Study Is First Ever To Document Protein Therapy Induces Creation Of New Blood Vessels To The Human Heart

February 24, 1998

DALLAS, Feb. 24 -- For the first time, scientists have published research evidence that recombinant protein therapy can create new blood vessels to increase blood supply to the human heart. The report from German scientists appears in today's Circulation: Journal of the American Heart Association.

FGF-I, a human growth factor obtained through genetic engineering, was used in 20 patients with some form of ischemic or coronary heart disease, which results from blockages in the vessels leading to and from the heart. By injecting the growth factor near the blocked vessels, the scientists were able to induce neoangiogenesis -- the process by which the body can grow its own new capillary network to bypass occluded vessels.

"This capillary network is a true de novo vascular system," says Thomas-Joseph Stegmann, M.D., head of the department of thoracic and cardiovascular surgery at the Fulda Medical Center, Fulda, Germany. "We were able to use the recognized physiological effects of FGF-I to induce neoangiogenesis in the human ischemic heart."

As early as four days after application of FGF-I, the vascular structure around the diseased vessels was completely altered in all 20 of the patients. Like the spokes of a bicycle wheel, the new capillary vessels radiated outward from the point of injection, resulting in a twofold to threefold increase in blood flow to the heart, says the study's lead author.

Researchers found, on average, the ejection fraction of the 20 patients improved from 50.3 percent to 63.8 percent in the three years following the procedure. Ejection fraction measures how much blood leaves the heart with each beat and indicates how well the left ventricle -- the heart's main pumping chamber -- is functioning.

In follow-up angiographic imaging of the patients, it was clear that the growth factor injection had stimulated the creation of a new vascular system, says Stegmann. Three months after the procedure, he and his colleagues examined angiograms -- X-ray images of the heart -- of both the treated and control (untreated) patients and found that no blockages had formed in the new vessels.

All of the patients who received the FGF-I three years ago are still alive. The scientists report that no negative side effects have been seen in the patients who received the FGF-I.

Elizabeth Nabel, M.D., an American Heart Association board member, has done extensive research in gene and recombinant protein therapy over the past 12 years. She says this new research is encouraging for cardiovascular surgeons.

"It's a very important therapy for patients who have blocked arteries that are not amenable to bypass," says Nabel, professor of internal medicine and physiology and chief, division of cardiology at the University of Michigan. "This is not to say that bypass should be abandoned, but this research shows angiogenesis is a powerful therapy to be used with bypass surgery."

The procedure is still experimental, but scientists say the use of FGF-I may particularly benefit patients whose blocked vessels cannot be treated by cardiac bypass operations.

"At the moment, this procedure could not replace conventional bypass surgery," says Stegmann. "The question remains to be answered whether FGF-I or other growth factors are able to treat occlusions of greater coronary vessels, but currently, this is not possible."

Scientists have used gene therapy to grow vessels in other parts of the body -- such as in the legs in order to improve the health of patients who have blockages in lower leg blood vessels -- but this is the first published account of the use of recombinant protein therapy to induce angiogenesis in human hearts.

FGF-I was obtained from strains of Escherichia coli by genetic engineering, then isolated and highly purified the recombinant FGF-I protein. After several series of animal experiments demonstrated the potency of FGF-I, it was used in humans for the first time.

When scientists create recombinant protein, they take the DNA of a growth factor (in this case FGF-I) and manipulate it into RNA (ribonucleic acid) by growing it in bacteria cultures in the laboratory. RNA is then manufactured into protein, which is isolated and purified before it is injected into the hearts of patients.

Twenty patients -- 14 men and 6 women who were at least 50 years old -- who had no prior history of heart attack or cardiac surgery had an operation to clear blockages in more than one vessel. All of them had stenosis -- narrowed blood flow due to atherosclerosis -- in their internal mammary artery/left anterior descending coronary artery. During the operative procedure, the growth factor protein -- in a dosage of 0.01 milligrams per kilogram of body weight -- was directly injected into the heart muscle near the blockage.

Prior to using the treatment in humans, the scientists performed several series of animal experiments, most specifically in ischemic rat hearts. Having found that the FGF-I injection worked in those animal models, the researchers theorized that it would also work in humans.

Study co-authors are P. Pecher, M.D.; B.U. von Specht, M.D. and B. Schumacher, M.D.
Media advisory: Dr. Schumacher can be contacted by phone at 011 49 661 842 461 or by fax at 011 49 661 842 463. (Please do not publish numbers.) q\nmr\jrnls98\feb24\Schumacher

American Heart Association

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