Think Arnold Schwarzenegger. That is the image that surprisingly comes to mind when Harvard researcher Victor J. Dzau describes an experimental gene therapy technique designed to help improve the long-term outcome of the heart bypass operation.
The goal is to genetically enhance bypass grafts to produce stronger blood vessels that are less likely to become clogged after surgery. "It is what I call the Schwarzenegger effect," said Dzau, comparing the more robust vessels to the bodybuilder and actor.
Preliminary results from the first human tests suggest that this gene therapy appears to be a promising, safe way to help reduce the failure rate of the more than 750,000 bypass surgeries carried out in the United States each year. "It could make a big difference to patient well-being and cut down the costs of repeat surgeries and interventions," said Dzau, a Harvard Medical School professor and chief of medicine at Brigham and Women's Hospital in Boston.
Most bypass surgery is conducted on patients with atherosclerosis, a condition in which the major coronary arteries are clogged with fatty plaque deposits that cut off blood supply to the heart. About 10 to 30 percent of bypass surgeries fail within the year after surgery, said Dzau. The risk continues, so within a decade after conventional bypass surgery, many patients need further treatment, he said.
A bypass usually involves removing a piece of vein from the patient's leg and sewing it onto the artery to reroute blood flow around the blocked portion. The problem is that the transplanted vein is not as tough as an artery: Its walls are thinner and more vulnerable to the increased blood pressure that arteries must endure. As a result, the cells lining the grafted vein are stimulated to divide rapidly and fill in the vessel cavity, creating thicker walls. In many cases the bypass graft becomes sufficiently blocked to again put the patient in danger.
The new procedure presents a "unique opportunity," Dzau said, to re-engineer the genetic makeup of the vein so that its walls will be less prone to clog up. The vein can be genetically treated in the operating room within 10 minutes after it is removed from the leg.
To do this, the researchers stick the vein snippet in a small plastic tube with a solution containing genetically engineered DNA intended to help block cell growth. The tube is sealed and pressurized to help push the DNA into the vein's walls. For several weeks after it is put into the body, the modified DNA acts as a decoy to attract a gene product known as E2F and keep it from promoting cell division. The result is a more muscular graft that acts "more like an artery," said Dzau at a science forum organized by Harvard Medical School.
Working with colleague Michael Mann, Dzau has been developing the new gene therapy approach for about five years, starting with rat and human tissue in the laboratory and then testing it on more than 400 rabbits before moving to a small group of patients.
The initial study, conducted at Brigham and Women's Hospital with a team headed by vascular surgeon Anthony Whittemore, involved 17 high-risk patients who underwent the new procedure and were compared to a similar number who underwent conventional bypass surgery. The study was "blinded" so that neither the doctors nor patients knew who was getting the new procedure. Dzau said that one year after surgery, nearly 70 percent of the patients with conventional therapy suffered from clogged bypass grafts or needed repeat surgery. In contrast, in the experimental gene therapy group, about 30 percent suffered relapses. In this study, the patients were being treated for peripheral artery disease in their legs, which causes pain and problems walking. The peripheral bypass procedure that was used is similar to the one employed for a coronary artery bypass, and the approach should be applicable to this procedure as well, said Dzau.
Most important, said Dzau, the study demonstrated that this gene therapy technique appears to be "absolutely safe." While it seems to show a significant benefit in the small group studied, he stressed that far more research is needed and studies are planned.