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Background: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction., Methods: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (N ε -(carboxymethyl)lysine [CML], N ε -(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored., Results: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (-12%) and hypoxia-exposed placentas (-16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (-26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2., Conclusions: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia., Competing Interests: Disclosures None.

Recent studies suggest that substituting sitting with light physical activity has beneficial metabolic effects, but it is unclear if this is associated with parallel changes in endothelial function. Data from three randomized cross-over studies were analyzed, in which 61 subjects (with normal weight, overweight and type 2 diabetes) followed different activity regimens (Sit, SitLess and/or Exercise) of four days each. Subjects were instructed to sit 14 h/day ('Sit'), to substitute 1 h/day of sitting with moderate-to-vigorous cycling ('Exercise') or to substitute 5-6 h/day sitting with light-intensity walking and standing ('SitLess'). Physical activity was assessed 24 h/day by accelerometry (ActivPAL) and diet was standardized. Fasted circulating biomarkers of endothelial dysfunction, lipids and insulin sensitivity were assessed the morning after each activity regimen. The endothelial dysfunction score (ED-score) was computed by averaging the Z-scores of the circulating biomarkers of endothelial dysfunction. Compared to Sit, Exercise resulted in lower ED-score, sICAM1 and sE-selectin (p < 0.05), while no significant changes were observed after SitLess. The ED-score, sVCAM1 and sE-selectin were lower after Exercise compared to SitLess (p < 0.05). In contrast, compared to Sit, insulin sensitivity (HOMA2-IR) and plasma lipids (HDL-cholesterol, non-HDL-cholesterol, total cholesterol and Apo B) did not change significantly after Exercise but were improved after SitLess (p < 0.05). In conclusion, light physical activity and moderate-to-vigorous physical activity had a differential effect on risk markers of cardio-metabolic health and suggest the need of both performing structured exercise as well as reducing sitting time on a daily basis.

Aims/hypothesis: Vascular inflammation and endothelial dysfunction are thought to contribute to arterial stiffening and hypertension. This study aims to test this hypothesis with longitudinal data in the context of type 1 diabetes., Methods: We investigated, in an inception cohort of 277 individuals with type 1 diabetes, the course, tracking and temporal inter-relationships of BP, specifically pulse pressure (a marker of arterial stiffening) and hypertension, and the following biomarkers of systemic and vascular inflammation/endothelial dysfunction: C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cellular adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin). These biomarkers and other risk factors were measured at baseline and repeatedly up to 20 years after the onset of type 1 diabetes. Data were analysed with generalised estimating equations including adjustments for age, sex, smoking status, BMI, HbA 1c , serum creatinine, total cholesterol, urinary AER, insulin treatment dose and mean arterial pressure., Results: Increases were noted in all biomarkers except sE-selectin, which decreased over time. Levels differed from baseline at 2-4 years and preceded the increase in pulse pressure, which occurred at 8-10 years after the onset of type 1 diabetes. Higher levels of sICAM-1 and sVCAM-1, but not CRP or sE-selectin, at baseline and throughout the 20 year follow-up, were significantly associated with higher (changes in) pulse pressure at subsequent time points. Higher levels of sVCAM-1 at baseline and during follow-up were also significantly associated with the prevalence (OR 3.60 [95% CI 1.36, 9.53] and OR 2.28 [1.03, 5.25], respectively) and incidence (OR 2.89 [1.08, 7.75] and OR 3.06 [1.01, 9.26], respectively) of hypertension. We also investigated the longitudinal associations between BP or hypertension as determinants of subsequent (changes in) levels of CRP, sICAM-1, sVCAM-1 and sE-selectin, but did not find evidence to support a reverse causality hypothesis., Conclusions/interpretation: These findings support the involvement of vascular endothelial dysfunction and inflammation in the development of premature arterial stiffening and hypertension in type 1 diabetes.

