Plasma adiponectin levels and sonographic phenotypes of subclinical carotid artery atherosclerosis : Data from the SAPHIR study

Copyright: Copyright 2008 Elsevier B.V., All rights reserved.Background and Purpose - Adipose tissue produces and secretes a number of bioactive molecules, conceptualized as adipocytokines. Adiponectin has been identified as one of the adipocytokines, and hypoadiponectinemia was demonstrated in patients with obesity, diabetes mellitus, and coronary artery disease. Whether decreased adiponectin levels are cause or consequence is an important issue in the discussion on the association between adiponectin and atherosclerosis. In the present study, we investigated the association of plasma adiponectin levels with sonographic phenotypes of subclinical atherosclerosis, which may represent different stages of disease as well as common and distinct determinants. Methods - A total of 1515 middle-aged healthy white subjects (940 males and 575 females) were included. Common carotid artery intima-media thickness (CIMT) and presence of atherosclerotic plaques were assessed by B-mode ultrasound. Results - After adjustment for established risk factors, per 1 μg/mL decrease in adiponectin CIMT increased on the average by 3.48 μ in males (95% CI, 1.23 to 5.73 μm) and by 2.39 μ in females (95% CI, 0.50 to 4.27 μm). After dichotomizing adiponectin levels at the median and adjustment for established risk factors, the mean difference of CIMT between subjects with low and high adiponectin levels was 20.42 μm in men (95% CI, 6.80 to 34.04; P=0.003) and 20.75 μ in women (95% CI, 1.08 to 40.42; P=0.039). No significant relationship was found between adiponectin levels and presence of atherosclerotic plaques. Conclusion - Our results demonstrate an independent negative association of adiponectin levels and CIMT, whereas no relationship with presence of atherosclerotic plaques was found, thus suggesting hypoadiponectinemia as a risk factor in the development of early atherosclerosis.publishersversionPeer reviewe

Response to letter by Pilz et al

Copyright: Copyright 2008 Elsevier B.V., All rights reserved.publishersversionPeer reviewe

The SREBF-1 locus is associated with type 2 diabetes and plasma adiponectin levels in a middle-aged Austrian population

Funding Information: This study was supported by grants from the Oesterrei-chische Nationalbank (Project No. 10678 and 10932), the Medizinische Forschungsgesellschaft Salzburg and a grant from the Land Salzburg. Copyright: Copyright 2011 Elsevier B.V., All rights reserved.Context: The sterol regulatory element-binding protein-1c (SREBP-1c) is a transcription factor involved in the regulation of lipid and glucose metabolism and has been implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). Objective: We aimed to confirm associations of the SREBF-1 gene with T2DM in an Austrian population and to study possible associations with diabetes-related quantitative traits. Design, settings and participants: We genotyped a diabetic cohort (n=446) along with a control group (n=1524) for a common C/G variation that is located in exon 18c (rs2297508) and has been associated with obesity and T2DM in French populations. Main outcome measures: Body mass index (BMI), indices of insulin sensitivity and β-cell function, plasma adiponectin, T2DM and single-nucleotide polymorphism rs2297508. Results: Genotype distributions associated with rs2297508 differed by T2DM status (P=0.0045), but not by BMI. The variant G allele was associated with a modest, but significant, increase in the prevalence of T2DM after adjustment for age, sex and BMI (G/G: odds ratios (OR) (95% confidence intervals)=1.45 (0.99-2.11) and G/C: OR=1.37 (1.04-1.81)). In a cross-sectional population of non-diabetic subjects, associations of rs2297508 genotypes with plasma adiponectin levels adjusted for age, sex and BMI (P=0.0017) were observed in that the risk G/G genotype displayed the lowest adiponectin levels. Conclusions: We observed associations of rs2297508 with T2DM prevalence and plasma adiponectin. SREBP-1c has been implicated in the regulation of adiponectin gene expression. Our results therefore raise the possibility that sequence variations at the SREBF-1 gene locus might contribute to T2DM risk, at least in part, by altering circulating adiponectin levels.publishersversionPeer reviewe

