Longer Life for Bypass Grafts?

A two-fisted protein slows the clogging of veins grafted into pig arteries. The finding, reported in tomorrow's Circulation, raises the prospect of gene therapy that could help people who've had coronary bypass surgery avoid a second operation.

In as few as 10 years, veins grafted into the heart often clog as badly as the diseased arteries they're meant to replace. Trouble starts when enzymes called matrix metalloproteinases (MMPs) eat away the scaffolding that attaches muscle cells to the vein walls. Freed to spread and multiply, the muscle cells build up and narrow the graft. The constriction traps fatty deposits, eventually narrowing enough to bring on a heart attack. Researchers led by Sarah George, a biologist at the University of Bristol, United Kingdom, knew that a protein called TIMP-3 can slow the migration of muscle cells by taking MMPs out of action, and instructing those cells that do break free to self-destruct.

George and her colleagues used a virus to insert the gene for TIMP-3 into cells of a portion of human vein kept in tissue culture. After 14 days, the protein had bound itself to the matrix surrounding the cells in the vein walls and had put the kibosh on MMP activity. The result: 84% less narrowing than in control veins. And as they had expected, the itinerant muscle cells committed suicide before getting the chance to create obstructions. The researchers next put veins from a dozen pigs through the TIMP-3 treatment, then grafted them into the animals' carotid arteries. After 28 days, the treated grafts showed 58% less narrowing than controls. Again, the researchers found plenty of TIMP-3 in the vein walls, little MMP activity, and evidence of muscle cell suicide.

While the results are promising, George warns that a gene therapy for people is not a sure thing. "We need to do longer term studies before we can think of moving to clinical trials," she says. Joseph Loscalzo of Boston University agrees. In an editorial also appearing in Circulation, Loscalzo writes, "[the findings] represent a proof of principle for vascular gene therapy." But he warns that it is too early to say whether TIMP-3 prevents graft clogging or merely delays it.