Despite the promise of proangiogenic gene therapy most clinical trials have failed to show benefit for the primary end point analysis. The NOGA angiogenesis Revascularization Therapy: assessment by RadioNuclide imaging (NORTHERN) trial was a double-blind, placebo-controlled study of intramyocardial vascular endothelial growth factor (VEGF165) gene therapy versus placebo, involving seven sites across Canada, designed to overcome major limitations of previous proangiogenic gene therapy trials. A total of 93 patients with refractory Canadian Cardiovascular Society (CCS) class 3 or 4 anginal symptoms were randomized to receive 2,000 microg of VEGF plasmid DNA or placebo (buffered saline) delivered via the endocardial route using an electroanatomical NOGA guidance catheter. There was no difference between the VEGF-treated and the placebo groups in the primary end point of change in myocardial perfusion from baseline to 3 or 6 months, assessed by single photon emission tomography (SPECT) imaging, although a significant reduction in the ischemic area was seen in both groups. Also, similar improvements in exercise treadmill time and anginal symptoms were seen in the VEGF and the placebo groups at 3 and 6 months, although again there were no differences between these groups. Despite the intramyocardial administration of a high "dose" of plasmid DNA using a percutaneous guidance catheter system, there was no benefit of VEGF gene therapy at 3 or 6 months for any of the end points studied.