Background: We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors., Methods and Results: We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition-NL (EPIC-NL). The associations of 23 biomarkers (adiponectin, C-reactive protein, epidermal-type fatty acid binding protein, heart-type fatty acid binding protein, basic fibroblast growth factor, soluble FMS-like tyrosine kinase-1, soluble intercellular adhesion molecule-1 and -3, matrix metalloproteinase [MMP]-1, MMP-3, MMP-9, N-terminal prohormone of B-type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E-selectin, P-selectin, tissue inhibitor of MMP-1, thrombomodulin, soluble vascular cell adhesion molecule-1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c-statistic and net reclassification index (NRI; continuous and based on 10-year risk strata 0-10%, 10-20%, 20-30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N-terminal prohormone of B-type natriuretic peptide, osteopontin, and MMP-3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c-statistic with 0.03 (95% CI 0.01-0.05), and the continuous NRI was 0.37 (95% CI 0.21-0.52). In EPIC-NL, the multimarker model increased the c-statistic with 0.03 (95% CI 0.00-0.03), and the continuous NRI was 0.44 (95% CI 0.23-0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03-0.21) in SMART and 0.07 (95% CI -0.04-0.17) in EPIC-NL., Conclusions: Of the 23 evaluated biomarkers from different pathophysiological pathways, N-terminal prohormone of B-type natriuretic peptide, osteopontin, MMP-3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: We evaluated markers of inflammation and endothelial dysfunction and their associations with incident cardiovascular disease (CVD), all-cause mortality and progression of coronary artery calcium (CAC) in patients with type 2 diabetes (T2D) and microalbuminuria but without known coronary artery disease (CAD)., Methods: Prospective study including 200 patients receiving multifactorial treatment. Markers of inflammation (TNF-ɑ, sICAM-1, sICAM-3, hsCRP, SAA, IL-1β, IL-6, IL-8) and endothelial dysfunction (thrombomodulin, sVCAM-1, sICAM-1, sICAM-3, sE-selectin, sP-selectin) were measured at baseline. Adjustment included traditional CVD risk factors, and full adjustment additionally NT-proBNP and CAC. The "SQRT method" assessed CAC progression after 5.8years, and cut-point was an annualised difference >2.5., Results: Occurrence of CVD (n=40) and all-cause mortality (n=26) was traced after 6.1years. In adjusted and fully adjusted Cox models, TNF-ɑ was a determinant of CVD and all-cause mortality (p≤0.007). Further, in adjusted and fully adjusted logistic regression, TNF-ɑ was related to CAC progression (p≤0.042). Of the other biomarkers, sICAM-3 and thrombomodulin were also associated with both endpoints (p≤0.046), IL-1β with CVD endpoints (p=0.021), and sVCAM-1 and sICAM-1 with all-cause mortality (p≤0.005). Higher composite z-scores including all markers of inflammation and endothelial dysfunction were associated with CVD and all-cause mortality (p≤0.008)., Conclusions: In patients with T2D and microalbuminuria without known CAD and receiving multifactorial treatment, biomarkers of inflammation and endothelial dysfunction were independently associated with CVD, all-cause mortality and CAC progression. Especially TNF-ɑ was a robust determinant, even after adjusting for NT-proBNP and CAC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The aims of this study were to investigate (i) associations between uric acid and prevalent cardiovascular disease (CVD), ankle-arm blood pressure index (AAIx) and carotid intima-media thickness (CIMT) in the total population and in predefined subgroups according to glucose metabolism status and (ii) the extent to which these associations are explained by low-grade inflammation., Methods: Cross-sectional analyses were conducted among 530 individuals [60.6% men, mean age 58.9 years (s.d. 6.9), 52.6% normal glucose metabolism (NGM)] at increased risk of CVD from the Cohort of Diabetes and Atherosclerosis Maastricht study. A low-grade inflammation score was computed by averaging the z-scores of eight inflammation markers [CRP, TNF-α, IL-6, IL-8, serum amyloid A, intercellular adhesion molecule 1 (ICAM-1), ceruloplasmin and haptoglobin]., Results: After adjustment for traditional CVD risk factors, plasma uric acid (per s.d. of 81 μmol/l) was associated with CVD in individuals with NGM [odds ratio (OR) = 1.66, 95% CI 1.06, 2.58] but not with disturbed glucose metabolism (DGM) (OR = 0.81, 95% CI 0.55, 1.19, P interaction = 0.165). Uric acid was associated with CIMT in the total population (β = 0.024, 95% CI 0.007, 0.042) and slightly more strongly in individuals with NGM (β = 0.030, 95% CI 0.006, 0.054) than DGM (β = 0.018, 95% CI -0.009, 0.044, P interaction = 0.443). There was no association between uric acid and AAIx in any group (P interaction = 0.058). Uric acid was associated with low-grade inflammation in the total population (β = 0.074, 95% CI 0.013, 0.134, P interaction = 0.737). Adding low-grade inflammation to the models did not attenuate any of the associations., Conclusion: The associations for uric acid with CIMT, and with CVD in NGM only, were not explained by low-grade inflammation. A difference in the strength of the associations between individuals with NGM and DGM was suggested., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Growing evidence indicates that the metabolic syndrome (MS) is rooted in adverse exposures during fetal life. The aim of this study was to assess the possible associations between biomarkers of inflammation during third trimester of pregnancy and markers of MS in adult offspring., Methods: High-sensitive C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleuki-6 (IL-6) were measured in serum samples obtained in gestational week 30. Offspring were clinically examined at age 20 years. Analyses based on 439 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, prepregnancy body mass index (BMI), education, and offspring's sex. Offspring MS markers included waist circumference, BMI, blood pressure, HOMA insulin resistance, and plasma levels of fasting glucose, triglycerides, cholesterol fractions, insulin, and leptin., Results: The median level was 2.8 (interquartile range = 3.3) µg/ml for CRP, for TNF-α: 5.7 (3.2) pg/ml, for IL-1β: 0.5 (0.4) pg/ml, and for IL-6: 1.1 (0.7) pg/ml. Concentrations were not significantly associated with MS markers in the offspring. The results remained essentially unchanged after correction for potential confounding., Conclusion: Markers for subclinical inflammation in third trimester in healthy women were not associated with components of MS in their adult offspring., (Copyright © 2013 The Obesity Society.)

