May 14, 1998
Harvard
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New Arteries Grown In Diseased Hearts

By William J. Cromie

Gazette Staff

Almost anything Hugh Curtis did gave him a pain in the heart. Even when lying in bed, he felt the stabbing chest pains of angina, a hurtful signal that his heart was not getting enough oxygen.

Curtis underwent a quadruple bypass in 1986, then a single bypass late last year. Surgeons removed veins from his legs and grafted them onto his heart to bypass his blocked coronary arteries. But that didn't solve his problem.

He also received a series of angioplasties, wherein tiny balloons were threaded into his heart's arteries, then inflated. This process pushed the blockages aside, opening his arteries. Five pieces of metal mesh were installed to keep them open, but his coronary arteries closed in other places.

"I couldn't walk very far, couldn't even make my bed," says the 55-year-old resident of Danvers, Mass. "Climbing stairs was out, so was any thought of going on vacation."

Late last year, he was asked by researchers at Beth Israel Deaconess Medical Center in Boston if he wanted to volunteer for an experimental procedure at the Harvard-affiliated hospital. The procedure involved doctors injecting proteins called growth factors into his heart to stimulate growth of new blood around those clogged with plaque.

"I didn't hesitate to give them the go-ahead," Curtis recalls.

The cardiologists threaded a thin hollow tube from his groin into his heart. Through the tube they injected what is called basic fibroblast growth factor, or bFGF.

Four months after the treatment, Curtis is back working full time at a desk job in a printing company. "I no longer take 3-to-6 nitroglycerin tablets a day, and I'm painting the hallway in my house," he says cheerily. "I may never go back to playing racquetball, but I'm leading a normal life, and that's all I'm looking for."

"All his symptoms are gone," says Michael Simons, associate professor of medicine at Harvard Medical School. "He is one of 18 patients who participated in a trial of bFGF. All are now largely without symptoms such as chest pain, shortness of breath, and fatigue."

 

Bypassing Bypass Surgery

Eighteen other patients who received heart-artery bypasses got bFGF at the same time. Frank Sellke, an associate professor of surgery at Harvard Medical School, implanted capsules that slowly release the drug at sites where blocked vessels were too small or too diffusely diseased to bypass.

"These patients have undergone treadmill stress tests," Simons comments. "They also have been examined with a new type of magnetic resonance imaging (MRI) that measures blood flow and detects new vessel development. It is too early to scream and shout with success, but we are pleased with the results obtained so far."

"I had an MRI a couple of weeks ago, and it showed new arteries growing and bypassing some blockage," says Curtis. "I'm getting 70 percent blood flow to an area of the heart that was down to 30 percent flow. And there's reason to think things will improve more with time."

John Modugno, 48, received bFGF in February, and his MRI tests also show evidence of new arterial growth. "I feel much better," he says, "although I'm still on drugs and get a little angina at the end of the day."

Tests of bFGF and other growth factors now under way at various research centers raise hopes that newly grown blood vessels will replace arteries choked off by atherosclerosis, thus heading off thousands, maybe millions, of heart failures and heart attacks.

If these tests continue to be successful in humans, they could lead to heart drugs that will be cheaper, safer, and a lot easier on patients than bypass surgery and angioplasty. About a million people undergo such procedures in the United States each year, but they don't always work. As in Hugh Curtis's case, some vessels are too small or located where they can't be bypassed with sections of vein. After arteries have been opened by an inflated balloon or other types of angioplasty, about one-third of them close again, some in a matter of months.

"We once thought people in which neither procedure worked accounted for only a small subgroup of patients," Simons says. "But now we're getting phone calls almost every day, so we must conclude that there are more people with this problem than we imagined."

The revolutionary potential of growth factors, of course, goes far beyond such people. Simons sees it as "having the potential to replace or reduce the use of bypass surgery." The American Heart Association estimates that 500,000 bypasses are performed each year at an average cost of $45,000 per treatment.

Severely blocked coronary arteries cause more than 3 million heart failures a year, and 7 million more people suffer the chest pains of angina. "Growth-factor treatments might be expanded to many, if not all, of these patients," Simons declares.

The Side-Effects Question

Researchers at Beth Israel Deaconess Medical Center initiated such treatments in 1996. Today, seven teams worldwide work on growing new blood vessels with bFGF and another protein known as vascular endothelial growth factor, or VEGF (see April 23 Gazette, page 1).

In a trial conducted at several medical centers, VEGF was given to 17 people whose blocked coronary arteries lay out of reach of angioplasty. Fifteen of the 17 patients showed various levels of improvement.

Jeffrey Isner, a cardiologist at St. Elizabeth's Medical Center in Boston, has used VEGF to grow new vessels around blockages in the leg veins of diabetics. He has treated 30 diabetic patients, as well as five other patients with heart disease.

"Preliminary results look good in both types of disease," Isner says. "This is a very encouraging and exciting area of treatment."

The great promise of bypassing blood-vessel blockages won't become a reality, however, if the growth factors cause severe side effects.

Both bFGF and VEGF lower blood pressure. "That fact limits the amount you can give a person," Simons notes. "But that's something we can work around."

More serious is the possibility of damage to sight caused by overgrowth of blood vessels in the eye. "We have been looking carefully for this, but have not seen any as yet with bFGF," Simons comments. Also, no new blood vessels were seen growing in the eyes of patients treated with VEGF, another encouraging sign.

The most worrisome possibility concerns growth of blood vessels that might nourish small, hidden cancer tumors. Judah Folkman, another Harvard researcher, found that such tumors remain benign unless new blood vessels carry nutrients to them. Once connected to a steady blood supply, tumors grow and spread.

Folkman and Michael O'Reilly developed two exciting new cancer drugs, endostatin and angiostatin, which block rather than promote development of blood vessels.

"We hope that tumor growth can be avoided because we give the growth factor for a very short time and in small amounts," Simons notes. "It's not like we're adding a foreign substance to the body; everyone has such small amounts of bFGF circulating naturally in their bloodstream."

The side-effects issue will be addressed in tests involving larger numbers of patients. Plans call for testing both growth factors on 400 to 500 people at a combination of medical centers throughout the country. Simons expects to start expanded trials of bFGF this summer in a collaboration with Emory University in Atlanta.

A question still to be answered is exactly how new blood vessels form. The bare-bones explanation has bFGF binding to the surface of, then stimulating growth of endothelial cells, those that line the inside of capillaries, the smallest vessels. These cells leave the vessels, migrate to the tip of the capillaries, and form a tube that extends their reach.

Simons's team took startling photos of new vessels growing around blocked arteries in animals. They show small extensions sprouting like twigs on a tree limb, moving around the barricade and reconnecting on the other side.

"It's amazing to see," Simons says. "If we can continue to do the same thing in humans, without deleterious side effects, we have a chance to benefit millions of people."

 


Copyright 1998 President and Fellows of Harvard College