Abstract 14611: Elevated Levels of The Mediator of Catabolic Bone Remodelling Rankl in the Bone Marrow Environment Link Chronic Heart Failure with Osteoporosis
Background: Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodelling.
Methods/Results: In a total cohort of 188 subjects (123 patients with CHF, 30 patients with CAD and preserved cardiac function, and 35 healthy controls) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of nuclear factor kappa B ligand, RANKL, and its antagonist, osteoprotegerin (OPG) were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/OPG were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were the only independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover CTX (r=0.6; p<0.0001). Alterations in BM plasma levels of RANKL/OPG were confirmed in a mouse model of post-infarction heart failure . Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts (p=0.01 vs healthy controls), and this effect was blocked by the RANKL inhibition.
Conclusions: CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk.
- © 2012 by American Heart Association, Inc.