Early blockade of the renin-angiotensin system is successful in delaying the development of hypertension in spontaneously hypertensive rats (SHRs) and ameliorating organ damage by inhibition of the inflammatory response. In this study, we investigated the role of the angiotensin II type 1 receptor (AT1R) in the early renal inflammatory response in SHR. Blood pressure development and renal inflammatory markers were measured in 4-, 8- and 12-week-old SHR and age-matched Wistar Kyoto (WKY) rats. Separate groups of SHRs were transiently treated with the AT1R blocker losartan between 4 and 8 weeks of age. Urinary excretion of the renal injury markers osteopontin and neutrophil gelatinase-associated lipocalin increased in young SHR. Further, renal expression of inflammatory genes was also increased in young SHR. Losartan inhibited the increase of these inflammatory markers. In contrast, gene expression of the renal injury marker and T-cell inducer kidney injury molecule-1 (KIM-1) was reduced in 4-week-old SHR when compared with WKY. Similarly, the T-cell marker CD3 was significantly decreased in 4-week-old SHR. These effects were not antagonized by AT1R blockade. This study confirms the presence of an early renal inflammatory response in SHR that can be blocked by AT1R antagonism. In addition, it demonstrates that KIM-1 does not behave as a pure kidney injury marker in young SHR, but may reflect kidney maturation.

Background: In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available., Methods: We measured, in a large ongoing cohort study (n = 574), by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD) and single-biomarker techniques (ELISA or immunoturbidimetric assay), the following biomarkers of low-grade inflammation: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects' cardiovascular risk factors by ANOVA., Results: Despite that both methods ranked individuals' levels of biomarkers very similarly (Pearson's r all≥0.755) absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP), 0.711 (SAA), 0.895 (sICAM-1) and 0.858 (sVCAM-1). Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method., Conclusions: Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies.

Objective: Heat shock protein 27 (HSP27) is a member of the small heat shock protein family of proteins. HSP27 expression is enhanced in target tissues of diabetic microvascular complications, and changes in circulating serum HSP27 levels (sHSP27) have been reported in patients with macrovascular disease. We investigated whether sHSP27 levels were associated with micro- and macrovascular complications in type 1 diabetic patients., Research Design and Methods: A cross-sectional, nested, case-control study from the EURODIAB Prospective Complications Study of 531 type 1 diabetic patients was performed. Case subjects (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were defined as those with no evidence of any complication. We measured sHSP27 levels and investigated their associations with diabetes complications., Results: Mean sHSP27 levels were significantly higher in case subjects with distal symmetrical polyneuropathy (DSP) than in control subjects, even after adjustment for age and albumin excretion rate (AER) (785.9 vs. 574.7 pg/ml, P = 0.03). In logistic regression analysis, sHSP27 levels in the upper quartile were associated with a twofold increased odds ratio (OR) of DSP, independently of conventional risk factors, markers of inflammation, and AER (OR 2.41 [95% CI 1.11-5.24])., Conclusions: In this large cohort of type 1 diabetic subjects, we found an independent association between sHSP27 and DSP. This suggests that sHSP27 levels may be a novel marker for diabetic neuropathy.

