Interleukin-6 – a Better Predictor of Future Cardiovascular Events Than C-Reactive Protein?

In a study published in the journal Cytokine, Hidenori Nishida and colleagues from the National Cerebral and Cardiovascular Center, Suita, Japan, demonstrate that an increased level of serum IL-6 is a significant predictor of future cardiovascular (CV) events in high-risk Japanese patients, independently of a variety of influencing factors.

One of the paradigm shifts in our understanding about atherosclerosis in the last 10-15 years is the development of the concept that it is potentially caused by a chronic inflammation.

In fact, it is now well recognized that low-grade inflammation is an important factor contributing to the initiation and progression of CV lesions.

It is important to distinguish between local inflammation within the plaque microenvironment and systemic inflammation, as evident by acute-phase protein production and circulating proinflammatory mediators. Systemic mediators and markers of inflammation include C-reactive protein (CRP), interleukin (IL)-6 and IL-8.

Large epidemiological studies have suggested that CRP measurement predicts the risk of future CV events, but others have failed to identify CRP as a significant independent risk factor. Thus, the value of CRP as an independent risk marker for CV events remains controversial at present.

IL-6 is a central mediator of the acute-phase response, and serum or plasma levels of IL-6 are elevated in various cardiovascular (CV) disorders. The degree of increase in IL-6 levels is in proportion to the clinical severity of these diseases, whereas elevated levels of IL-6 are associated with increased risk of the progression of atherosclerotic lesions and future CV events.

Notably, increased IL-6 is also associated with elevated fibrinogen levels, which leads to an increased tendency to thrombosis, independent of the effects of IL-6.

In the Cytokine study the authors compared the predictive value of IL-6 with that of high-sensitivity (hs)-CRP, and found that hs-CRP was not a significant predictor of future CV events, in contrast to the powerful prognostic value of IL-6. The authors discuss why serum IL-6, but not CRP may be a significant predictor of CV events.

According to the authors IL-6 is produced not only by leukocytes but also by vascular endothelial cells and smooth muscle cells, and IL-6 protein and gene expression has been demonstrated in human atherosclerotic lesions. Thus, IL-6 may directly reflect vascular inflammation and endothelial injury during the initiation and development of atherosclerosis.

Furthermore, since ischemic and hypoxic conditions stimulate IL-6 production, it is possible that the increase in baseline IL-6 might be induced by silent cerebral, myocardial, or peripheral arterial ischemia before the event. Thus, serum IL-6 might represent a sensitive marker for progression of vascular lesions and future CV events.

SOURCE:  Cytokine 2011, 53:342. Epub 2010 Dec 28.

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