A compound called alagebrium, which is very similar to another used in anti-wrinkle creams, may be useful in reducing the deleterious effects of arterial aging in the majority of elderly Americans with systolic hypertension, a new study from researchers at Johns Hopkins shows.
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.