Objective: We evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in glomerular filtration rate (GFR) in type 1 diabetic patients., Research Design and Methods: We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with persistent normoalbuminuria. Biomarkers were measured at baseline., Results: We constructed two Z scores: the mean inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (sICAM-1), and secreted phospholipase A2 and the mean Z score for endothelial dysfunction combined soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1, and sICAM-1. The mean Z score of inflammatory biomarkers was associated with mortality and the combined end point in patients with diabetic nephropathy after multivariate adjustment (hazard ratio 1.7 [95% CI 1.1-2.6]; P = 0.025 and 1.5 [1.1-2.2]; P = 0.017). The mean Z score for endothelial dysfunction biomarkers was associated with mortality in a model adjusting for age and sex in patients with diabetic nephropathy (1.6 [1.0-2.3]; P = 0.031). The mean Z score for endothelial dysfunction correlated with decline in GFR (r = -0.243; P = 0.001); the correlation persisted after multivariate adjustment (coefficient -1.38 [95% CI -2.27 to -0.50]; P = 0.002)., Conclusions: Mean Z scores of inflammatory biomarkers are significantly associated with all-cause mortality and cardiovascular morbidity and mortality in patients with nephropathy after multivariate adjustment. These data suggest that the high risk of cardiovascular disease in type 1 diabetes may be explained in part by inflammatory activity. Mean Z score of endothelial dysfunction correlated after multivariate adjustment with the rate of decline in GFR.

Objective: To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether these markers predict later diabetes in a case-control study within a longitudinal health study in Pima Indians., Research Design and Methods: Participants with normal glucose tolerance at baseline were selected. Case subjects (who later developed type 2 diabetes), and control subjects (n = 71 pairs) were matched for BMI, age, and sex. Adiponectin, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha, phospholipase A2 (sPLA2), soluble E-selectin (SE-selectin), soluble intracellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor (vWF) were measured in baseline samples., Results: Adiponectin was negatively correlated with CRP (r = -0.25, P < 0.05), IL-6 (r = -0.20, P < 0.05), sPLA2 (r = -0.22, P < 0.05), and SE-selectin (r = -0.20, P < 0.05). CRP and IL-6 did not predict diabetes. Only vWF predicted the development of diabetes (incidence rate ratio 0.67 for a 1-SD difference, 95% CI 0.41-1.00, P = 0.05), but this was not significant after adjustment for age, glucose, HbA(1c), waist circumference, and fasting insulin (hazard rate ratio 0.73, 95% CI 0.46-1.16, P = 0.18)., Conclusions: Adiponectin is negatively correlated with markers of inflammation in vivo. In case and control subjects matched for BMI, with the exception of vWF, none of the inflammatory markers predicted diabetes. Adiponectin may be the link between adiposity, inflammation, and type 2 diabetes.

Objective: In 196 type 1 diabetic subjects and 195 nondiabetic subjects aged 30-55 years, we examined whether C-reactive protein (CRP) is elevated in diabetes and whether CRP is associated with coronary artery calcification (CAC)., Research Design and Methods: CRP was measured with a highly sensitive immunoassay. CAC was measured using electron beam computed tomography., Results: CRP was elevated in diabetic women compared with nondiabetic women (median 1.62 vs. 0.85 mg/l, P < 0.001) independently of other factors, but was similar in diabetic and nondiabetic men (median 0.82 vs. 0.81 mg/l). Insulin dose per day was positively correlated with CRP in diabetic women (Spearman's rho = 0.36, P = 0.0003) but much less so in men (rho = 0.16, P = 0.09). Being in the top tertile for CRP was associated with CAC in diabetic and nondiabetic men even after adjustment for other risk factors (adjusted odds ratio [OR] = 4.6 and 4.3, respectively, P = 0.02 for both). In nondiabetic women, being in the top tertile for CRP was associated with CAC (OR 3.1, P = 0.04), but not independently of BMI (OR = 1 after adjustment). Among diabetic women the association was not significant even before adjustment for BMI (OR = 2.6, P = 0.07)., Conclusions: Elevated CRP in diabetic women might reflect a particular sensitivity to insulin levels or might reflect insulin resistance. In general, CRP is an important marker of subclinical atherosclerosis, but the clinical significance of elevated CRP in diabetic women needs to be addressed in prospective studies, since CRP was not clearly associated with CAC in this group.

