Increased serum S100A12 levels are associated with higher risk of acute heart failure in patients with type 2 diabetes

Abstract

Aims The hyperglycaemic stress induces the release of inflammatory proteins such as S100A12, one of the endogenous ligands of the receptors for advanced glycation end products (RAGE). Chronic activation of RAGE has multiple deleterious effects in target tissues such as the heart and the vessels by promoting oxidative stress, inflammation by the release of cytokines, macrophages infiltration, and vascular cell migration and proliferation, causing ultimately endothelial cell and cardiomyocyte dysfunction. The aim of our study was to investigate the prognostic value of circulating S100A12 beyond established cardiovascular risk factors (CVRF) for heart failure (HF) and major adverse cardiovascular events (MACE) in a cohort of patients with type 2 diabetes. Methods and results Serum S100A12 concentrations were measured at baseline in 1345 type 2 diabetes patients (58% men, 64 ± 11 years) recruited in the SURDIAGENE prospective cohort. Endpoints were the occurrence of acute HF requiring hospitalization (HHF) and MACE. We used a proportional hazard model adjusted for established CVRF (age, sex, duration of diabetes, estimated glomerular filtration rate, albumin/creatinine ratio, history of coronary artery disease) and serum S100A12. During the median follow‐up of 84 months, 210 (16%) and 505 (38%) patients developed HHF and MACE, respectively. Baseline serum S100A12 concentrations were associated with an increased risk of HHF [hazard ratio (HR) (95% confidence interval) 1.28 (1.01–1.62)], but not MACE [1.04 (0.90–1.20)]. After adjustment for CVRF, S100A12 concentrations remained significantly associated with an increased risk of HHF [1.29 (1.01–1.65)]. In a sub‐analysis, patients with high probability of pre‐existing HF [N terminal pro brain natriuretic peptide (NT‐proBNP) >1000 pg/mL, n = 87] were excluded. In the remaining 1258 patients, the association of serum S100A12 with the risk of HHF tended to be more pronounced [1.39 (1.06–1.83)]. When including the gold standard HF marker NT‐proBNP in the model, the prognostic value of S100A12 for HHF did not reach significance. Youden method performed at 7 years for HHF prediction yielded an optimal cut‐off for S100A12 concentration of 49 ng/mL (sensitivity 53.3, specificity 52.2). Compared with those with S100A12 ≤ 49 ng/mL, patients with S100A12 > 49 ng/mL had a significantly increased risk of HHF in the univariate model [HR = 1.58 (1.19–2.09), P = 0.0015] but also in the multivariate model [HR = 1.63 (1.23–2.16), P = 0.0008]. After addition of NT‐proBNP to the multivariate model, S100A12 > 49 ng/mL remained associated with an increased risk of HHF [HR = 1.42 (1.07–1.90), P = 0.0160]. However, the addition of S100A12 categories on top of multivariate model enriched by NT‐pro BNP did not improve the ability of the model to predict HHF (relative integrated discrimination improvement = 1.9%, P = 0.1500). Conclusions In patients with type 2 diabetes, increased serum S100A12 concentration is independently associated with risk of HHF, but not with risk of MACE. Compared...

The Association Between S100A12 Protein and C-Reactive Protein with Malignant Ventricular Arrhythmias Following Acute Myocardial Infarction in the Elderly

“…This binding of S100A12 to RAGE mediates the secretion of cytokines. 36 , 37 Previous research has indicated that S100A12 may serve as a distinct biomarker for cardiovascular pathological processes and has a close association with MVA, 38 , 39 mirroring our findings and further supporting the potential of S100A12 as a predictor for MVA in AMI patients.…”

Study on potential differentially expressed genes in idiopathic pulmonary fibrosis by bioinformatics and next generation sequencing data analysis

