The first double-blind, placebo-controlled randomized trial of vascular endothelial growth factor gene injections into the myocardium of patients with coronary artery disease showed significant effects on heart wall motion, although blood flow was not significantly improved, according to an article in the April 5th issue of the Journal of the American College of Cardiology.

“It appears to be remarkable that a treatment effect can be observed with such a limited number of patients as in this study,” said Christer Sylven, MD, FACC, at the Karolinska University Hospital at Huddinge in Stockholm, Sweden.
The researchers, including lead author Jens Kastrup, MD, at the University Hospital Rigshospitalet in Copenhagen, Denmark, studied the effects of injecting patients with a special plasmid that could transfer a gene for vascular endothelial growth factor. The growth factor is involved in angiogenesis.

The 80 participants had severe coronary artery disease that could not be successfully treated with bypass surgery, angioplasty or stenting. Researchers injected the gene-transfer plasmid into the myocardium of half the patients. The other half received similar injections with a plasmid that did not carry the active gene. Neither the patients nor the researchers knew who received active or placebo injections until the end of the study.

“As in all studies in this field, the placebo effect is pronounced; so both groups improved and there were no significant differences between the two treatment groups in reports of angina pectoris, chest pain, at follow-up. The primary endpoint was myocardial perfusion. This improved in the vascular endothelial growth factor group compared to baseline, but not to the placebo group. However, compared to placebo, regional heart wall motion in the treated region improved as assessed by two independent methods,” Sylven said.

The researchers used a device called the NOGA-Myostar system to deliver the gene transfer plasmid to myocardium. The catheter device is threaded into the heart, where it is used to map the area of myocardium to be treated and then injects the treatment into the muscle.

Five patients suffered complications, including temporary loss of vision, infections, heart arrhythmia, myocardial infarction, and pericardial effusion. During a diagnostic NOGA procedure, before randomization, one patient developed pericardial effusion and then died from a myocardial infarction during emergency surgery.

“The NOGA method is definitely a very invasive procedure with obvious adverse events. It is important to consider it as an investigational method until it has become refined with an acceptable rate of adverse events,” Sylven said. “As regards VEGF, two potential adverse effects may be considered. One is promoting tumor growth and the other is atherosclerosis. Patients were screened for signs of tumor growth, which was an exclusion criterion. No signs of tumor growth or increased atherosclerosis were observed.”

Douglas W. Losordo, MD, FACC, at the Tufts University School of Medicine in Boston, who was not connected with this study, said it is very important for two reasons.

“First, it is the largest study of intramyocardial gene therapy and shows that the procedure can be done safely in a multicenter study. Second, and perhaps most exciting, is the finding that the heart muscle function improved after angiogenic gene therapy. This is important from a practical standpoint, indicating that this approach could play a role in heart failure treatment. It also underscores the importance of the microvasculature of the heart, the tiny vessels that actually feed the muscle cells. There has been a long standing notion that this system of tiny tributaries could be a key player in the progression of heart problems, and this study provides very clear evidence that the microvasculature is a therapeutic target of potentially great importance,” Losordo said.