New marker of inflammation predicts death from artery disease

American Heart Association
Monday, 3 June 2002

People with coronary artery disease who had high blood levels of an inflammatory marker had more than triple the risk of death from cardiovascular disease than those with the lowest levels, researchers report in today's rapid track publication of Circulation: Journal of the American Heart Association. Rapid track articles are released online early because they have major clinical impact or represent important basic science discoveries.

The inflammatory marker is called interleukin-18 (IL-18). In previous animal studies it has been shown to accelerate atherosclerosis and influence plaque instability. In humans, its influence has been unclear, but it has been found within artery-clogging plaque.

"We show now for the first time that IL-18 is strongly and independently predictive of future fatal cardiac events," says Stefan Blankenberg, M.D., a cardiology fellow at the Johannes Gutenberg-University Mainz in Germany. "It also strongly supports the possibility that inhibiting IL-18 might be a new therapeutic strategy for plaque stabilization.

"Our study transfers earlier experimental results on IL-18 into a clinical setting and opens the door for more precise risk prediction in patients with coronary artery disease (CAD) as well as new therapeutic options, such as inhibiting IL-18," he says.

Although IL-18 inhibition seems a highly promising approach, he stressed that more studies are needed. First, there must be more prospective studies on IL-18's action in humans as well as better tests to measure the inflammatory marker because current tests are too complex for a clinical setting. In addition, more must be learned about possible side effects of therapy with IL-18 inhibitors in humans, he adds.

Plaque is the fatty build-up that clogs arteries over time. When plaque is "unstable," part of it is more likely to break off, and a blood clot can form on the ruptured area of the blood vessel. If the clot blocks blood flow to the heart or brain, a heart attack or stroke can occur.

IL-18 was a stronger predictor of future death from cardiovascular causes than other inflammatory markers, such as the better-known C-reactive protein (CRP). In contrast to the other markers studied, the predictive value of IL-18 is not weakened after controlling for age and ejection fraction (a measure of the heart's pumping ability).

The researchers, led by professor Hans Juergen Rupprecht, M.D., followed 1,229 people with CAD treated at the University of Mainz and the Bundeswehrzentralkrankenhaus Koblenz as part of the AtheroGene Study to evaluate the impact of a variety of inflammatory markers and other factors on predicting future cardiovascular events. The study was an attempt to identify genes involved in CAD and its complications.

Researchers analyzed the patients' blood at baseline and divided patients into four groups according to their IL-18 levels. The researchers then followed the subjects for about four years looking for associations between their IL-18 level and heart disease events.

They found that the median blood concentrations of IL-18 at baseline were significantly higher among patients who had a fatal cardiovascular event during follow-up than among those who did not [68.4 vs. 58.7 pg/ml (picograms per milliliter)].

The hazard risk ratio of future cardiovascular death increased with higher blood levels of IL-18. After adjusting for most potential confounders, including ejection fraction and other markers of inflammation such as interleukin-6 (IL-6), CRP and fibrinogen (a blood clotting protein), the researchers found that patients in the highest quartile for IL-18 (more than 77.7 pg/ml) had a 3.3-fold increased risk of cardiovascular death compared to those in the lowest quartile (less than 45 pg/ml).

The association was unaffected by whether the patient had stable angina (chest pain only upon exertion) or unstable angina (chest pain at rest), he adds. Unstable angina is considered a worse prognosis because it is believed to indicate unstable plaque. However, in this study, patients in both groups fared equally well, perhaps indicating the increasing quality of care for the unstable patients.

This result strongly supports recent experimental evidence of IL-18-mediated inflammation leading to acceleration and vulnerability of atherosclerotic plaques, the researchers write. This line of research dovetails with other recent studies that suggest inflammation may play a role in the progression or destabilization of atherosclerosis. Infections might be discussed as distant triggers of IL-18 which could provide a potential link between the controversial association of previous infections and future cardiovascular events in CAD patients, Blankenberg adds.

Blankenberg is also a post-doctoral fellow in molecular genetics and genetic epidemiology at INSERM U525, the acronym for the French government's National Institute of Health and Medical Research, Faculté de Médecine Pitié-Salpétrière in Paris.

For more information, or to contact American Heart Association, see their website at: www.americanheart.org