By Tim Bonfield
The Cincinnati Enquirer

Researchers say the latest way to prevent a serious complication from coronary bypass surgery could be a good soaking.

Two Tristate hospitals have begun recruiting patients who need bypass operations to participate in a nationwide study of a genetic therapy that could sharply reduce complications and make bypass vein grafts last years longer.

Soaking the leg vein often used in bypass surgeries in a special solution could make it less vulnerable to closure later, which can lead to health problems and even second bypass operations.

INFOGRAPHIC

• A new step in bypass surgery

The soaking therapy - called "E2F Decoy" - could be one of the biggest advances in years for an operation performed on more than 300,000 Americans a year. It's big enough that the U.S. Food and Drug Administration recently put the product on its fast-track approval process.

Now, more than 100 medical centers nationwide are involved in final testing of the product in up to 3,000 patients. As many as 40 Tristate patients could be enrolled in the study this year through Good Samaritan or Bethesda North hospitals, the only local hospitals participating.

"The data we've seen so far is compelling," said Dr. J. Michael Smith, a cardiothoracic surgeon at Good Samaritan who recently has started using a robot to perform heart surgery. "Not only can this therapy prevent early closure, it could make vein grafts last almost indefinitely."

Blocking inflammation

The technology at the heart of the E2F Decoy reflects the boom in advances flowing from research into genetic therapies for many kinds of disease.

In this case, researchers at Brigham and Women's Hospital in Boston and Stanford University in California discovered a way to block an inflammation reaction that has been noted for years as a complication of bypass surgery.

In about 70 percent of traditional bypass operations, surgeons harvest a segment of vein from the patient's leg to use as a new artery that allows blood to flow around a blocked coronary artery. Bypass operations also can be done using a mammary artery.

The leg vein, which doesn't carry blood under the same pressure or volume as vessels near the heart, naturally has thinner walls than coronary arteries. In reaction to the sudden change in function, to the trauma of being cut from the leg, and possibly to other factors, the interior lining of the vein graft begins to grow and swell.

For most patients, the swelling settles down within weeks after surgery, resulting in a thicker vein wall that mimics an artery. But for some, the swelling doesn't stop soon enough, and can close off the bypass.

As many as 15 percent of bypass patients suffer vein graft closure with three months to a year of their operation. Another 10 percent to 12 percent suffer graft closure five to 10 years later, Smith said.

Graft failures can result in chest pain, loss of energy and other symptoms. In rare situations the complication can lead to heart attack and death, but more commonly the problem is caught soon enough to perform an angioplasty or a second bypass operation.

Repeat bypass operations are not desirable because patients must endure a risky surgery in a weakened state of health and because they add to the overall costs of health care.

"Getting a bypass is a road you only want to go down once," said Dr. Michael Mack, president and chairman of the Cardiopulmonary Research Science and Technology Institute in Dallas, where 90 patients already are enrolled in the E2F Decoy trial.

"Potentially this is a big deal because it could make bypasses last longer, and that would have a major impact on people with heart disease," Mack said.

Various medications have been studied to control the inflammation process, but they have not been effective because they block only a few of at least 12 known biological "pathways" that can trigger the inflammation, Smith said.

The E2F Decoy appears to block all the pathways at once.

How it works

After harvesting the vein segment, surgeons place the graft in a thin glass tube filled with a special solution containing the E2F Decoy.

The decoy is a genetically engineered segment of DNA that binds to cells in the vein graft. The decoy does nothing to the cell. However, it occupies receptors that normally would catch a human "messenger" protein that is known to trigger rapid cell growth and inflammation.

"It's not gene therapy in the truest sense of the word because you are not injecting genetic material that changes a person's DNA," Mack said. "But it is genetically related because you are blocking the function of a gene within the cells of the vein wall that make a product that turns on the unwanted cell growth."

To properly infuse the cells with the E2F decoy, the solution must be soaked into the vein under pressure. After a 10-minute soak, surgeons complete the bypass operation by connecting the vein from the aorta to a point beyond the blocked coronary artery.

In small-scale clinical trials, the therapy reduced the rate of early bypass complications by about 40 percent. Side effects have been minimal. .

It will require several more years of study to measure the product's long-term effect. But any improvement would be welcome, Smith said, because more than 30 percent of patients who get bypass operations wind up coming back within 10 years for another heart procedure, including angioplasty and replacement bypass operations.

The E2F Decoy is made by Corgentech Inc., a California biotech company founded in 1999. Since publishing early findings in 1999 in the British medical journal Lancet, the company has attracted more than $50 million in development financing from investors.

In addition to studying the product for coronary bypass operations, Corgentech is researching whether the product will work in leg bypass operations and in vein grafts used by kidney dialysis patients.

The coronary bypass trial is being coordinated by the Duke Clinical Research Institute at Duke University Medical Center, and by the Society of Thoracic Surgeons.

In Cincinnati, about 20 patients will be enrolled at Good Samaritan and another 20 at Bethesda North. The clinical trial is a "double-blind" study, which means that neither patients nor their doctors will know if the patient gets the actual E2F Decoy solution or a placebo solution made from saline. Results will be measured by angiograms performed 12 months after surgery.

E-mail tbonfield@enquirer.com