Mar. 20, 2001 Dallas, March 20 – In the first study of its kind, a drug used to treat breast cancer improved blood flow in men with coronary artery disease, researchers report today in Circulation: Journal of the American Heart Association.
The drug tamoxifen also reduced cardiovascular risk factors such as cholesterol and triglyceride levels in men in the study, suggesting that it may lead to a new line of therapy. Previous research found that tamoxifen reduced cardiovascular risk factors in women being treated for breast cancer.
Tamoxifen is one of a family of drugs known as selective estrogen receptor modulators (SERMs), that have estrogen-like effects in some tissues, but block the effects of estrogen in others. For instance, tamoxifen works as an antiestrogen in some forms of breast cancer preventing the proliferative effects of the hormone. Another drug in the class, raloxifene, has estrogen-like effects that aid in the treatment of the bone-weakening condition called osteoporosis, explains co-author James C. Metcalfe, Ph.D., a professor of biochemistry at the University of Cambridge, in the United Kingdom.
Researchers at the University of Cambridge and nearby Papworth Hospital studied 31 men with coronary artery disease (CAD). Sixteen were treated with tamoxifen for 56 days and 15 were untreated. For at least six weeks before the study, the CAD patients also received two common therapies for coronary artery disease: aspirin and cholesterol-lowering drugs known as statins. Ten men who had chest pain (angina), but normal coronary arteries, were also treated with tamoxifen for comparison to the men with CAD.
Measurements were taken several times throughout the study to determine the blood vessels’ ability to dilate, or expand, as well as several heart disease risk factors such as total cholesterol, triglyecrides, lipoprotein (a) – a cholesterol component linked to heart and blood vessel disease – and fibrinogen, which plays a role in the clotting that can lead to a heart attack.
In the most striking effect, tamoxifen counteracted the toll of aging on the arteries’ ability to expand in response to increased blood flow, known as endothelium-dependent flow-mediated dilation.
In men with CAD, the vessel dilation increased from 2.1 percent at the start of the study to 7.5 percent after 28 days of tamoxifen treatment. In the group with normal coronary arteries, it rose from 3.8 percent to 7.9 percent.
"Others have shown that the blood vessels’ ability to dilate usually declines with age," says Metcalfe. "The average dilation for a man under age 40 is about 7 percent, declining to about 3.5 percent at 63 years of age – near the average age of the CAD patients in this study. Tamoxifen made the CAD patients’ vessels more responsive, somehow overcoming the age-related decline in vessel dilation."
Reduced cholesterol levels also improve vessel dilation. Because CAD patients took cholesterol-lowering drugs as well as tamoxifen, their cholesterol was further lowered. "However, while tamoxifen did reduce cholesterol levels, the effects on vessel dilation seemed to go beyond that of cholesterol-lowering alone, suggesting some new mechanism," says Metcalfe. He notes that tamoxifen even improved dilation in the men without artery disease who were not taking statins.
In addition, the cholesterol-lowering effects of statins and tamoxifen seem additive, he says. "This strongly suggests that combined therapy with the two classes of drugs can be considered and is likely to provide additive benefits," Metcalfe says.
Intriguingly, researchers say, tamoxifen also significantly reduced the blood fat known as triglycerides in men, although it causes a slight increase in triglycerides in women. Excess calories, particularly those from carbohydrates, are converted to triglycerides and transported to fat cells to be stored. Hormones regulate the release of triglycerides from fat tissue to meet the body’s energy needs between meals.
Metcalfe stresses that it is too soon to say whether tamoxifen should be used to treat CAD. Although tamoxifen caused no side effects in this study, a much larger trial to study safety and efficacy is required before SERMs could be considered for treatment of coronary artery disease. Such a trial, the Raloxifene Use for the Heart (RUTH), is currently under way in 10,000 women, he says.
Co-authors include: Sarah C. Clarke, M.B.; Peter M. Schofield, M.D.; Andrew A. Grace, Ph.D.; and Heide L. Kirschenlohr, Ph.D.
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