The first double-blind, placebo-controlled randomized trial of VEGF gene injections into the heart muscle of patients with coronary artery disease with the intention of spurring growth of new blood vessels showed significant effects on heart wall motion, although blood flow was not significantly better in treated patients, according to a new study in the April 5, 2005, 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 Sylvén, M.D., F.A.C.C., at the Karolinska University Hospital at Huddinge in Stockholm, Sweden.
The researchers, including lead author Jens Kastrup, M.D., 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 (VEGF). VEGF is involved in angiogenesis, the growth of new blood vessels. A plasmid is a circular, double-stranded unit of DNA that is usually found in bacteria.
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 heart muscle of half the patients. The other half of the patients received similar injections with a plasmid that did not carry the active gene. Neither the patients nor the researchers knew whether the active or placebo injections were being used 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 VEGF 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,” Dr. Sylvén said.
Dr. Sylvén, who was the principal investigator on this trial, said these results should encourage phase III clinical trials of the gene therapy technique for promoting new blood vessel growth in the hearts of patients. However, he said academic research into this “biological bypass” technique has been hampered by commercial interests.
“Unfortunately, genes are patented, so progress and the benefit of the patient cannot be provided if the patent holder does not have an interest in it. Instead, we see that studies are being made with genes that have suboptimal capacity for angiogenesis. This situation is not the best for the advancement of science and the benefit of the patient,” Dr. Sylvén said.
The researchers used a device called the NOGA-Myostar system to deliver the gene transfer plasmid to the heart muscle of patients. The catheter device is threaded into the heart through major blood vessels, where it is used to map the area of heart muscle to be treated and then inject the treatment into the muscle. Five patients suffered complications, including temporary loss of vision, infections, heart arrhythmia, heart attack, and fluid around the heart. During a diagnostic NOGA procedure, before randomization, one patient developed fluid around the heart and then died of a heart attack 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,” Dr. Sylvén 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, M.D., F.A.C.C., 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,” Dr. Losordo said.
The American College of Cardiology, a 31,000-member nonprofit professional medical society and teaching institution, is dedicated to fostering optimal cardiovascular care and disease prevention through professional education, promotion of research, leadership in the development of standards and guidelines, and the formulation of health care policy.