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

Aims/hypothesis Type 2 diabetes has been demonstrated to predispose to aortic valve calcification. We investigated whether type 2 diabetes concomitant to aortic stenosis (AS) enhances valvular inflammation and coagulation activation via upregulated expression of NF-kappa B, with subsequent increased expression of bone morphogenetic protein 2 (BMP-2). Methods In this case-control study, 50 individuals with severe isolated AS and concomitant type 2 diabetes were compared with a control group of 100 individuals without diabetes. The median (IQR) duration of diabetes since diagnosis was 11 (7-18) years, and 36 (72%) individuals had HbA(1c) >= 48 mmol/mol (>= 6.5%). Stenotic aortic valves obtained during valve replacement surgery served for in loco NF-kappa B, BMP-2, prothrombin (FII) and active factor X (FXa) immunostaining. In vitro cultures of valve interstitial cells (VICs), isolated from obtained valves were used for mechanistic experiments and PCR investigations. Results Diabetic compared with non-diabetic individuals displayed enhanced valvular expression of NF-kappa B, BMP-2, FII and FXa (all p <= 0.001). Moreover, the expression of NF-kappa B and BMP-2 positively correlated with amounts of valvular FII and FXa. Only in diabetic participants, valvular NF-kappa B expression was strongly associated with serum levels of HbA(1c), and moderately with fructosamine. Of importance, in diabetic participants, valvular expression of NF-kappa B correlated with aortic valve area (AVA) and maximal transvalvular pressure gradient. In vitro experiments conducted using VIC cultures revealed that glucose (11 mmol/l) upregulated expression of both NF-kappa B and BMP-2 (p < 0.001). In VIC cultures treated with glucose in combination with reactive oxygen species (ROS) inhibitor (N-acetyl-l-cysteine), the expression of NF-kappa B and BMP-2 was significantly suppressed. A comparable effect was observed for VICs cultured with glucose in combination with NF-kappa B inhibitor (BAY 11-7082), suggesting that high doses of glucose activate oxidative stress leading to proinflammatory actions in VICs. Analysis of mRNA expression in VICs confirmed these findings; glucose caused a 6.9-fold increase in expression of RELA (NF-kappa B p65 subunit), with the ROS and NF-kappa B inhibitor reducing the raised expression of RELA by 1.8- and 3.2-fold, respectively. Conclusions/interpretation Type 2 diabetes enhances in loco inflammation and coagulation activation within stenotic valve leaflets. Increased valvular expression of NF-kappa B in diabetic individuals is associated not only with serum HbA(1c) and fructosamine levels but also with AVA and transvalvular gradient, indicating that strict long-term glycaemic control is needed in AS patients with concomitant type 2 diabetes. This study suggests that maintaining these variables within the normal range may slow the rate of AS progression.

Automated summary

Type 2 diabetes enhances local inflammation and coagulation activation within stenotic valve leaflets. Increased valvular expression of NF-kappa B in diabetic individuals is associated not only with serum HbA(1c) and fructosamine levels but also with AVA and transvalvular gradient, indicating the importance of strict long-term glycemic control in AS patients with concomitant type 2 diabetes. Maintaining these variables within normal range may slow the rate of AS progression.