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

Abstract

Background Aortic stenosis ( AS ) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products ( AGE s) and the receptor for AGE s ( 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 AGE s 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 AGE s 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.

Diabetes concomitant to aortic stenosis is associated with increased expression of NF-κB and more pronounced valve calcification

“…Baseline characteristics of participants with AS, with and without type 2 diabetes, are shown in Table 1. The median duration of diabetes was 11 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) years and 36 (72%) individuals had HbA 1c ≥48 mmol/mol (≥6.5%).…”

“…Hyperglycaemia has been proposed as one of the metabolic states enhancing aortic valve fibrosis and calcification [12][13][14] through a complex mechanism involving increased valvular protein glycation, of reactive oxygen species (ROS) generation, inflammation and coagulation activation [15,16]. Although the pivotal mechanism leading to such dysregulation is not fully understood, formation of AGEs has been suggested as a factor initiating and/or escalating valvular calcification [17,18].…”

Diabetes mellitus as a risk factor for aortic stenosis: from new mechanisms to clinical implications

“…Immunohistochemistry analysis of AS valves revealed that concomitant DM was associated with an increased percentage of C-reactive protein-positive areas and correlated with the percentage of TF-positive areas [7]. Moreover, increased valvular protein glycation due to an accumulation of advanced glycoxidation end products (AGEs) has been suggested as a contributor to faster AS progression [54][55][56][57]. AGEs are a heterogonous group of proteins or lipids irreversibly glycated by the attachment of reducing sugars onto the free amino groups.…”

<p>Role of Sortilin and Matrix Vesicles in Nϵ-Carboxymethyl-Lysine-Induced Diabetic Atherosclerotic Calcification</p>

“…4,5 Studies have also suggested that the receptor of CML may play a role in the pathogenesis of calcified aortic stenosis. 6 This evidence suggests that CML plays an important role in the occurrence and development of diabetic AC.…”