People With Cholesterol In "High Normal" Range Have Blood Vessel Abnormality, New Research Shows

November 17, 1997

DALLAS, Nov. 18 -- Can cholesterol levels considered "normal" still cause damage to blood vessels and thus be potentially harmful to your health? Scientists reporting today in the American Heart Association journal Circulation say the answer is "yes."

In novel experiments conducted on healthy volunteers, Indiana researchers found that blood vessels' ability to widen, or dilate, normally declines in a more or less straight-line fashion as blood levels of cholesterol go up.

"The risk for cardiovascular disease is continuous -- there's no break point where you have no risk and suddenly you have it," concludes the research team, led by Helmut O. Steinberg, M.D, assistant professor of medicine at Indiana University School of Medicine, Indianapolis.

The findings are the first to show that people with "high-normal" cholesterol (200 mg/dl) may be at risk for heart attack or stroke because their blood vessels do not dilate normally, says Steinberg.

He adds that the results suggest that individuals who have normal cholesterol levels perhaps could benefit from futher reductions in cholesterol.

The conclusions are based on a small study that focused on the relationship between cholesterol levels and the working of the endothelium, the inner lining of blood vessels. To carry blood throughout the body and maintain normal blood pressure, the blood vessel must be able to widen.

The key to vessel widening is the blood vessel's ability to release nitric oxide. This highly versatile workhorse molecule performs a variety of chores within the complex biology of the vessel wall. Nitric oxide not only causes vessels to dilate, it also can inhibit cell growth that leads to the plaque buildup in the blood vessels that causes atherosclerosis. It also can work as an "anti-oxidant" to retard the conversion of low-density lipoprotein into a toxic particle. Nitric oxide also can retard clotting, adds Steinberg.

When the endothelium, a thin, sensitive layer of cells lining the inside surface of blood vessels, is functioning normally, nitric oxide is released to order smooth muscle cells inside the vessel wall to relax. When the vessel relaxes, the diameter is widened and blood flow is increased. Paradoxically, when the endothelium is damaged by atherosclerosis, it tends to constrict, not dilate, in response to nitric oxide release.

Other studies have confirmed this abnormality in nitric oxide release and lack of normal vessel dilation in people with cholesterol above 240 mg/dl and LDL above 170 mg/dl, a disease known as hypercholesterolemia. In a Circulation editorial, Boston scientists say the new findings "extend these observations to individuals considered to have normal cholesterol levels."

Whether the techniques such as the one in the study to measure endothelium-directed vessel dilation can be used to predict future blood vessel blockages and enable earlier treatment for high cholesterol lowering in the natural course of blood vessel disease "is an important research question," write Mark A. Creager, M.D., and Andrew Selwyn, M.D., of Brigham and Women's Hospital in Boston. "For now, we should consider eliminating the term 'normal cholesterol' and continue use of existing guidelines to manage treatment strategies."

In the study, the scientists divided 29 men and four women, all under age 44, into two groups: 13 individuals with "high-normal" cholesterol and 20 with "low-normal" levels. The scientists measured how blood flow in the leg changed in response to infusions of a chemical agent (methacholine chloride) that's known to act on the endothelium to widen vessels and increase blood flow.

Leg blood flow responses to the infusions were "significantly blunted" in the individuals with high-normal cholesterol, compared to those with low-normal cholesterol.

The extent of vessel dilation in people with "high-normal" cholesterol was half that of similar individuals whose cholesterol was categorized as "low normal." The high-normal levels averaged 195 mg/dl of blood and "bad" LDL averaged 160 mg/dl, while the low-normal total cholesterol levels averaged 146 mg/dl and LDL averaged 130 mg/dl.

"Our findings provide a rationale for the decision of the National Cholesterol Education Program and the American Heart Association to abandon normal cholesterol levels and to recommend 'desirable' lower cholesterol levels in the population that, if achieved, would be expected to result in greatly reduced rates of coronary artery disease and cardiovascular mortality. And 'desirable' is actually as low as you can get it," adds Steinberg.

Physicians should be much more aware of the underlying negative effects of cholesterol even if the person has a normal number. "As for the general public, the ongoing movement to reduce dietary cholesterol is important, but a more aggressive approach would help improve the health of the population as a whole," he adds.

Obviously there are limits to desirable cholesterol lowering, but he says those limits appear now to be lower that has been previously thought. Should people be tested for the ability of their blood vessels to release nitric oxide? That's premature, Steinberg says.

Experts don't agree that what happens in "peripheral" arteries such as the leg vessels necessarily equate with the status of blood vessels serving the heart. "I think that if you have poor peripheral vessel function, it's very likely that your have poor heart vessel function, too," he says.

Other factors such as obesity and variations in insulin metabolism may account for some of the differences observed in the study, the researcher concedes. But people in the study were carefully matched with similar medical profiles and all were rated as healthy.

Co-authors of the study were Basel Bayazeed, M.D.; Ginger Hook, R.N.; Ann Johnson, R.N.; Jessica Cronin, R.N.; and Alain D. Baron, M.D.

Circulation is one of five journals published in Dallas by the American Heart Association.
Media advisory: Dr. Steinberg can be reached in Indianapolis by calling (317) 274-1339.

Reporters may call (214) 706-1173 for copies of the AHA journal report and editorial. (Please do not publish telephone numbers.)

American Heart Association

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