Researcher Michael Simons. Photo by Rose Lincoln.

A year ago, John Modugno, 49, couldn't lift a bag of groceries or take out the garbage without feeling sharp angina pains in his heart. Now he can work out a half-hour a day on an exercise bike.

Steve Cadoret, 41, "ate nitroglycerin pills like candy," and a triple bypass failed to stop progressive blocking of his coronary arteries. Today he is back working part time and feels "fantastic."

Both men were what surgeons darkly refer to as "no- option" patients, those dying from heart disease who have run out of the standard surgical and drug remedies. Both volunteered to have growth factors implanted or injected into their hearts in the hope that these proteins would stimulate growth of new blood vessels and relieve their distress. So far, it has worked.

The tests began in 1996 at Harvard Medical School and its affiliate, the Beth Israel Deaconess Medical Center in Boston. Now researchers are reporting the first evidence that this type of treatment is successful. Seven out of seven patients who had high doses of basic fibroblast growth factor (bFGF) implanted in their hearts last year report almost miraculous improvement in their lifestyles and ability to work and exercise.

Out of 66 patients given the growth factor by injection, "about 80 percent show a reduction in their symptoms and an increased capability for exercise," according to Michael Simons, associate professor of medicine at Harvard.

Not all the patients, however, are enjoying such extraordinary recovery. "Some are remarkably better, some are somewhat better, and some received no benefit at all," Simons admits. "But we believe the science behind the therapy is good, and we're optimistic that it will work when we learn how to give the right agents in the right doses at the right time."

"There has not been this much excitement and enthusiasm since the advent of bypass surgery [in 1967]," notes Roger Laham, a cardiologist who has implanted and injected bFGF into dozens of patients at Beth Israel Deaconess Medical Center. "If this works, it will be a revolution in treating heart disease patients."

Heart Injections

Simons and Laham reported on the first 24 patients who received bFGF at a meeting of the American College of Cardiology in New Orleans last week.

All of the patients underwent bypass surgery, in which leg veins are grafted into the heart to carry blood around arteries blocked by deposits of fat and calcium. At the same time, surgeons implanted plastic capsules that leaked high or low doses of bFGF into the hearts of 16 patients. The remaining eight received placebos, capsules that released an inactive substance.

A few months later, seven of the high-dose patients were free of chest pain (angina), shortness of breath, fatigue, and other symptoms of heart disease. John Modugno, who received the drug in February 1998, was one of these people. Four of seven who received a low dose of bFGF, and three of seven who got the placebo also improved. (Three patients did not complete the full treatment.)

"We were very pleased to see this response," Simons says. "But the number of patients was too small to tell us much more than that the drug is safe and can be effective in certain cases."

The next step involved giving bFGF to 52 patients by injecting it directly into their hearts; 14 others got intravenous shots. For the heart injection, cardiologists made a small incision in patients' groins, then threaded a narrow tube through blood vessels leading to their hearts. The injection was given through the tube, or catheter. Steve Cadoret underwent this treatment last July.

"Although many patients are doing well, we don't know why others are not," notes Laham, who performed 35 of these procedures. Researchers gave no placebos in this study, making it impossible to separate the results of the medication from improvements that might occur naturally.

"People have been told, 'there's nothing more we can do for you,'" Simons points out. "Then you offer them a possible miracle cure. That makes them quite susceptible to the placebo effect, to significant improvements gained from hope and expectations."

"I think we'll find that growth factors are effective," Laham says. "But we need larger placebo- controlled studies to prove that to ourselves and to others."

Such a study began in February. It involves 300 people at 15 medical centers worldwide.

An Exploding Field

Researchers at different centers have been injecting another protein, called vascular endothelial growth factor (VEGF), into sick hearts. In one experiment with 165 patients, results were disappointing. It was hoped that these volunteers would improve enough to exercise on a treadmill without chest pain, but that didn't happen.

"This may not mean that VEGF doesn't work," Simons cautions. "The drug might not have been given in the right way or in the right dose. It might not have stayed in the heart long enough to grow new blood vessels." Simons has also experimented with VEGF but believes that bFGF is a better drug.

Others are investigating the potential of gene therapy. Instead of injecting growth factor into a heart, they inject a gene that instructs the body to make the factor. This technique may provide a longer- lasting supply of the protein.

"This whole field is exploding," Simons says. "I don't know if the agents we're currently using will be the best, and it may take 5 to 10 years to figure out how to do it right. But eventually I think we'll be able to grow new blood vessels, significantly changing the way cardiac patients are treated."

The American Heart Association estimates that between 400,000 and 500,000 bypass surgeries are performed each year in the United States alone, at a cost of about $45,000 per treatment. "Growth factor treatment could greatly reduce these numbers," Simons says.

Many of the patients participating in the bFGF studies previously were treated with bypass surgery and angioplasty. In the latter, a physician maneuvers a thin catheter carrying a tiny balloon into a partly blocked blood vessel, then inflates the balloon to push the obstruction aside. Although metal "stents" are sometimes inserted to keep the vessel open, about one-third of them close again, some in a matter of months.

Cadoret underwent "10 or 12 angioplasties and a triple bypass before getting bFGF," he notes.

Simons and his colleagues have taken photographs of new vessels growing around blocked arteries in animals given growth factors. You can see small extensions of the vessels sprouting like twigs on a tree limb, moving around the obstruction, then reconnecting to the vessel on the other side.

"If we can do the same in humans, and I feel confident we can, we will have an opportunity to benefit, not only 'no- option' patients, but millions of others in danger of heart failure and suffering the chest pains of angina."