Abstract
Aims/hypothesisType 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-κB, with subsequent increased expression of bone morphogenetic protein 2 (BMP-2).MethodsIn 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 HbA1c ≥48 mmol/mol (≥6.5%). Stenotic aortic valves obtained during valve replacement surgery served for in loco NF-κB, 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.ResultsDiabetic compared with non-diabetic individuals displayed enhanced valvular expression of NF-κB, BMP-2, FII and FXa (all p ≤ 0.001). Moreover, the expression of NF-κB and BMP-2 positively correlated with amounts of valvular FII and FXa. Only in diabetic participants, valvular NF-κB expression was strongly associated with serum levels of HbA1c, and moderately with fructosamine. Of importance, in diabetic participants, valvular expression of NF-κB 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-κB 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-κB and BMP-2 was significantly suppressed. A comparable effect was observed for VICs cultured with glucose in combination with NF-κB 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-κB p65 subunit), with the ROS and NF-κB inhibitor reducing the raised expression of RELA by 1.8- and 3.2-fold, respectively.Conclusions/interpretationType 2 diabetes enhances in loco inflammation and coagulation activation within stenotic valve leaflets. Increased valvular expression of NF-κB in diabetic individuals is associated not only with serum HbA1c 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.Graphical abstract
Highlights
Aortic stenosis (AS) is a progressive disease associated with reduction of the aortic valve orifice and leaflet mobility due to a build-up of calcium
In the whole population of diabetic participants, no associations were found between serum glucose, HbA1c or fructosamine levels and echocardiographic variables
We propose the following mechanism underlying the influence of type 2 diabetes on AS progression: hyperglycaemia leads to enhanced accumulation of AGEs/receptor for AGEs (RAGE) and, as a consequence, enhanced production of reactive oxygen species (ROS) within valves [18]
Summary
Aortic stenosis (AS) is a progressive disease associated with reduction of the aortic valve orifice and leaflet mobility due to a build-up of calcium. AS is the most common acquired valvular heart disease in the western adult population, with no available pharmacological treatment. The prevalence of AS in individuals >65 years of age ranges between 2% and 7% [1]. It is estimated that 4.5 million cases of AS will be present worldwide by the year 2030 [2]. Whether surgical or percutaneous, is the only definitive treatment for AS. While both methods present excellent outcomes, surgical intervention remains the treatment of choice for the vast majority of patients [3]
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