Abstract
BACKGROUND: Diabetes mellitus (DM) has been shown to increase the rate of aortic stenosis (AS) progression. However, the impact of impaired plasma glucose on valvular calcification remains poorly understood. Using ex vivo micro-computed tomography (micro-CT), we aimed to determine whether plasma glucose, glycated haemoglobin (HbA(1c)), or concentrations of advanced glycation end products (AGEs) and their soluble receptor (sRAGE) are associated with a specific pattern of valvular calcification in severe AS. METHODS: In this case-control study, 14 (48%) normoglycaemic patients with AS were compared to 15 individuals (52%) with elevated glucose levels (≥ 5.6 mmol/L), all with HbA(1c) ≤ 6.5%. Stenotic aortic valves obtained surgically were analysed using micro-CT to assess structure of tissue mineralization. Calcium volume (CV), surface volume (SV), CV/SV ratio, and trabecular thickness (TbTh) were evaluated. Plasma AGEs and sRAGE were assessed by ELISAs. DM patients or those using antidiabetic agents were excluded from the study. RESULTS: Patients with impaired and high glucose, including 10 (67%) with glucose between 5.6 and 6.9 mmol/L and 5 (33%) ranging from 7 to 7.6 mmol/L, exhibited higher HbA(1c) (+ 17%) and AGEs levels (+ 44.6%), but not sRAGE compared to those with normal glucose. Patients with impaired and high glucose had also 19.2% higher maximal transvalvular pressure gradient (PG(max)) and 9.3% higher peak transvalvular velocity (V(max)) compared to normoglycaemic individuals. Micro-CT indices correlated with fasting glucose, HbA(1c), and AGEs levels (all p < 0.05), but not with sRAGE (p > 0.05). Valves extracted from patients with impaired and high glucose exhibited higher mineralization volume, folding, and structural integrity, as reflected by increased CV (+ 127.6%), CV/SV ratio (+ 59%) and calcium deposits microarchitecture as indicated by about 50% higher TbTh, compared to normoglycaemic patients. When patients with AS were divided into three groups based on their glucose levels (< 5.5 mmol/L, 5.6-6.9 mmol/L, and 7.0-7.6 mmol/L), micro-CT analysis showed more distinct structural differences among the groups. The valves in the highest glucose group were the most severely affected. Micro-CT parameters were also associated with both transvalvular pressure gradients (PG(mean) and PG(max)), V(max) and aortic valve area (all p < 0.05). CONCLUSIONS: Strict glycaemic control could potentially reduce the rate of valve mineralization and calcium deposit accumulation in patients with AS. RESEARCH INSIGHTS: WHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: Diabetes mellitus (DM) is a risk factor for the progression of aortic stenosis (AS). Accumulation of advanced glycation end products (AGEs) enhances glycation of valvular proteins. WHAT IS THE KEY RESEARCH QUESTION?: Is dysglycaemia associated with more severe aortic valve calcification in patients with severe AS? Is ex vivo micro-CT suitable for assessing differences in calcification pattern within stenoticvalves? WHAT IS NEW?: Pre-diabetic patients with AS show increased valvular calcium volume, surface corrugation, and calcium deposit integrity. Micro-CT parameters associate with glycaemic status and echocardiographic measures of AS severity. Micro-CT provides precise assessment of calcification, offering insights beyond traditional methods. HOW MIGHT THIS STUDY INFLUENCE CLINICAL PRACTICE?: Strict glycaemic control together with CT calcium scoring should be performed in patients with AS to monitor disease progression.