BACKGROUND: Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity. METHODS AND RESULTS: Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (β per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. CONCLUSIONS: These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.

Background Dicarbonyls are major reactive precursors of advanced glycation endproducts (AGEs). Dicarbonyls are formed endogenously and also during food processing. Circulating dicarbonyls and AGEs are associated with inflammation and microvascular complications of diabetes, but for dicarbonyls from the diet these associations are currently unknown. Objectives We sought to examine the associations of dietary dicarbonyl intake with low-grade inflammation and microvascular function. Methods In 2792 participants (mean ± SD age: 60 ± 8 y; 50% men; 26% type 2 diabetes) of the population-based cohort the Maastricht Study, we estimated the habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by linking FFQ outcome data to our food composition database of the MGO, GO, and 3-DG content of >200 foods. Low-grade inflammation was assessed as six plasma biomarkers, which were compiled in a z score. Microvascular function was assessed as four plasma biomarkers, compiled in a z score; as diameters and flicker light–induced dilation in retinal microvessels; as heat-induced skin hyperemic response; and as urinary albumin excretion. Cross-sectional associations of dietary dicarbonyls with low-grade inflammation and microvascular function were investigated using linear regression with adjustments for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle and dietary factors. Results Fully adjusted analyses revealed that higher intake of MGO was associated with a lower z score for inflammation [standardized β coefficient (STD β): −0.05; 95% CI: −0.09 to −0.01, with strongest inverse associations for hsCRP and TNF-α: both −0.05; −0.10 to −0.01]. In contrast, higher dietary MGO intake was associated with impaired retinal venular dilation after full adjustment (STD β: −0.07; 95% CI: −0.12 to −0.01), but not with the other features of microvascular function. GO and 3-DG intakes were not consistently associated with any of the outcomes. Conclusion Higher habitual intake of MGO was associated with less low-grade inflammation. This novel, presumably beneficial, association is the first observation of an association between MGO intake and health outcomes in humans and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Hyperglycaemia occurs frequently in the critically ill. Dietary intake of advanced glycation end‐products (AGEs), specifically Nε‐(carboxymethyl)lysine (CML), may exacerbate hyperglycaemia through perturbation of insulin sensitivity. The present study aimed to determine whether the use of nutritional formulae, with varying AGE loads, affects the amount of insulin administered and inflammation. Methods: Exclusively tube fed patients (n = 35) were randomised to receive Nutrison Protein Plus Multifibre®, Diason® or Glucerna Select®. Insulin administration was standardised according to protocol based on blood glucose (<10 mmol L–1). Samples were obtained at randomisation and 48 h later. AGEs in nutritional formula, plasma and urine were measured using mass spectrometry. Plasma inflammatory markers were measured using an enzyme‐linked immunosorbent assay and multiplex bead‐based assays. Results: AGE concentrations of CML in nutritional formulae were greatest with delivery of Nutrison Protein Plus® (mean [SD]; 6335 pmol mol–1 [2436]) compared to Diason® (4836 pmol mol–1 [1849]) and Glucerna Select® (4493 pmol mol–1 [1829 pmol mol–1]) despite patients receiving similar amounts of energy (median [interquartile range]; 12 MJ [8.2–13.7 MJ], 11.5 MJ [8.3–14.5 MJ], 11.5 MJ [8.3–14.5 MJ]). More insulin was administered with Nutrison Protein Plus® (2.47 units h–1 [95% confidence interval (CI) = 1.57–3.37 units h–1]) compared to Diason® (1.06 units h–1 [95% CI = 0.24–1.89 units h–1]) or Glucerna Select® (1.11 units h–1 [95% CI = 0.25–1.97 units h–1]; p = 0.04). Blood glucose concentrations were similar. There were associations between greater insulin administration and reductions in circulating interleukin‐6 (r = –0.46, p < 0.01), tumour necrosis factor‐α (r = −0.44, p < 0.05), high sensitivity C‐reactive protein (r = −0.42, p < 0.05) and soluble receptor for advanced glycation end‐products (r = −0.45, p < 0.01) concentrations. Conclusions: The administration of greater AGE load in nutritional formula potentially increases the amount of insulin required to maintain blood glucose within a normal range during critical illness. There was an inverse relationship between exogenous insulin and plasma inflammatory markers. Key points: Enteral nutrition formula comprise varying amounts of advanced glycation end‐products, specifically Nε‐(carboxymethyl)lysine (CML), which has the potential to exacerbate hyperglycaemia as seen in the healthy population.Patients in the control arm, receiving the highest carbohydrate and CML quantity, had a higher exogenous insulin requirement compared to the two interventional formulae.Our findings also showed an association between increasing doses of insulin and a reduction in inflammatory markers (interleukin‐6, tumour necrosis factor‐α and high sensitivity C‐reactive protein).Further research is required to determine whether manipulation of AGEs in enteral nutrition formula impacts insulin sensitivity and inflammation. [ABSTRACT FROM AUTHOR]

