Drug compound restores youth to aging arterial cells in elderly hypertensives

Systolic hypertension refers to higher than normal levels of the “upper” number in a blood pressure reading, or with a lower than normal “bottom” number, in this case a pressure of 140 millimeters of mercury or greater and/or a diastolic pressure of less than 90 millimeters of mercury. Hypertension of this sort indicates stiffening of the body’s arteries.

“This is the first demonstration that this class of drugs, known as collagen-crosslink breakers, can turn back the clock and make old arteries behave like young ones,” says senior study investigator and geriatric cardiologist Susan Zieman, M.D., an assistant professor at The Johns Hopkins University School of Medicine and its Heart Institute. “There are many medications for routine hypertension, and coronary artery disease or atherosclerosis, which can lead to heart attack and heart failure, but none that help counteract the aging of cells inside the arterial walls that often precedes symptoms of disease.”

According to the American Heart Association, more than 65 million Americans have high blood pressure, most of it of the systolic kind. In systolic hypertension, the pressure or force of blood flow through the arteries is too strong as blood is pumped by the heart’s ventricles (systole) to the rest of the body. Diastolic pressure, on the other hand, is a measure of the pressure against arterial walls when the heart is resting and refilling between beats.

The Hopkins researchers found that alagebrium, formally known as ALT-711 or 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride, reduced stiffening in the vessel wall in the main artery of the neck (carotid artery) by as much as 37 percent. The drug also improved endothelial function, the ability of the vessels’ inner lining to relax and dilate in response to increased stress from blood flow, by 102 percent.

Chemically, alagebrium is a so-called crosslink breaker, responsible for destroying the rigid chemical bonds known as advanced glycation endproducts, or AGE for short, that form between body proteins and sugars over time. According to Zieman, both stiffening and reduced capacity of the arteries to expand in response to stress are common effects of aging that occur when the crosslinks form in the body’s key structural proteins, such as collagen, or when AGEs interact directly with enzymes that regulate blood flow.

Crosslinking effectively carmelizes the collagen - found in all parts of the body, especially in the skin, eyes, blood vessels and nerves - leading to tissue “wrinkles,” cataracts, as well as stiffening and increased speed and force of blood flow. These processes are accelerated in diabetics whose blood sugar content is often elevated.

As hypertension becomes chronic, aging blood vessels lose their ability to stretch and relax between heartbeats. The anti-wrinkle effects of a crosslink-breaker treatment occur on facial skin because the compound similarly lets collagen there relax, giving the skin a plumper, smoother look

The Hopkins findings, to be presented at the American Heart Association’s Scientific Sessions 2005 on Nov. 15 in Dallas, Texas, also suggest that the cellular effects of aging caused by AGE are potent targets for new therapies.

In the Hopkins study, 13 elderly men and women with systolic hypertension took either daily doses of alagebrium (210 milligrams) for eight weeks or a look-alike pill (placebo), containing no active drug. AGE and collagen levels were monitored through blood tests. Stiffness was measured using a small pressure-sensor device called a tonometer.

Ultrasound readings, taken before and after drug therapy, were made as a blood pressure cuff was inflated for five minutes and deflated. This allowed researchers to calculate endothelial function based on how much the blood vessel lining relaxed as a percentage increase of how much the blood vessel could expand.

After treatment with alagebrium, neck arteries became less stiff, as shown by tonometer readings and decreased levels of collagen in the blood as AGE crosslinks were broken down. Analysis of additional pressure-wave readings also showed flatter patterns more closely resembling younger arteries than older, stiffer ones, which have wave patterns with higher peaks.

While the results did not explain why endothelial function improved, the researchers believe it has to do with the drug’s effects on AGE and cell function. Their theory, Zieman says, is that one chemical reaction, the breakdown of AGE crosslinks, both reduces the structural causes of arterial stiffness in the artery wall and alleviates the detrimental effects of AGE on other enzymes or related proteins, possibly nitric oxide and other chemicals causing vessel inflammation, which are essential to regulating heart and blood vessel function.

“These results confirm that this drug does have important effects on the aging process in the arteries, but we still have to prove that there’s some benefit to patients in terms of reducing cardiovascular disease,” Zieman says. “Our next step will be a study, expected to begin in late 2006, of the drug’s potential benefit at preventing or reversing heart failure in the elderly.”

Alagebrium has been under investigational study since 1999, originally as a treatment for hypertension. While clinical studies have demonstrated the drug’s ability to loosen up stiff arteries, two larger studies in older people with hypertension have not shown significant results in lowering blood pressure.

Funding for this study, which took one year to complete, was provided by the National Heart, Lung, and Blood Institute, a member of the National Institutes of Health. Medication was supplied free of charge by the drug’s manufacturer, Alteon Inc., of Parsippany, N.J.

Improved Flow-Mediated Arterial Vasodilation by Advanced Glycation Crosslink Breaker, Alagebrium Chloride (Alt-711), in Older Adults with Isolated Systolic Hypertension. Vojtech Melenovsky M.D., Ph.D.; Lia Clattenburg, B.A.; Mary Corretti, M.D.; Patricia Fitzgerald, R.N., B.S.N.; Anne Capriotti; Gary Gerstenblith, M.D.; David Kass, M.D., and Susan Zieman, M.D., Ph.D.