Soluble receptor activator of nuclear factor-κB ligand and risk for cardiovascular disease

Background - Overexpression of receptor activator of nuclear factor-kappa 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.