Background: Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation (AF). Our previous study has indicated that DM causes atrial structural remodeling with intraatrial conduction disturbances. We tested the hypothesis that the advanced glycation end products (AGEs) and the receptor for AGE (RAGE), which have been implicated in diabetic complications, are responsible for the atrial structural remodeling.

Methods and Results: Diabetes was induced by streptozotocin (65 mg/kg i.p.) in 8‐week‐old female Sprague–Dawley rats. When 24 weeks old, their atria were subjected to histology, Western blotting, and immunohistochemistry. The HbA_1c value of induced‐DM rats was significantly higher than that of control rats. Histological and immunohistochemical examinations revealed that the atria of diabetic rats showed remarkable structural changes characterized by diffuse interstitial fibrosis with abundant expressions of RAGE and connective tissue growth factor (CTGF), which findings were also confirmed by Western blotting analysis. This diabetes‐induced atrial fibrosis was remarkably prevented by administration of an inhibitor of AGEs formation, OPB‐9195, along with reduction of CTGF expression.

Conclusions: DM promoted atrial structural remodeling via the activation of the AGEs‐RAGE system with upregulating CTGF. The inhibition of AGEs formation could be a novel upstream therapeutic approach for diabetes‐related atrial fibrosis.