P1829Accumulation of advanced glycoxidation end products (AGEs) is associated with the severity of aortic stenosis in patients with concomitant type 2 diabetes

Abstract

Abstract Background Accumulation of advanced glycoxidation end products (AGEs) leads to chronic inflammation, glycation of proteins and tissue damage, particularly in patients with diabetes mellitus (DM). Purpose To evaluate whether increased valvular accumulation of AGEs in patients with aortic stenosis (AS) and concomitant diabetes (AS-DM) is associated with enhanced valvular inflammation, increased oxidative stress and AS progression. Methods We enrolled 50 patients (28 women), aged 67.2±7.9 years with severe AS (transvalvular gradients: PGmean=52.9±13.4 mmHg, PGmax=84.9±18.7 mmHg), including 30 subjects with type 2 DM (glycaemia 6.3±1.9 mM/l, glycated haemoglobin [HbA1c] 6.9±1.4%), who underwent aortic valve replacement. Valvular expression of AGEs, AGE receptors (RAGE), interleukin-6 (IL-6), prothrombin (FII), C-reactive protein (CRP), and reactive oxygen species (ROS) were evaluated ex vivo by single/double-immunostaining. The percentage of immuno-positive areas was analyzed for each valve. Results There were no differences with regard to age and AS severity between AS and AS-DM patients. Subjects with AS-DM had elevated valvular expression of both AGE and RAGE (41.3±15.2% and 17.6±7.1%, respectively) as compared to non-DM (9.4±3.9% and 3.4±2.4%, respectively; all p<0.001). In AS-DM patients AGE/RAGE showed co-expression in 51.5% of areas. The percentage of ROS-, CRP-, and IL-6-positive areas was elevated within AS-DM compared to AS valves (10.9±2.4%, 6±0.3%, and 5.7±1.4% vs 4.8±1.7%, 2.5±0.1%, and 1.6±0.9%, respectively; all p<0.05). Valvular expression of FII was elevated in AS-DM patients compared to those with AS (17.3±2.5% vs. 11±2%, p<0.05). In AS-DM patients the percentage of valvular AGE-positive areas correlated with HbA1c (r=0.44, p<0.05) and blood glucose levels (r=0.57, p<0,05). The amount of valvular RAGE correlated with HbA1c (r=0.63, p=0.009) but not with blood glucose levels. In AS-DM patients we found positive associations between the amount of valvular AGE and IL-6 with disease severity measured as aortic valve area (AVA; r=−0.83, p<0.0001; r=−0.64, p<0.001, respectively) and PGmax (r=0.54, p<0.05; r=0.52, p<0.05, respectively) but not with PGmean. There were no associations between PGmax/PGmean and HbA1c levels in the whole AS-DM group. However, patients with HbA1c >6.5% (n=19) or ≤6.5% (n=11) were characterized by higher PGmax and PGmean compared to those with HbA1c ≤6.5% (93.3±8.9 mmHg vs 67.5±7.2 mmHg and 63.6±6.5 mmHg vs 52±77 mmHg, respectively, all p<0.05). Conclusions Patients with AS-DM compared to those with AS demonstrate enhanced valvular AGEs accumulation and increased RAGE expression along with accelerated inflammation and oxidative stress. The accumulation of valvular AGE correlated with both hyperglycaemia and AS severity. Acknowledgement/Funding This work was supported by the grant from the Polish National Science Center (UMO-2015/19/B/NZ5/00647 to J.N).