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American Heart Association journal report: New class of drugs shows potential for treating heart failure
DALLAS, Feb. 20 -- New drugs that relax blood vessels may improve blood flow in people with heart failure, according to two preliminary studies reported in today's Circulation: Journal of the American Heart Association.
The experimental drugs in these two studies belong to a class of medications called endothelin receptor antagonists. They target a substance produced by blood vessels, called endothelin-1 (ET-1). In heart failure patients, ET-1 is produced in excess. As heart failure worsens, the amount of ET-1 in the blood increases.
"This is a whole new strategy to treat patients with congestive heart failure," says Guillermo Torre-Amione, M.D., an assistant professor of medicine at Baylor College of Medicine in Houston and director of the heart transplant program for the DeBakey Heart Center at the Methodist Hospital.
Endothelin-1 binds to two different receptors in the blood vessels: A and B. When it binds to the A form, it causes the blood vessels to constrict in CHF patients, forcing the ailing heart to work harder to pump blood through the narrowed channels. However, ET-1 binding to the A receptor does not seem to play a role in vessel constriction in people with normal hearts. When ET-1 binds to the B receptor, it seems to both constrict and dilate the vessels depending on where it occurs.
Torre-Amione's study found that a fast-acting, injectible ET-1 antagonist called tezosentan seems to improve heart function in people with acute congestive heart failure, possibly by increasing blood flow to the heart.
Congestive heart failure (CHF) occurs when the heart is damaged or overworked and unable to pump out all the blood that returns to it. As the amount of blood pumped lessens, the blood returning to the heart backs up and fluid builds up in other parts of the body, causing swelling in the legs and ankles and breathlessness when the fluid builds up near the lungs.
In his study of 61 CHF patients who received either a placebo or one of four dosages, the drug took effect within 30 minutes and continued to work during the six hours it was given intravenously. The participants' cardiac index -- a measure of blood flow -- increased from 24.4 percent to 49.9 percent as the dose of tezosentan increased. The cardiac index increased only 3 percent in the placebo group.
In a second study of chronic heart failure patients led by Thomas Neunteufl, M.D., and Rudolf Berger, M.D., at the University of Vienna, Austria, researchers tested the effects of the yet-to-be-named drug LU 135252, a long-acting, oral drug that targets endothelin A receptors. Twenty-one participants received the drug and were compared to 11 individuals who received a placebo. The study found that flow-mediated vasodilation significantly improved during three weeks of treatment in 14 heart failure patients receiving daily doses of LU 135252. Flow-mediated vasodilation is a measure of the blood vessels ability to dilate -- thereby increasing blood flow -- if needed, such as during exercise. Two doses of the drug were given: 30 mg/dL and 300 mg/dL. The lower dose resulted in a vasodilation measurement of about 5.5 percent compared to 2.4 percent before treatment. The higher dose did not cause significant vasodilation. Vasodilation did not change in participants given a placebo.
It is too soon to know whether the improved blood flow reported in these studies will result in improved symptoms. These small, preliminary studies were limited to assessing changes in blood flow and addressing safety concerns. Four large, multicenter studies to determine whether tezosentan will improve symptoms are under way and should be completed by the end of the year, says Torre-Amione.
In animal studies of CHF, long-term endothelin receptor antagonists have been shown to reverse the structural changes of heart failure, such as heart enlargement, he adds.
"I think this will be a very good alternative to other agents that are currently used for treatment of acute heart failure," says Torre-Amione. "If borne out by future research, it certainly will become a very useful strategy."
An estimated 22 percent of male and 46 percent of female heart attack patients will become disabled with heart failure within six years. Hospital discharges for CHF rose from 377,000 in 1979 to 978,000 in 1998, and the incidence of CHF is expected to continue to increase as the population ages. Torre-Amione says better treatments are needed to reduce hospitalizations and to delay or avoid heart transplants.
Torre-Amione's co-authors include James B. Young, M.D.; Jean-Bernard Durand, M.D.; Bykem Bozkurt, M.D.; Douglas L. Mann, M.D.; Isaac Kobrin, M.D.; and Craig Pratt, M.D. Their work was supported by a grant from Actellion, Ltd., the Swiss company that makes tezosentan.
Berger and Neunteufl's co-authors include Brigitte Stanek, M.D.; Martin Holsmann, M.D.; Bernhard Frey, M.D.; Sandra Heher, M.D.; and Richard Pacher, M.D.
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NR01-1259 (Circ/Torre-Amione)
Media advisory: Dr. Torre-Amione can be reached by phone at (713) 798-1404; by fax (713) 798-8744; or by e-mail [email protected]. Dr. Neunteufl can be reached by phone at 43-1-40400 4614; by e-mail [email protected]; or by fax 43-1-40400-4216.
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