Published Online
on July 9, 2007

A more recent version of this article appeared on July 24, 2007

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Submitted on December 25, 2006
Accepted on May 18, 2007

Soluble Receptor Activator of Nuclear Factor-B Ligand and Risk for Cardiovascular Disease

Stefan Kiechl MD^*, Georg Schett MD, Judith Schwaiger MD, Klaus Seppi MD, Paula Eder MD, Georg Egger MD, Peter Santer MD, Agnes Mayr MD, Qingbo Xu MD, and Johann Willeit MD

From the Department of Neurology (S.K., J.S., K.S., J.W.), Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine III and Institute for Clinical Immunology (G.S.), University of Erlangen-Nuremberg, Erlangen, Germany; Departments of Laboratory Medicine (P.S., A.M.) and Internal Medicine (P.E., G.E.), Bruneck Hospital, Bruneck, Italy; and Cardiovascular Division (Q.X.), King’s College London, University of London, London, UK.

^* To whom correspondence should be addressed. E-mail: Stefan.Kiechl{at}i-med.ac.at.

Background--Overexpression of receptor activator of nuclear factor-B ligand (RANKL) is a prominent feature of vulnerable atherosclerotic lesions prone to rupture and was thought to contribute to the transition from a stable to an unstable plaque phenotype in both human and murine atherosclerosis because of its ability to promote matrix degradation, monocyte/macrophage chemotaxis, and vascular calcification.

Methods and Results--The Bruneck Study is a prospective, population-based survey of men and women 40 to 79 years of age at the 1990 baseline examination. Levels of soluble RANKL and other variables were assessed in 909 subjects (1990). All cases of cardiovascular disease were carefully recorded between 1990 and 2005. During follow-up, cardiovascular disease (defined as ischemic stroke and transient ischemic attack, myocardial infarction, and vascular death) manifested in 124 of the 909 subjects. Baseline serum level of RANKL emerged as a highly significant predictor of vascular risk (adjusted hazard ratio per 1-unit increase in soluble RANKL, 1.27; 95% confidence interval, 1.16 to 1.40; P<0.001). Predictive significance was independent of that afforded by the classic vascular risk factors, C-reactive protein, osteoprotegerin concentration, and severity of carotid atherosclerosis. Findings were internally consistent and robust in a variety of sensitivity analyses. Notably, soluble RANKL was not associated with carotid or femoral artery atherosclerosis.

Conclusions--Our study lends large-scale epidemiological support to a role for RANKL in cardiovascular disease. In the absence of a significant association between RANKL and atherosclerosis, the idea that RANKL promotes plaque destabilization and rupture is a highly appealing concept.

Key words: atherosclerosis • cardiovascular diseases • myocardial infarction • osteoprotegerin • RANK ligand • stroke

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