Increased serum chemerin level to predict early onset of aortic valve stenosis

Publisher Copyright: © 2018, Spandidos Publications. All rights reserved.Inflammation appears to be the cause of aortic valve (AoV) stenosis and identification of predictive biomarkers is therefore imperative. The aim of the current study was to evaluate the potential role of serum chemerin and fibroblast growth factor-21 (FGF-21) in the pathogenesis of the disease. A total of 102 patients were selected based on certain criteria and divided into an aortic stenosis group and a control group. Patients with AoV stenosis were subdivided into three groups depending on the severity according to the echocardiography criteria: Aortic jet velocity, Vmax (m/ sec); mean pressure gradient, PG (mmHg); aortic valve area (AVA), cm2; and indexed AVA, cm2/m2. Patients were graded as: Severe: Vmax >4 m/sec, PG >40 mmHg, AVA 1.5 cm2, indexed AVA >0.85. ELISA was used for the detection of chemerin and FGF-21. Post-hoc analysis with Tukey's correction was performed. The highest chemerin levels were found in mild and moderate AoV stenosis and decreased along with the grade of severity, compared with the control group. The FGF-21 level was increased in all the stenosis groups, reaching the highest level at severe stenosis. Receiver-operating characteristic analysis of chemerin in all the AoV stenosis groups without grading the severity included, area under the curve (AUC)=0.76; 0.70-0.80= fair; P<0.001 and for mild AoV stenosis was AUC=0.82; 0.80-0.90= good; P<0.001. In conclusion, chemerin is a good diagnostic biomarker for mild AoV stenosis, while FGF-21 is a moderate diagnostic marker.publishersversionPeer reviewe

HDL-C role in acquired aortic valve stenosis patients and its relationship with oxidative stress

Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.Background and objectives: Mechanical stress is currently considered as the main factor promoting calcific aortic valve stenosis (AS) onset. It causes endothelial damage and dysfunction. The chronic inflammatory process causes oxidative stress. Oxidative stress-induced high-density lipoprotein cholesterol (HDL-C) dysfunction is an important component of the development of AS. The aim of the study was to evaluate the role of HDL-C in AS patients in three severity grades and in relation to the biomarkers of oxidative stress, thioredoxin reductase 1 (TrxR1) and myeloperoxidase (MPO). Materials and Methods: 18 patients with mild, 19 with moderate. and 15 with severe AS were included in the study, and 50 individuals were enrolled in the control group. Stenosis severity was determined by echocardiography. The TrxR1 and MPO were analyzed by ELISA, and HDL-C by commercially available tests. Data were analyzed using GraphPad Prism 8. Results: HDL-C in AS patients vs. control substantially decreases and this decline was observed in all three AS severity groups: mild (p = 0.018), moderate (p = 0.0002), and severe (p = 0.004). In both the control and the stenosis group, the HDL-C was higher in women than in men. In comparison to control, the HDL-C level was lower in the AS group, and more pronounced in women (p = 0.0001) than in men (p = 0.049). A higher TrxR1 level was observed in patients with mild (p = 0.0001) and severe AS (p = 0.047). However, a clear correlation between TrxR1 and HDL-C was not obtained. Analysis of MPO showed differences in all severity grades vs. control (p = 0.024 mild stenosis; p = 0.002 moderate stenosis; p = 0.0015 severe stenosis). A negative correlation (p = 0.047; rp = −0.28) was found between MPO and HDL-C, which confirms the adverse effects of MPO resulting in HDL-C dysfunction. Conclusions: In this study, we justified HDL-C level association with AS development process. The results unequivocally substantiated the association between HDL-C and AS in all severity grades in women, but only in moderate AS for men, which we explained by the small number of men in the groups. The obtained correlation between the HDL-C and MPO levels, as well as the concurrent decrease in the HDL-C level and increase in the TrxR1 level, indicate in general an HDL-C association with oxidative stress in AS patients.publishersversionPeer reviewe

Impact of several proinflammatory and cell degradation factors in patients with aortic valve stenosis

Aortic valve (AoV) stenosis is the third most common cardiovascular disease. The pathogenesis of AoV stenosis is associated with an inflammatory process where MMPs serve important roles. The aim of the present study was to determine the association between matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and inflammatory factors, and AoV stenosis at various degrees of severity compared with the control. A total of 18 patients with mild, 19 with moderate and 15 with severe AoV stenosis were included in the present stud, and 50 individuals were enrolled in the control group. The severity of stenosis was determined by echocardiography. The expression levels of chemerin, fibroblast growth factor 21, MMP‑1, ‑3, and ‑9, and TIMP‑1 and ‑3 were analyzed by ELISA. Data were analyzed using GraphPad Prism7 software. The expression levels of MMP‑1 was increased in patients with stenosis compared with the control group (P=0.0043). Distribution of the trimodal MMP‑1 values was obtained in the stenosis group and monomodal in the control group. A total of 80% of patients in the stenosis group presented significantly increased expression levels of MMP‑1 compared with the control group (P=0.0002). Expression of MMP‑1 was significantly higher in all stenosis groups compared with the control. The highest expression level of MMP‑1 appeared in patients with moderate stenosis (P<0.0001). There was no significant difference in the expression of MMP‑3, MMP‑9 and TIMP‑1 in the aortic stenosis group, compared with the control group. A positive correlation between MMP‑1 and MMP‑9 expression levels was identified (r=0.37; P=0.017). The increase of MMP‑1 was correlated with the increase of MMP‑9, but not with the level of MMP‑3. The expression levels of chemerin was significantly elevated in patients with stenosis compared with healthy patients. The highest expression levels of chemerin were determined in patients with mild (P=0.0001) and moderate (P=0.0007) stenosis and decreased with the grade of severity compared with the control group. The expression of FGF‑21 was significantly different between the control and mild (P=0.013), moderate (P=0.015) and severe stenosis (P=0.003) groups. The expression levels of FGF‑21 increased with the increase in severity grade, reaching the maximum for severe stenosis. The results of the present study indicated that the inflammatory process is predominantly occurring at the early, mild stage of stenosis and the most prominent extracellular matrix remodeling occurs in moderate stenosis (demonstrated by MMP‑1 levels). In patients with severe stenosis, the levels of MMP‑1 and chemerin (which are lower than in a case of mild or moderate stenosis) could indicate the development of calcinosis and the reduction in activity or inactivation of the inflammatory process.Peer reviewe