“…MAP3K15 [94], PRTN3 [95], CX3CR1 [96], AGRP (agouti related neuropeptide) [97], MPO (myeloperoxidase) [98], CD5L [99], S100A8 [100], NPR3 [101], VEGFD (vascular endothelial growth factor D) [102], CXCL11 [103], IL1A [104], CBS (cystathionine beta-synthase) [105], WNT7A [106], SCD (stearoyl-CoA desaturase) [107], LRP2 [108], SLC6A4 [109], BDNF (brain derived neurotrophic factor) [110], CXCL10 [111], ANGPTL7 [112], S100A9 [113], NPY1R [114], IL1B [115], GPIHBP1 [116], CYP1B1 [117], CD36 [118], MACROD2 [119], TRIB3 [120], SPX (spexin hormone) [121], PCSK9 [122], GPD1 [123], CDH13 [124], FFAR4 [125], FGF2 [126], FASN (fatty acid synthase) [127], DGAT2 [128], DACH1 [129], PNPLA3 [130], FGF9 [131], SLC7A11 [132], CLIC5 [133], VIP (vasoactive intestinal peptide) [134], SMAD6 [135], BMPR2 [136], APOA1 [137], INSIG1 [138], TLR3 [139], NLRP12 [140], ADRB1 [141], TLR8 [142], GATA3 [143], CCR2 [144], TLR7 [145], CCRL2 [146], BMPER (BMP binding endothelial regulator) [147], CAV1 [148], TFPI (tissue factor pathway inhibitor) [149], FADS1 [150], SUCNR1 [151], CADM2 [152], SLC19A3 [153], SGCG (sarcoglycan gamma) [154], ADH1B [155], NEGR1 [156], HSD17B12 [157], OXTR (oxytocin receptor) [158] and ANKK1 [159] were frequently altered in obesity. MAP3K15 [94], CX3CR1 [160], S100A12 [161], PF4 [162], FFAR2 [163], MPO (myeloperoxidase) [98], HMGCS2 […”

“…PRTN3 [226], CX3CR1 [227], S100A12 [228], CSF2 [229], FGG (fibrinogen gamma chain) [230], LHX9 [231], MPO (myeloperoxidase) [232], F11 [233], S100A8 [234], CXCL11 [235], BPI (bactericidal permeability increasing protein) [236], BDNF (brain derived neurotrophic factor) [237], CXCL10 [238], S100A9 [239], IL1B [240], CXCR1 [241], CXCR2 [242], CYP1B1 [243], EDNRB (endothelin receptor type B) [244], CEBPA (CCAAT enhancer binding protein alpha) [245], CDH13 [246], GPX3 [247], FGF2 [248], SHH (sonic hedgehog signaling molecule) [249], VIP (vasoactive intestinal peptide) [250], KL (klotho) [251], SMAD6 [252], BMPR2 [253], APOA1 [254], TLR3 [255], GATA3 [256], CCR2 [257], CAV1 [258], TRPC3 [259], EPAS1 [260], SIGLEC14 [261], MAPK15 [262], DNAH5 [263] and AQP5 [264] were identified to be associated with chronic obstructive pulmonary disease. DEFA3 [265], CX3CR1 [266], S100A12 [161], TUBB1 [267], ANKRD1 [268], ADRA1A [269], FGG (fibrinogen gamma chain) [270], AGER (advanced glycosylation end-product specific receptor) [271], PF4 [272], FFAR2 [273], MPO (myeloperoxidase) [274], CD5L [275], HMGCS2 [164], RXFP1 [276], F11 [277], S100A8 [278], PGLYRP1 [279], VEGFD (vascular endothelial growth factor D) [280], CHRM2 [281], CBS (cystathionine beta-synthase) [282], BPI (bactericidal permeability increasing protein) [283], LRP2 [284], BDNF (brain derived neurotrophic factor) [285], GCOM1 [286], CXCL10 [287], ANGPTL7 [288], PRODH (proline dehydrogenase 1) [289], P2RY1 [290], LRRN4 [291], S100A9 […”

FABP4 and S100A12, a notable link between inflammatory mediators and cardiovascular risk in rheumatoid arthritis

“…S100A12 induces the production of in ammatory cytokines and recruits immune cells to the site of in ammation. As a result, the concentration of this protein in the serum and synovial uid of RA patients increases and is used to monitor the disease [27][28][29][30][31]. Also, the RAGE receptor is located on the heart and blood vessels, and S10012, by binding to it, causes the production of in ammatory cytokines and the ltering of macrophages to the vessel wall, which eventually leads to cardiovascular disorders [30,31].…”