Sep. 12, 2001 An experimental drug may reverse stiffening of the cardiovascular system that occurs with aging, according to a national study led by Johns Hopkins physicians.
In a group of older people with vascular stiffening, the drug, ALT-711, significantly reduced arterial pulse pressure, defined as the difference between systolic blood pressure (the upper number) and diastolic blood pressure (the lower number). It also improved the blood vessels' ability to stretch by about 14 percent. Results are to be reported in the Sept. 25 issue of Circulation, an American Heart Association journal, but were posted online Sept. 3. ALT-711 is manufactured by Alteon Inc., Ramsey, N.J.
Vascular stiffening and its related increase in the heart's workload is a "huge epidemiological problem," affecting about half of all individuals over age 60, says David A. Kass, M.D., lead author of the study and professor of medicine and biomedical engineering at Hopkins. "Many recent epidemiological studies have shown that pulse pressure is the leading risk factor for cardiovascular disease in the elderly," he says. Left untreated, the condition can lead to high blood pressure, congestive heart failure, heart attack and other disorders.
ALT-711 works by breaking up chemical links between sugar and proteins called advanced glycosylated (sugar-based) crosslink endproducts, or AGE. In the cardiovascular system, AGE results in a loss of artery elasticity. This leads to an increase in the blood pressure pulse and selective rise in the systolic pressure, putting patients at an increased risk of heart attack, heart failure and coronary artery disease.
The crosslinks form in patients with abnormal sugar control – such as diabetics – but also with normal aging. They particularly target long-lived proteins, like those that make up the structure of artery walls and are responsible for their ability to stretch. The more crosslinks, the stiffer the related tissues. This affects the cornea, bladder, arteries and possibly the heart. Diabetics face these problems earlier because of their altered body chemistry. These crosslinks also have recently been reported to affect neural function and may play a role in Alzheimer's disease.
"Prior drugs to treat this common type of blood pressure problem mostly have focused on lowering the mean or average pressure by relaxing the peripheral arteries that regulate resistance," says Kass. "ALT-711 appears to be different. It likely acts on the larger vessels that regulate stiffness. This may represent a novel therapeutic approach for patients with arterial stiffening associated with aging, diabetes and systolic hypertension."
During the trial, researchers at nine sites around the country studied 93 adults age 50 and up with measurably stiffened blood vessels and a systolic blood pressure of at least 140 mmHg. Patients took a drug tablet or a placebo once a day for eight weeks, during which researchers recorded their blood pressure, the flexibility or compliance of their arteries and blood flow through the heart, among other factors. ALT-711 was well tolerated in the patients who received the active drug.
Scientists are continuing to evaluate the medication and its ability to treat systolic hypertension in larger groups of patients.
Kass is a consultant to Alteon Inc. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
The study was supported by the National Institute on Aging and Alteon Inc. Other authors were Edward P. Shapiro, M.D., Miho Kawaguchi, M.D., and Anne R. Capriotti of Hopkins; Angelo Scuteri, M.D., Ph.D., and Edward G. Lakkata, M.D., of the NIA's Gerontology Research Center in Baltimore; and Robert C. deGroof, Ph.D., of Alteon Inc.
Kass, D.A., et al., "Improved Arterial Compliance by a Novel Advanced Glycation End-Product Crosslink Breaker," (Rapid Track) Circulation, 104: R8-R14.
Related Web sites:
Johns Hopkins' Division of Cardiology: http://www.cardiology.hopkinsmedicine.org
Alteon Inc.: http://www.alteonpharma.com
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