Test For Genetic Trait May Indicate Heart Benefits Of Hormone Replacement Therapy

November 08, 1998

DALLAS, Nov. 8 -- A new study shows that a woman's genetic makeup can reveal how well hormone replacement therapy will reduce her risk of developing heart disease.

"Women do not respond equally to hormone replacement therapy (HRT). Not all postmenopausal women will receive the same heart benefit of lower LDL cholesterol -- the "bad" low-density lipoproteins -- by taking HRT," says H. Robert Superko, M.D., FACC, in research presented today at the American Heart Association's 71st Scientific Sessions.

Superko, director of research and clinical affairs at the Berkeley HeartLab and the Lawrence Berkeley National Laboratory, Berkeley, Calif., and his colleagues found that women with larger sized LDL particles may be more likely than women with smaller LDLs to reap heart-related benefits from HRT.

HRT, which combines the hormones estrogen and progestin, can reduce menopause symptoms such as "hot flashes" and decrease the risk of osteoporosis, a disease causing weakened bones that break easily. Several studies suggest that HRT also may protect the heart by raising blood levels of the high-density lipoproteins (HDL, or "good" cholesterol) that help clear cholesterol from the blood vessels. Excess cholesterol in the blood contributes to fatty deposits that clog blood vessels, triggering heart attacks and strokes.

Research conducted by Superko and other researchers during the last decade suggests that a person's response to cholesterol-lowering diets and drugs is inherited -- driven, in part, by what is called the atherosclerosis susceptibility trait, he says. The Berkeley researchers tested whether this trait might also influence how a woman's cholesterol levels respond to HRT. The trait determines if a person has one of two patterns of LDL. Pattern A people have mostly large, buoyant LDL particles; those with pattern B have smaller, dense forms of LDL. Pattern B increases heart disease risk three-fold. "If you are a pattern A woman who wants to lower her LDL cholesterol profile, it turns out HRT isn't the best choice," he says. Superko suggests that these women try the American Heart Association Step II diet or ask their doctor about cholesterol-lowering drugs.

Superko says that women with pattern B are subject to a sort of "bad metabolic stew" of characteristics that put them at higher risk for heart disease. The first being that their smaller LDLs lodge into the artery wall 40 percent faster and contain about half the amount of protective antioxidants as the larger LDLs -- this makes pattern B LDLs more susceptible to oxidative damage. Oxidation occurs to lipoproteins that are lodged in the vessel walls -- not while they flow in the bloodstream -- and speeds up atherosclerosis.

Pattern B women are also insulin resistant, he says, making them more susceptible to diabetes, a known risk factor for heart disease. Superko says pattern B women also tend to have defects in the particular type of HDL that transports LDL away from vessel walls. There are several forms, but only one type is primarily responsible for removing LDL. Superko says that triglycerides and other blood fat levels, as well as cholesterol, are higher in pattern B women than in those with pattern A. Levels of these fats rise higher and stay higher after eating in pattern B women.

It is interesting to note, says Superko, that in pattern B patients with established heart disease, arteries clog twice as fast as those of pattern A patients with heart disease. If not treated, he says the disease in people with pattern B tends to get worse faster than in those with pattern A, but with treatment, they improve faster.

Researchers studied 44 postmenopausal women, average age 58 years. Half of the women took estrogen plus progestin and the other half took a placebo. After four months, the researchers reversed the two groups' medications. "We wanted to test if the reduction would be greatest in the pattern B women, which we believed it would be based on clinical experience," Superko says. The average decrease in LDL cholesterol was 7.9 percent and the average increase in HDL was 10 percent for all women.

"The really interesting part came when we looked at how the women with pattern A compared to women who were pattern B," Superko says. The pattern B women reduced their LDL cholesterol by 15 percent compared to a drop of only 4.6 percent in the pattern A group. HDL cholesterol rose 14 percent in the pattern B women compared to only eight percent for those with pattern A.

Superko and his colleagues have some thoughts on why HRT may work better for pattern B women than pattern A women, but do not have solid proof of their theories. "We think pattern A women don't have the inherited disorder causing the 'bad metabolic stew' and B women do. However, estrogen suppresses the genes that cause pattern B women to have the high risk for coronary artery disease. These problems are evident after menopause because the women no longer produce enough estrogen to suppress these bad effects," he says.

"We're always concerned when health advocates recommend that everybody should be on the same diet or the same drug because there is tremendous diversity within the human population. Metabolically, people just work differently, " he says. The researchers suggest that postmenopausal women with a family history of heart disease or with actual heart disease be tested to determine if they are pattern A or pattern B. "This will allow physicians to more closely custom fit HRT treatment to each individual," Superko says.

"The message people need to understand about a lot of these inherited conditions is that you can treat them now," he says. The test used to distinguish pattern A from pattern B was developed at the Lawrence Berkeley National Laboratory, University of California, and is now marketed by the Berkeley HeartLab, in San Mateo, Calif. Superko says the test is available to physicians through a government program at the Lawrence Berkeley National Laboratory and the Office of Technology Transfer. The program includes the test, interpretation of test results, education and reimbursement information. Further information about the testing program can be obtained by calling 1-800-HEART-89.

About 5,000 physicians around the country use the new test on a routine daily basis. The cost is $160 and most insurance covers about 80 percent of the price. Superko says the base price of the test is likely to drop as it becomes more widely available.

Co-authors are Ronald M. Krauss, M.D; Michael J. Schoenfeld, M.D.; Laura Hall, B.A.; Patricia Blanche, B.S.; and Joseph Orr, B.S.

For more information Nov. 8-11 contact Carole Bullock or Brian Henry at the Dallas County Convention Center: (214) 853-8056.

Media Advisory: Dr. Superko can be reached by phone at (650) 372-1960; or by fax at (650) 372-1948. (Please do not publish numbers)

American Heart Association

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