NEW ORLEANS, Nov. 12 – In one of the largest follow-up studies to date, researchers have shown that gene therapy for heart disease may relieve chest pain and does not increase the risk for cancer, according to a study reported today at the American Heart Association’s Scientific Sessions 2000. Since gene therapy is used to stimulate the growth of new blood vessels, there has been concern that therapy may lead to overgrowth of other cells in the body, increasing the risk for cancer or other problems.
Among 102 patients in the study, there were no significant differences in deaths, heart attacks or cancer over the course of one year, whether they received placebo or a high or low dose of the protein used in the gene therapy.
“The long-term safety looks excellent,” says lead author Timothy D. Henry, M.D., director of interventional cardiology at Hennepin County Medical Center and associate professor of medicine at the University of Minnesota in Minneapolis. “There was no increase in adverse events, which some scientists have suggested might occur. If anything, it looks as if there is a lower rate of adverse events in patients getting the higher dose.”
A new concept in heart research is that prodding new vessel growth will increase the blood flow to the heart in people whose arteries are narrowed by fatty deposits. Such deposits reduce the flow of blood and oxygen to the heart, which can cause chest pain known as angina. The deposits can also trigger heart attacks.
The protein, called vascular endothelial growth factor (VEGF), is produced by the body and initiates the growth of new blood vessels, a process called angiogenesis. VEGF is one of a number of proteins involved in vessel growth.
Researchers are exploring two ways to use it: One is gene therapy, in which the gene that commands cells to produce VEGF is introduced into heart cells, that will then produce the protein. The other approach, which Henry and his colleagues used, is to treat patients with the VEGF protein. The study included individuals who participated in the VEGF in Ischemia for Vascular Angiogenesis (VIVA) trial. The 178 patients in that study all suffered severe angina, almost 90 percent had undergone at least one bypass operation, and almost 75 percent had undergone at least one angioplasty to open their narrowed arteries.
Participants received a placebo, 17 nanograms of VEGF, or 50 nanograms of VEGF per kilogram of body weight each minute during four treatments. In the first treatment, participants received their dose by infusion directly into the heart arteries for 20 minutes. On the third, sixth, and ninth days after their initial therapy, they received a 4-hour intravenous infusion.
The study participants were followed for four months. Results of the initial VIVA trial were reported at the American Heart Association’s Scientific Sessions in 1999. Those in the follow-up study reported today were tracked for another eight months.
“One of the prominent findings of the VIVA trial was a very strong placebo effect; even the placebo patients got better,” Henry says. “In the follow-up study we wanted a longer-term look at the safety of VEGF itself and at this placebo effect as well.”
Theoretically, stimulating new blood vessel growth could increase a person’s risk of cancer or a heart attack. A cancer tumor requires blood vessels to grow to a life-threatening size. If a person had a tumor the size of a pinhead, there was a question of whether giving VEGF might spur vessel growth into the cancer and cause it to grow. “That didn’t happen,” Henry says.
One study in animals also suggests that if tiny new blood vessels grow into the walls of arteries, these new vessels might speed up the growth of fatty deposits or make them more likely to rupture and cause a heart attack. That scenario also failed to play out.
“The incidence of death and heart attack in this group of high risk patients was surprisingly low,” Henry says.
At the end of one year, 3 percent of the placebo group, 6 percent of the low-dose, and none of the high-dose VEGF group had died. Three percent of those receiving the placebo, none of the low-dose, and 6 percent of the high-dose group had suffered a heart attack.
As for cancer, 8 percent on placebo, 3 percent on low-dose VEGF, and no one on the high dose developed cancer. Overall, 26 percent of the placebo group, 22 percent of the low-dose group, and 13 percent of those on high-dose VEGF died, had a heart attack, developed cancer, or required a revascularization procedure, such as bypass surgery.
The effect on patients’ angina was also encouraging, Henry says. He reports that after one year, those in the high-dose group had less chest pain than the placebo group.
“The findings are encouraging, but certainly not conclusive,” he says. “On the other hand, it’s the best data we have so far in this field, and it is strong evidence that VEGF protein is safe. This is an initial study that needs to be confirmed with additional studies.”
Co-authors are George R. McKendall, M.D.; Michael A. Azrin, M.D.; John Lopez, M.D.; Raymond Benza, M.D. James T. Willerson, M.D.; John Giacomini, M.D.; Rachel Olson, R.N.; Bradley A. Bart, M.D.; Joseph P. Roel, B.S.; and Brian H. Annex, M.D.
NR00-1193 (SS2000/Henry)