Linking extracellular inhibitors of Wnt/beta-catenin signaling to carotid intima-media thickness in heart failure with reduced ejection fraction

Abstract

Abstract Background The Wnt/β-catenin signaling pathway plays an important role in endothelial inflammation, vascular calcification, contributing to atherosclerosis development and progression. Sclerostin and Dickkopf-1 (DKK-1) are soluble extracellular canonical Wnt signaling inhibitors frequently associated with atherosclerotic disease. Purpose We investigated the possible association between carotid intima-media thickness (cIMT) and circulating levels of sclerostin and DKK-1 in patients with heart failure with reduced ejection fraction (HFrEF). Methods 65 patients with HFrEF were assigned to one of two groups based on cIMT measurements: 30 patients had normal cIMT, whereas 35 patients showed pathological cIMT. CIMT was assessed by vascular ultrasonography, and values above 0.9 mm were considered abnormal. Serum sclerostin and DKK-1 levels were measured using commercially available ELISA kits. Unpaired t-test and Mann-Whitney test were used for statistical analysis (p<0.05 was considered statistically significant). Results Patients belonging to the group with abnormal cIMT were older (70±9 years vs. 57±12 years, p<0.0001), had higher systolic blood pressure (123±16 mm Hg vs. 112±15 mm Hg, p=0.005), and had more often type 2 diabetes mellitus (40.00% vs. 13.33%, p=0.017). Sclerostin levels were significantly higher in the abnormal cIMT population (537.91±816.69 pg/mL vs. 276.37±173.21 pg/mL, p=0.017), whereas serum DKK-1 concentrations did not differ significantly (398.34±218.73 pg/mL vs. 352.35±188.08 pg/mL, p=0.498). The two groups had similar C-reactive protein levels (1.78±2.77 mg/dL vs. 1.88±2.77 mg/dL, p=0.200), estimated glomerular filtration rates (73.60±22.32 mL/min/1.73m2 vs. 66.25±23.69 mL/min/1.73m2, p=0.254) and body mass index (27.58±4.95 kg/m2 vs. 26.65±5.75 kg/m2, p=0.490). Conclusion Patients with HFrEF and increased cIMT had elevated levels of serum sclerostin. DKK-1 levels did not increase with the progression of cIMT. Further studies with large sample size are needed to establish the involvement of these proteins in vascular calcification and atherosclerosis in the setting of HFrEF. Funding Acknowledgement Type of funding sources: None.