Dysregulated atrial gene expression of osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand axis in the development and progression of atrial fibrillation.

Background: Atrial structural remodeling is increasingly emphasized in initiation and perpetuation of atrial fibrillation (AF). Osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis, a key regulatory system in bone homeostasis, was recently linked to some cardiovascular disorders for its regulatory functions to myocardial remodeling. It was hypothesized that OPG/RANK/RANKL axis is involved in the development and progression of AF by regulating atrial structural remodeling. Methods and Results: Clinical data, and biopsies of right atrial appendage were collected from sex- and age-matched subjects: 24 persistent AF patients, 24 paroxysmal AF patients, 24 sinus rhythm patients undergoing isolated mitral valve surgery and 24 healthy heart donors. AF groups had higher atrial gene expression of OPG/RANK/RANKL axis and RANKL/OPG ratio, particularly in paroxysmal AF. This upregulated expression and activity were positively correlated with higher regulatory indicators of atrial structural remodeling as reflected by higher transcripts of tumor necrosis factor (TNF)-related apoptosis-inducing ligand, matrix metalloproteinase (MMP)-2 and MMP-9, pro-inflammatory factors TNF-α and interleukin-6, and higher ratios of MMP-9/tissue inhibitor of metalloproteinase (TIMP)-1 and MMP-2/TIMP-2 in AF. Conclusions: The present findings suggest a potential role for known mediators of bone metabolism in the development and progression of AF and possibly represent new targets for therapeutic intervention in this disorder. (Circ J 2011; 75: 2781-2788)