Form of cholesterol singled out as cause of chest pain, heart attack

April 16, 2001

DALLAS, April 17 - In the first study of its kind, researchers have found that blood levels of the oxidized form of low density lipoprotein (LDL) are directly related to the severity of heart disease, according to a report in today's Circulation: Journal of the American Heart Association.

In the two-part study, Japanese researchers also found that oxidized LDL was higher in the plaques of individuals with unstable angina than those with stable angina. Oxidized LDL (ox-LDL) is a form of LDL that has combined with oxygen. It is considered more dangerous than LDL because it promotes clogging of blood vessels. Stable angina is chest pain that occurs during exertion. People with unstable angina experience chest pain even while at rest.

"It is accepted that inflammation within the plaque plays a key role in destabilizing the lesions, which leads to coronary events such as heart attacks. Our findings not only support this concept, but suggest a pivotal role of oxidized LDL in this process." says study author Makiko Ueda, M.D., professor of pathology, Osaka City University Medical School in Japan.

The first part of the study included 135 patients who had various signs and symptoms of heart attack or angina. There were 45 patients with heart attack, 45 patients with unstable angina, 45 patients with stable angina, and a control group. The patients with heart attack were studied within 24 hours of the onset of chest pain. Blood samples were taken from all patients when they were admitted to the hospital.

Researchers found that average levels of ox-LDL in patients who had a heart attack were 1.95 nanograms (ng) per 5 micrograms of LDL protein, compared to 1.19 ng/5 micrograms LDL for those with unstable angina, 0.89 ng/5 micrograms LDL for stable angina and 0.58 ng/5 micrograms LDL for controls. The more serious the condition, the higher the oxidized LDL. The researchers say this observation strongly suggests that the amount of oxidized LDL in circulating plasma could serve as a marker for cardiovascular events.

Levels of ox-LDL were measured using a "sandwich ELISA" test in which LDL is separated from other lipids in the blood plasma. The LDL is then combined with an anti-oxidized LDL monoclonal antibody, which isolates oxidized LDL. A second monoclonal antibody, called anti-apolipoprotein B antibody, is used to detect additional oxidized LDL particles in the plasma. The technique is able to identify tiny amounts of LDL particles and is superior to other methods in obtaining a sensitive and accurate measurement of ox-LDL.

For the second part of the study, researchers analyzed sections of coronary arteries from 10 individuals with stable and 23 with unstable angina. The sections were taken directly from the area believed to have caused the blockage responsible for the chest pain. They gave the samples a score according to ox-LDL levels at that site. They found that individuals with unstable angina had an average ox-LDL score of 0.49 and those with stable angina had an average score of 0.07.

"Our study of atherectomy specimens clearly demonstrates that oxidized LDL is higher in the arterial plaque of patients with unstable angina compared to those with stable angina," says Ueda.

Sotirios Tsimikas, M.D., assistant professor of medicine, division of cardiology, University of California at San Diego, says this research is unique because it looks at different groups of patients using the same LDL measurements.

"The levels of oxidized LDL circulating in the blood correlate well with the severity of disease," says Tsimikas. "The sicker the patient, the higher the levels of circulating oxidized LDL, indicating that it is a marker of atherosclerotic plaques."

Atherosclerosis is a narrowing of the arteries caused by plaques on the inner lining. The plaques consist of LDL, decaying muscle cells, fibrous tissue, clumps of blood platelets and cholesterol.

When plaques are disrupted or rupture, the oxidation process is activated and is reflected in circulating LDL.

In an editorial accompanying the study, Tsimikas and Joseph Witztum, M.D., professor of medicine and director of endocrinology and metabolism at UCSD, suggest the Osaka study is another step forward that may lead to the development of a new diagnostic test to assess the risk of heart attack and discriminate between patients at risk. At present, they say the test probably cannot be applied outside the research setting.
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