Background Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat. Objectives We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort. Methods In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC–tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light–induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors. Results Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light–induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: −0.04 SD; 95% CI: −0.08, −0.00 SD), the effect sizes were small and their biological relevance can be questioned. Conclusions We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions. [ABSTRACT FROM AUTHOR]

The mechanisms underlying cognitive impairment are incompletely understood but may include arterial stiffness and microvascular dysfunction. In the population-based Maastricht Study, we investigated the association between arterial stiffness and cognitive performance, and whether any such association was mediated by microvascular dysfunction. We included cross-sectional data of 2544 participants (age, 59.7 years; 51.0% men; 26.0% type 2 diabetes mellitus). We used carotid-femoral pulse wave velocity and carotid distensibility coefficient as measures of aortic and carotid stiffness, respectively. We calculated a composite score of microvascular dysfunction based on magnetic resonance imaging features of cerebral small vessel disease, flicker light-induced retinal arteriolar and venular dilation response, albuminuria, and plasma biomarkers of microvascular dysfunction (sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [von Willebrand factor]). Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the average of these domains. Higher aortic stiffness (per m/s) was associated with lower cognitive function (β, -0.018 SD [95% CI, -0.036 to -0.000]) independent of age, sex, education, and cardiovascular risk factors, but higher carotid stiffness was not. Higher aortic stiffness (per m/s) was associated with a higher microvascular dysfunction score (β, 0.034 SD [95% CI, 0.014 to 0.053]), and a higher microvascular dysfunction score (per SD) was associated with lower cognitive function (β, -0.089 SD [95% CI, -0.124 to -0.053]). Microvascular dysfunction significantly explained 16.2% of the total effect of aortic stiffness on cognitive function. The present study showed that aortic stiffness, but not carotid stiffness, is independently associated with worse cognitive performance, and that this association is in part explained by microvascular dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: End-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy (dialysis and kidney transplantation) are scarce. Methods: We compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED (sVCAM-1, E-selectin, P-selectin, thrombomodulin, sICAM-1, sICAM-3) and LGI (hs-CRP, SAA, IL-6, IL-8, TNF-α) were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology. Results: In linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter. Conclusions: Levels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) related mortality and morbidity are high in end-stage renal disease (ESRD). The pathophysiology of CVD in ESRD may involve non-traditional CVD risk factors, such as accumulation of advanced glycation endproducts (AGEs), dicarbonyls, endothelial dysfunction (ED) and low-grade inflammation (LGI). However, detailed data on the relation of AGEs and dicarbonyls with ED and LGI in ESRD are limited. Methods: We examined cross-sectional Spearman’s rank correlations of AGEs and dicarbonyls with serum biomarkers of ED and LGI in 43 individuals with chronic kidney disease (CKD) stage 5 not on dialysis (CKD5-ND). Free and protein-bound serum AGEs (N∈-(carboxymethyl)lysine (CML), N∈-(carboxyethyl)lysine (CEL), Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)) and serum dicarbonyls (glyoxal, methylglyoxal, 3-deoxyglucosone) were analyzed with tandem mass spectrometry, and tissue AGE accumulation was estimated by skin autofluorescence (SAF). Further, serum biomarkers of ED and LGI included sVCAM-1, sE-selectin, sP-selectin, sThrombomodulin, sICAM-1, sICAM-3, hs-CRP, SAA, IL-6, IL-8 and TNF-α. Results: After adjustment for age, sex and diabetes status, protein-bound CML was positively correlated with sVCAM-1; free CEL with sVCAM-1 and sThrombomodulin; glyoxal with sThrombomodulin; and methylglyoxal with sVCAM-1 (correlation coefficients ranged from 0.36 to 0.44). In addition, free CML was positively correlated with SAA; protein-bound CML with IL-6; free CEL with hs-CRP, SAA and IL-6; free MG-H1 with SAA; protein-bound MG-H1 with IL-6; and MGO with hs-CRP and IL-6 (correlation coefficients ranged from 0.33 to 0.38). Additional adjustment for eGFR attenuated partial correlations of serum AGEs and serum dicarbonyls with biomarkers of ED and LGI. Conclusions: In individuals with CKD5-ND, higher levels of serum AGEs and serum dicarbonyls were related to biomarkers of ED and LGI after adjustment for age, sex and diabetes mellitus. Correlations were attenuated by eGFR, suggesting that eGFR confounds and/or mediates the relation of serum AGEs and dicarbonyls with ED and LGI. [ABSTRACT FROM AUTHOR]

