Association of growth differentiation factor 15 (GDF-15) with aortic stenosis severity and long-term glycaemic control in patients with diabetes

Background Diabetes mellitus (DM) and aortic stenosis (AS) are prevalent chronic conditions that frequently coexist and share a progressive course. Growth differentiation factor-15 (GDF-15) has emerged as a biomarker of cardiovascular and metabolic stress, however, its role in AS remains unclear. This study aimed to compare GDF-15 levels in AS patients with and without DM and to evaluate the association of GDF-15 with AS severity, glycaemic parameters, and other routine laboratory markers. Methods We enrolled 149 patients with severe AS, including 51 with diagnosed DM. Medical history and current treatment were collected using a standardized questionnaire. Severe AS was defined as mean transvalvular gradient (PGmean) ≥40 mmHg, peak velocity (Vmax) ≥4.0 m/s, and aortic valve area (AVA) ≤1 cm2. Routine laboratory tests included glucose, glycated haemoglobin (HbA1c), creatinine, lipid profile, CRP, and fibrinogen. Serum GDF-15 levels were measured by ELISA. Additionally, 20 apparently healthy individuals were recruited to provide reference GDF-15 levels. Results Baseline characteristics of AS patients, including subgroups with and without DM, are summarized in Figure 1. The median age of AS patients was 68 [64-73] years, and 58.4% were male. Median GDF-15 concentration was 982.7 [723.4-1470.7] pg/ml in all AS patients and 661.8 [542.6-808.9] pg/ml in controls (Figure 2A), with the difference remaining significant after adjustment for age (p=0.027). In the AS cohort, GDF-15 was associated with AVA (r=-0.24, p=0.003), glucose (r=0.3, p=0.0002), HbA1c (r=0.32, p=0.0004), creatinine (r=0.33, p<0.0001) and eGFR(r=-0.37, p<0.0001). AS patients with DM had 55.9% higher GDF-15 than those with isolated AS (1326.4 [893.6-2292.7] vs 850.7 [652.5-1222.7] pg/ml; Figure 2B), even after adjustment for age (p=0.0002). In DM-AS patients, GDF-15 correlated with AS severity: PGmean (r=0.33, p=0.02), PGmax (r=0.44, p=0.001), Vmax (r=0.44, p=0.001) and AVA (r=-0.56, p<0.0001), as well as with glucose (r=0.34, p=0.014), HbA1c (r=0.43, p=0.002), creatinine (r=0.40, p=0.004) and eGFR (r=-0.38, p=0.006). Among DM-AS patients, those with HbA1c ≥6.5% (n=24) exhibited 90.5% higher GDF-15 than those with HbA1c <6.5% (n=27; 1918.4 [1188.8-2324.3] vs 1007 [697-1786.4] pg/ml; Figure 2C). In patients with HbA1c <6.5%, GDF-15 correlated with AVA (r=-0.45, p=0.02), creatinine (r=0.57, p=0.002) and eGFR (r=-0.52, p=0.005), whereas in those with HbA1c ≥6.5%, it was associated with PGmax, Vmax, AVA, glucose and HbA1c (Figure 2D-H). Conclusions GDF-15 levels are elevated in AS patients compared to controls and further increased in those with concomitant DM. GDF-15 remains associated with AS severity and metabolic parameters. The relationship between GDF-15 and HbA1c suggests that long-term glycaemic control may modulate GDF-15 concentrations in AS. These findings indicate that GDF-15 reflects combined valvular and metabolic burden.