Prognostic utility of circulating growth factors in aortic valve stenosis : A pilot study

Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.Background and Objectives: Aortic valve stenosis (AS) develops with a pronounced local inflammatory response, where a variety of growth factors are involved in the process, and may have a pro-inflammatory and anti-inflammatory effect. The aim of our study was to elucidate whether circulating growth factors: growth differentiation factor 15 (GDF-15), angiopoietin-2 (Ang-2), vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), and fibroblast growth factor 21 (FGF-21) could be proposed as clinically relevant biomarkers to improve risk stratification in AS patients. Materials and Methods: AS patients were classified into three groups: 16 patients with mild AS stenosis; 19 with moderate and 11 with severe AS, and 30 subjects without AS (echocardiographically approved) were selected as a control group. GDF-15, Ang-2, VEGF-A, FGF-2, and FGF-21 were measured in plasma by the ELISA method. Results: GDF-15 levels differed significantly not only when comparing AS patients with control groups (p < 0.0001), but also a statistically significant difference was achieved when comparing AS patients at a mild degree stage with control individuals. We found a strong relationship of GDF-15 levels regarding AS severity degree (p < 0.0001). VEGF-A, FGF-2 and FGF-21 levels were significantly higher in AS patients than in controls, but relationships regarding the AS severity degree were weaker (p < 0.02). ROC analysis of the study growth factors showed that GDF-15 might serve as a specific and sensitive biomarker of AS stenosis (AUC = 0.75, p = 0.0002). FGF-21 correlated with GDF-15, Ang-2, and FGF-2, but it did not reach the level to serve as a clinically relevant biomarker of AS stenosis. Conclusions: AS is associated with significantly increased GDF-15, VEGF-A, FGF-2, and FGF-21 levels in plasma, but only GDF-15 shows a pronounced relationship regarding AS severity degree, and GDF-15 might serve as a specific and sensitive biomarker of AS stenosis.publishersversionPeer reviewe

Thioredoxin‐1 and correlations of the plasma cytokines regarding aortic valve stenosis severity

Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Aortic valve stenosis (AS) develops not only with a pronounced local inflammatory re-sponse, but also oxidative stress is involved. The aim of this study was to evaluate the plasma levels of thioredoxin‐1 (TRX1), myeloperoxidase (MPO), chemerin, growth differentiation factor 15 (GDF‐ 15), angiopoietin‐2 (Ang‐2), vascular endothelial growth factor A (VEGF‐A), fibroblast growth factor 2 (FGF‐2), fibroblast growth factor 21 (FGF‐21), and metalloproteinase (MMP)‐1, ‐3, and ‐9 in acquired AS patients as well as to clarify the correlations of TXR1 and the plasma inflammatory biomarkers regarding AS severity. AS patients were classified into three groups: 16 patients with mild AS stenosis, 19 with moderate and 11 with severe AS, and 30 subjects without AS were selected as a control group. AS patients had significantly higher plasma levels of TRX1 compared to controls, but the highest difference was found in mild AS patients compared to the controls. We conclude that AS is associated with significantly increased plasma TRX1 levels, and TRX1 might serve as a specific and sensitive biomarker of AS. TRX1 and also chemerin, GDF‐15, VEGF‐A, FGF‐2 and FGF‐ 21 significantly correlate with AS severity degrees. TRX1 also showed positive association with FGF‐2, VEGF‐A, and MMP‐3 in all AS patients.publishersversionPeer reviewe

Genetic architecture of the APM1 gene and its influence on adiponectin plasma levels and parameters of the metabolic syndrome in 1,727 healthy Caucasians

Copyright: Copyright 2008 Elsevier B.V., All rights reserved.The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease.publishersversionPeer reviewe