Aims: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Methods: Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (µg/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. Results: Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA β = 0.28, ALA β = 0.13, EPA β = 0.34, and DHA β = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influenced associations for LA; gender influenced LA, EPA, and DHA; alcohol intake influenced LA and DHA; and glucose tolerance status influenced ALA (p values interaction <0.05). Coefficients for circulating FA as concentrations were LA β = 0.19, ALA β = 0.10, EPA β = 0.31, and DHA β = 0.41. Conclusions: This study suggests that characteristics such as BMI, alcohol intake, and expressing circulating FA as proportions or concentrations, influence associations between dietary and circulating FA. [ABSTRACT FROM AUTHOR]

Background: Haemodialysis (HD) patients are predisposed to dysregulated fluid balance leading to extracellular water (ECW) expansion. Fluid overload has been closely linked with outcome in these patients. This has mainly been attributed to cardiac volume overload, but the relation between abnormalities in fluid status with micro- and macrovascular dysfunction has not been studied in detail. We studied the interaction of macro- and microvascular factors in states of normal and over- hydration in HD-dependent CKD. Methods: Fluid compartments [total body water (TBW) and ECW] and overhydration index (OH) were measured with Multifrequency bio-impedance (BCM). Overhydration was defined as OH/ECW>7%. Overhydration was also assessed using the ECW/TBW ratio. Macrocirculation was assessed by pulse-wave velocity (PWV) and mean arterial pressure (MAP) measurements while microcirculation through sublingual capillaroscopy assessment of the Perfused Boundary Region of the endothelial glycocalyx (PBR 5-25mcg). A panel of pro-inflammatory and vascular serum biomarkers and growth factors was analysed. Results: Of 72 HD participants, 30 were in normohydration (N) range and 42 overhydrated according to the OH/ECW ratio. Average ECW/TBW was 0.48±0.03. Overhydrated patients had higher MAP (122.9±22.5 v 111.7±22.2mmHg, p = 0.04) and comorbidities (median Davies score 1.5 v 1.0, p = 0.03). PWV (p = 0.25) and PBR 5-25mcg (p = 0.97) did not differ between the 2 groups. However, Vascular Adhesion Molecule (VCAM)-1, Interleukin-6 and Thrombomodulin, and reduced Leptin were observed in the overhydrated group. Elevation in VCAM-1 levels (OR 1.03; 95% CI 1.01–1.06; p = 0.02) showed a strong independent association with OH/ECW>7% in an adjusted logistic regression analysis and exhibited a strong linear relationship with ECW/TBW (Bata = 0.210, p = 0.03) in an also adjusted model. Conclusion: Extracellular fluid overload is significantly linked to microinflammation and markers of endothelial dysfunction. The study provides novel insight in the cardiovascular risk profile associated with overhydration in uraemia. [ABSTRACT FROM AUTHOR]

