Pathological Role of Receptor for Advanced Glycation End Products in Calcified Aortic Valve Stenosis

BACKGROUND: Aortic stenosis (AS) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play a pivotal role for vascular calcification in atherosclerosis. We hypothesize that the AGEs–RAGE axis could also be involved in the pathophysiological mechanism of calcified AS. METHODS AND RESULTS: A total of 54 patients with calcified AS who underwent aortic valve replacement were prospectively enrolled from 2014 to 2016 (mean age 75.3±7.7 years). Aortic valve specimens were obtained from 47 patients and 16 deceased control subjects without aortic valve disease (mean age 63.2±14.5 years). The valvular expression of RAGE was evaluated by immunohistochemistry. Serum levels of AGEs and soluble RAGE were measured in 50 patients with calcified AS and 70 age‐matched and sex‐matched control subjects without heart disease. The valvular RAGE expression in patients with calcified AS was higher than controls (P=0.004) and was significantly associated with a decreased ankle‐brachial pressure index (P=0.007) and an increased intima‐media thickness (P=0.026). RAGE and α–smooth muscle actin were coexpressed and were partially costained with osteocalcin and alkaline phosphatase. The serum levels of AGEs and soluble RAGE were significantly higher in the patients with calcified AS than in the controls (P=0.013 and P<0.001, respectively). Soluble RAGE (inversely) and use of aspirin were independently correlated with changes in left ventricular systolic function after aortic valve replacement (P=0.012 and P=0.002, respectively). CONCLUSIONS: Our present study suggests that RAGE may play a role in the pathogenesis of calcified AS, which is a prognostic marker in patients with AS after aortic valve replacement.