Association of Body Mass Index, Blood Pressure, and Interictal Serum Levels of Cytokines in Migraine with and without Aura.

The aim of the study was to clarify correlations between body mass index (BMI), blood pressure (BP), and serum levels of cytokines in female migraine patients. A total of 14 migraineurs with aura, and 12 without aura during their interictal period were compared with 25 controls. Interleukin-8 (IL-8), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), matrix metalloproteinase-9 (MMP-9), interferon gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-α), and plasminogen activator inhibitor-1 (PAI-1) were measured. Migraineurs have elevated levels of IL-8, but decreased serum levels of PAI-1 and sICAM-1 during the interictal period, regardless of aura. BMI correlates with BP, and also with IFN-γ and MMP-9 only in patients with aura. There are three correlations in migraine patients with aura that are absent in patients without aura: between IL-8 and PAI-1; MMP-9 and IL-8; and IL-8 and sICAM-1. Migraineurs without aura, on the other hand, have correlations that patients with aura do not have (between PAI-1 and MCP-1, sICAM-1; between MMP-9 and sICAM-1, MCP-1; between TGF-α and PAI-1, MMP-9, sICAM-1; between sICAM-1 and MMP-9, PAI-1, MCP-1; as well as between sVCAM-1 and MCP-1). PAI-1, TGF, and MMP-9 could be used as biomarkers to distinguish migraineurs from healthy individuals.

Thioredoxin-1 and Correlations of the Plasma Cytokines Regarding Aortic Valve Stenosis Severity.

Aortic valve stenosis (AS) develops not only with a pronounced local inflammatory response, 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.

Prognostic Utility of Circulating Growth Factors in Aortic Valve Stenosis: A Pilot Study.

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.

HDL-C Role in Acquired Aortic Valve Stenosis Patients and Its Relationship with Oxidative Stress.

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.

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.

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

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 <1.0 cm2, indexed AVA <0.6; moderate: Vmax 3.0-4.0 m/sec, PG 20-40 mmHg, AVA 1.0-1.5 cm2, indexed AVA 0.60-0.85; mild: Vmax 2.5-2.9 m/sec, PG <20 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.

Relation of inflammatory chemokines to insulin resistance and hypoadiponectinemia in coronary artery disease patients.

BACKGROUND: Although many studies have shown that the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) both are associated with chronic inflammatory state and are risk factors for coronary artery disease (CAD), it is still unclear which condition is a more important contributor to the increased production of inflammatory chemokines. The purpose of this study was to assess monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) levels and their association with insulin resistance and adiponectin concentrations in CAD patients, who were categorized as having T2DM, MS, or neither. METHODS: CAD male patients were categorized into three groups: 24 non-obese patients with T2DM (D), 24 obese patients with MS (M) and 24 patients without T2DM or MS (W). 20 healthy subjects were selected as controls (C). Insulin resistance was assessed by the HOMA-IR method, but serum MCP-1, IL-8, and adiponectin levels were measured by xMAP technology. RESULTS: Serum levels of MCP-1 and IL-8 in D and M groups were increased in comparison with W and C groups (p<0.001, p<0.01), but the increase in the M group was significantly higher than that in the D group (p<0.05, p<0,001), besides MCP-1 and IL-8 concentrations were correlated with HOMA-IR indexes (r=0.52; r=0.49, p<0.0001) and adiponectin levels (r=-0.59, p<0.0001). The M group demonstrated a diminution in the adiponectin level (p<0.01) and pronounced increase of HOMA-IR in comparison with the other three groups (p<0.01). CONCLUSION: Obese CAD patients with MS have a more pronounced increase of MCP-1, IL-8 and HOMA-IR and more decreased adiponectin levels than non-obese CAD patients without MS.

The adiponectin gene is associated with adiponectin levels but not with characteristics of the insulin resistance syndrome in healthy Caucasians.

Low concentrations of adiponectin, the protein product of the APM1 gene, have been reported to be associated with obesity and insulin resistance. However, contrasting results have been described on the genetic variability in APM1 and characteristics of the metabolic syndrome and adiponectin serum concentrations. In the present study, we investigated the association of the two most well-known SNPs of APM1 (+45T>G and +276G>T) and their haplotypes, with serum adiponectin concentrations, metabolic parameters and intima-media thickness of the carotid arteries in 1,745 well-phenotyped asymptomatic unrelated Caucasian subjects of the SAPHIR cohort. The common T-allele (88.5%) of SNP +45T>G and the common G-allele (70.5%) of SNP +276G>T were associated with significantly lower serum adiponectin levels (P = 0.0008 and P = 0.00005, respectively). The most frequent haplotype TG (59.0%) defined by both loci showed a strong association with lower serum adiponectin concentrations (P = 0.000000002). A clear effect per copy of the respective haplotype was observed. This association was most pronounced in lean and insulin-sensitive subjects. The two less common haplotypes TT (29.5%) and GG (11.5%) were associated with higher serum adiponectin levels in a dose-dependent association. Interestingly, no significant association between the adiponectin 45-276 haplotypes and the majority of parameters of the metabolic syndrome or intima-media thickness of the carotid arteries was found in our study. In summary, we replicated a strong association of the adiponectin 45-276 genotypes and haplotypes with adiponectin levels in healthy Caucasians. However, we could not confirm an association of this gene locus with metabolic parameters of the insulin resistance syndrome.

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

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.

Plasma adiponectin levels and sonographic phenotypes of subclinical carotid artery atherosclerosis: data from the SAPHIR Study.

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 microg/mL decrease in adiponectin CIMT increased on the average by 3.48 microm in males (95% CI, 1.23 to 5.73 microm) and by 2.39 microm in females (95% CI, 0.50 to 4.27 microm). 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 microm in men (95% CI, 6.80 to 34.04; P=0.003) and 20.75 microm 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. CONCLUSIONS: 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.