Oxidative stress associates with advanced glycation end products accumulation and aortic stenosis severity in patients with concomitant type 2 diabetes.

Abstract

Diabetes mellitus (DM) is a known risk factor of aortic stenosis (AS). Among pathogenetic mechanisms associated with DM, increased oxidative stress plays a key role in the valvular degeneration progression. This study aimed to evaluate whether DM coexistence with severe AS is associated with parallel enhancement of oxidative stress in both circulating blood and stenotic valves. We enrolled 70 severe AS patients scheduled for aortic valve replacement, including 40 (57%) with concomitant type 2 DM (AS-DM) and 30 AS patients without type 2 DM (AS-nonDM). We assessed circulating oxidized phospholipids (oxPL), myeloperoxidase (MPO), advanced glycation end products (AGEs), and their soluble receptors (sRAGE). Valvular expression of oxPL and AGEs was determined using immunostaining of aortic valve samples. In the whole group of AS patients (n=70) oxPL, MPO and AGEs levels correlated with HbA1c concentration (r=0.79, p<0.001; r=0.60, p<0.001 and r=0.85, p<0.001, respectively). Similarly, oxPL and MPO were associated with plasma AGEs (r=0.66, p<0.001 and r=0.53, p<0.001). Moreover, serum MPO and oxPL correlated with aortic valve area (AVA; r= -0.49, p<0.001 and r= -0.45, p<0.001). Among 40 AS-DM patients we observed 2.55-fold higher serum oxPL, 1.38-fold higher serum MPO, 2.07-fold higher plasma AGEs and 2.22-fold higher plasma sRAGE compared to AS-nonDM (all p<0.001). In AS-DM group, valvular oxPL and AGEs expression was 1.8-fold and 1.6-fold higher when compared to AS-nonDM patients (all p<0.001). Of major importance, valvular expression of oxPL correlated both with serum oxPL and MPO levels (r=0.72 and r=0.63, respectively; both p<0.001). This study is the first to show that in severe AS patients with concomitant DM, valvular expression of oxPL is markedly higher compared to non-DM patients and associates with their circulating levels. Moreover, enhanced valvular oxidative stress was linked with glycemic status and more severe AS.