Increased levels of certain protein linked to risk of coronary heart disease

Increased levels of certain protein linked to risk of coronary heart disease

An article published in the open-access journal PLoS Medicine finds that there is a link between coronary heart disease and levels of interleukin-6 (IL-6), a protein triggered by inflammation that attracts immune system cells to an injury site. John Danesh (University of Cambridge) and colleagues also suggest that new drugs designed to fight vascular disease may target the IL-6 protein.

Coronary heart disease (CHD) is the leading cause of death in adults in developed countries. When deposits of plaque, calcium, and other cellular waste products harden against the arterial walls (atherosclerosis), there is an interruption of blood flow through the body. Blockages in the coronary arteries result in CHD, and myocardial infarction (heart attack) can occur if plaque breaks off the artery wall and restricts blood flow to the heart.

The research by Danesh and colleagues focuses on atherosclerosis as an inflammatory condition. They work with the premise that the immune system responds to injury by creating an area of redness and swelling (inflammation), a process which involves the production of cytokines. Cytokines are proteins that attract immune system cells to an injured site, such as an artery wall that has been damaged by atherosclerosis. Inflammation of the damaged artery, due to these cytokines, may further aid in the growth of atherosclerotic plaques. Thus, the researchers set out to see if a link could be established between prolonged moderate increases in a cytokine called interleukin-6 (IL-6) and CHD. If such a link exists, new therapies could be developed that target cytokines in order to reduce inflammation and slow down atherosclerosis.

Danesh and colleagues analyzed two large-scale studies conducted between 1967 and 1991 that included about 25,000 healthy middle-aged people - the Reykjavik Study (RS) and the British Regional Heart Study (BRHS). Over a 20-year period, 2,138 had a first non-fatal heart attack or died from CHD. The researchers had access to the baseline IL-6 levels in these participants and in 4,267 participants who did not have CHD. Adjusting for a year-to-year consistency of IL-6 levels, the researchers found that increased long-term IL-6 levels were associated with a doubling of the risk for CHD. In a brief meta-analysis, the authors indicate that their finding is consistent with findings from 15 previous relevant studies.

"Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6-mediated pathways to CHD," conclude the authors.

An accompanying perspective by Bruce Neal (George Institute for International Health, Sydney, Australia) is included in the same issue of the journal. Neal writes:

"While impressive in their rigour, the findings from this study are probably rather limited in regard to their clinical implications. Future studies of interventions for the control of vascular disease might gain insight into mechanisms of action through assay of IL-6. Likewise, IL-6 could be a target for the development of new chemical entities designed to modify vascular disease progression."

"It is now widely accepted that 90% or more of vascular disease can be explained on the basis of known risk factors, so these new data about IL-6 probably have relatively little to add in terms of our understanding of causation. There are also multiple interventions that modify these known risks and avert premature death and disability from vascular disease at low cost. Therefore there is little need for a new and probably costly drug that acts via IL-6. The better application of proven risk stratification methods and the more efficient delivery of proven management strategies could already cut a swathe through the current vascular disease burden. These proven strategies should remain the priority, particularly in developing regions of the world where most vascular disease now occurs. A focus on the identification of practical strategies for the delivery of existing interventions could deliver hugely cost effective global health gains."

Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review

John Danesh, Stephen Kaptoge, Andrea G. Mann, Nadeem Sarwar, Angela Wood, Sara B. Angleman, Frances Wensley, Julian P. T. Higgins, Lucy Lennon, Gudny Eiriksdottir, Ann Rumley, Peter H. Whincup, Gordon D. O. Lowe, Vilmundur Gudnason

PLoS Medicine . 5(4): e78.


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