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.