgeon with VEGF angiogenesis or placebo injections. Other coronary arteries in need of bypass grafting are grafted as per usual practice, using arterial grafts. Patients are therefore randomized to one of four groups at the time of coronary artery bypass grafting:

* growth factor (VEGF) angiogenesis along the diffusely diseased, non-directly bypassed LAD segment + L-arginine oral supplementation; * placebo "angiogenesis" along the diffusely diseased, non-directly bypassed LAD segment + L-arginine oral supplementation; * growth factor (VEGF) angiogenesis along the diffusely diseased, non-directly bypassed LAD segment + placebo oral supplementation; and * placebo "angiogenesis" along the diffusely diseased, non-directly bypassed LAD segment + placebo oral supplementation.

The angiogenesis treatment consists either of the injection of 2 mg (divided in 10 injections of 200 μg each) of plasmid DNA encoding for the VEGF165 gene or of 10 x 1 ml injections of a sterile physiologic saline solution in the myocardial territory and septum along the diffusely diseased, non-directly bypassed LAD segment. Other myocardial territories are concomitantly revascularized with arterial coronary bypass grafts.

The EMAT trial's primary end-points relate to objective myocardial perfusion indices and contractility of the intervened anterior myocardial portion, respectively measured with cardiac positron-emission tomography (PET) by using the investigational radioisotope 13-N ammonia, and by RNA or echocardiography. Using 13-N PET, collateral-dependent blood flow and ischemic zone size are measured in a double-blind fashion by a single observer at baseline and at 3 months. To better delineate the actual effects of angiogenic therapy, baseline perfusion scans are obtained 3 to 5 days after the operative procedure in order to account for the potentially confounding effect of CABG on myocardial perfusion to the proximal and distal anterior and septal territories. The functional, secondary end-points of the EMAT trial consist of clinical outcomes including major adverse cardiac events (MACE), freedom from angina, and angina class.