P&S Journal: Spring 1995, Vol.15, No.2
Research & Reports
Studies Focus on Heart Research
Several P&S researchers presented research last fall at the annual meeting of the American Heart Association. Summaries of a few of those studies:
Improved Organ Preserving Solution
A new solution developed at P&S could improve the allocation of organs for transplantation nationwide and enhance the long-term survival of transplant patients.
Unlike current solutions, the new solution developed by Dr. Mehmet Oz, assistant professor of surgery and Irving clinical research scholar, preserves vital blood supply routes to the heart, minimizing damage to tissue following transplantation.
The solution can keep routes to the organs open by combining a standard organ preserving fluid with nitroglycerin, increasing the nitric oxide levels in the blood and preventing blood vessels from constricting. Other solutions only preserve organ tissue. Keeping existing blood vessels intact helps the heart function longer and possibly better, allowing for organs to be transported longer distances and enabling physicians to test donor hearts and their compatibility with recipients.
In the clinical research, researchers have treated a donor heart with a standard preserving solution before transporting it to Columbia-Presbyterian. Nitroglycerin is injected to dilate the recipient patient's blood vessels. As the donor heart is being transplanted, a mix of nitroglycerin and a preserving solution is injected into the arteries to prevent spasms in the blood vessels. Dr. Oz has used components of his solution in 30 heart transplants and many heart bypass procedures. The solution also may be used in kidney, lung, and liver transplants.
Women's Mortality And Heart Transplantation
Since relatively few women receive heart transplants, few studies have examined the effect of gender on survival, with conflicting results. A retrospective study of 379 adult transplant patients, the largest of its kind, has confirmed that women experience a higher mortality rate after heart transplantation than do men.
In addition, two risk factors for women were identified: implantation with a donor heart that was exposed to cytomegalovirus (CMV) and a postoperative treatment called OKT3 induction therapy. Women with both risk factors face an even greater chance of death. Neither factor appears to have an effect on men. The findings were reported by Dr. Elsa-Grace Giardina, professor of clinical medicine and director of the Center for Women's Health at Columbia-Presbyterian Medical Center.
Dr. Giardina and her colleagues gathered data on 304 men and 75 women transplanted between 1985 and 1992 at CPMC, which has one of the largest heart transplant caseloads in the world.
"The first thing we saw was women tended to die more often than men," says Dr. Giardina. Overall, 35 percent of the women but only 25 percent of the men died within three years of transplantation.
The researchers analyzed a number of factors that might have contributed to the women's higher mortality, including age, race, cardiac diagnosis, episodes of tissue rejection, donor and recipient exposure to CMV, use of OKT3 induction therapy, blood type, HLA type, concurrent disease, prior cardiac surgery, and reproductive history.
"Of all the variables examined, only positive CMV status of the donor and OKT3 induction therapy impacted on survival," says Dr. Giardina. After three years, only 25 percent of the women who had received CMV-positive hearts plus induction therapy were alive, compared with 86 percent of those with neither risk factor.
"In the absence of OKT3 use, the greatest risk of death occurs in CMV-negative females transplanted with CMV-positive hearts," adds Dr. Giardina. The researchers did not determine why a CMV mismatch or OKT3 induction therapy lowers the survival rate among women. However, Dr. Giardina suspects that some sort of immunological reaction is responsible when there is a CMV mismatch. "We don't know the mechanism, but we do know that there are more autoimmune diseases among women than among men. Women for example, are more likely to get rheumatoid arthritis, lupus, Grave's disease, and certain immunological diseases of the thyroid gland.
"We don't know the whole story," says Dr. Giardina, "but we certainly suggest that a female patient who is mismatched should not get transplanted. She has a pretty good chance of dying from her basic heart disease, but that chance is enhanced if she's mismatched." If a transplant is performed in such a case, she adds, "at least do not give that patient induction therapy."
Vessels Re-clogging After Angioplasty
Studies suggest that restenosis, or re-clogging of the coronary arteries, may be prevented if the arteries are irradiated at the time of angioplasty, a finding that eventually could lead to fewer patients needing to be retreated.
Dr. Judah Weinberger, assistant professor of medicine, says approximately one-third of patients who undergo angioplasty must be retreated because of restenosis. "It doesn't make a difference what technique you use to open arteries-balloon angioplasty, lasers, stents, atherectomy-you still have a substantial rate of restenosis. A number of drugs have been tried to limit restenosis, but nothing has worked."
However, the study results indicate that high doses of localized radiation applied directly to the angioplasty site via catheters can do what drugs and devices cannot.
"It's akin to the way radiation oncologists treat cancer, which is characterized by uncontrolled cell proliferation," says Dr. Weinberger. "We view restenosis as a proliferative process too, the result of an injury to the vessel wall." The injury, he explains, stems from the angioplasty procedure, in which a balloon-tipped catheter is inserted into the vessel and inflated, compressing plaque against the vessel's interior. Although this dilates the artery, it damages a portion of the vessel wall in the process. "If you injure a cell, it reacts by proliferating. Smooth muscle cells migrate from the middle layer of the vessel wall into the intima (the inner layer), and they may cause a large lesion to form, which then clogs the artery."
But according to experiments performed on pigs, this process can be inhibited by applying radiation, via a specially designed catheter, directly to the angioplasty site. Once irradiated, the vessel wall becomes fibrotic, preventing lesions from forming. In the study, the area of restenosis was reduced by an average of 66 percent.
"Intracoronary radiation limits restenosis, and long-term follow-up shows no significant damage to the coronary artery or surrounding tissue," says Dr. Weinberger.
The idea of coronary irradiation is not new. Earlier experiments failed, however, because the radiation was applied externally through the chest wall. This limited the amount of radiation that could be applied without causing too much damage to surrounding tissue. A further complication, says Dr. Weinberger, is that low doses of radiation actually stimulate cell growth; it worsens the stenotic process. By delivering the radiation directly with a catheter, the dose at the arterial wall is much higher and much more precise than you can get with the external beam. Dr. Weinberger and his colleagues have yet to test the system in humans. But reports from Europe, where it has been used successfully to prevent restenosis in leg arteries, are encouraging. "The biological concept, as far as I'm concerned, is almost certainly valid in humans."