Background: Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with severe sepsis. Objective: 1) To explore the reliability of Skin Autofluorescence (AF) as an index of tissue AGEs in ICU patients, 2) to compare its levels to healthy controls, 3) to describe the time course of AGEs and influencing factors during ICU admission, and 4) to explore their association with disease severity, outcome, and markers of oxidative stress and inflammation. Methods: Skin AF, serum N"-(carboxyethyl)lysine (CEL), N"-(carboxymethyl)lysine (CML), and soluble RAGE (sRAGE) were serially measured for a maximum of 7 days in critically ill ICU patients with multiple organ failure and compared to age-matched healthy controls. Correlations with (changes in) clinical parameters of disease severity, LDL dienes, and CRP were studied and survival analysis for in-hospital mortality was performed. Results: Forty-five ICU patients (age: 59±15 years; 60% male), and 37 healthy controls (59±14; 68%) were included. Skin AF measurements in ICU patients were reproducible (CV right-left arm: 13%, day-to-day: 10%), with confounding effects of skin reflectance and plasma bilirubin levels. Skin AF was higher in ICU patients vs healthy controls (2.7±0.7 vs 1.8±0.3 au; p<0.001). Serum CEL (23±10 vs, 16±3 nmol/gr protein; p<0.001), LDL dienes (19 (15–23) vs. 9 (8–11) μmol/mmol cholesterol; <0.001), and sRAGE (1547 (998–2496) vs. 1042 (824–1388) pg/ml; p = 0.003) were significantly higher in ICU patients compared to healthy controls, while CML was not different (27 (20–39) vs 29 (25–33) nmol/gr protein). While CRP and LDL dienes decreased significantly, Skin AF and serum AGEs and sRAGE did not change significantly during the first 7 days of ICU admission. CML and CEL were strongly correlated with SOFA scores and CML above the median at baseline was associated with increased risk for mortality (Hazard ratio 3.3 (1.3–8.3); p = 0.01). All other markers did not correlate with disease severity and did not predict mortality. Conclusions: This study demonstrates that markers for the AGE-RAGE axis are elevated in critically ill patients compared to healthy controls but remain stable for at least 7 days despite clearly fading inflammation and oxidative stress. Circulating AGEs may be associated with disease severity and outcome. Further research should be conducted to elucidate the role of the AGE-RAGE axis in the exaggerated inflammatory response leading to multiple organ failure and death, and whether or not this may be a target for treatment. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) and low-grade inflammation (LGI) have a role in the development of CVD. The two studies reported here explored the effects of dietary proteins and carbohydrates on markers of ED and LGI in overweight/obese individuals with untreated elevated blood pressure. In the first study, fifty-two participants consumed a protein mix or maltodextrin (3×20 g/d) for 4 weeks. Fasting levels and 12 h postprandial responses of markers of ED (soluble intercellular adhesion molecule 1 (sICAM), soluble vascular cell adhesion molecule 1 (sVCAM), soluble endothelial selectin and von Willebrand factor) and markers of LGI (serum amyloid A, C-reactive protein and sICAM) were evaluated before and after intervention. Biomarkers were also combined into mean Z-scores of ED and LGI. The second study compared 4 h postprandial responses of ED and LGI markers in forty-eight participants after ingestion of 0·6 g/kg pea protein, milk protein and egg-white protein. In addition, postprandial responses after maltodextrin intake were compared with a protein mix and sucrose. The first study showed significantly lower fasting ED Z-scores and sICAM after 4 weeks on the high-protein diet (P≤0·02). The postprandial studies found no clear differences of ED and LGI between test meals. However, postprandial sVCAM decreased more after the protein mix compared with maltodextrin in both studies (P≤0·04). In conclusion, dietary protein is beneficial for fasting ED, but not for fasting LGI, after 4 weeks of supplementation. On the basis of Z-scores, postprandial ED and LGI were not differentially affected by protein sources or carbohydrates. [ABSTRACT FROM PUBLISHER]

High Na and low K intakes have adverse effects on blood pressure, which increases the risk for CVD. The role of endothelial dysfunction and inflammation in this pathophysiological process is not yet clear. In a randomised placebo-controlled cross-over study in untreated (pre)hypertensives, we examined the effects of Na and K supplementation on endothelial function and inflammation. During the study period, subjects were provided with a diet that contained 2·4 g/d of Na and 2·3 g/d of K for a 10 460 kJ (2500 kcal) intake. After 1-week run-in, subjects received capsules with supplemental Na (3·0 g/d), supplemental K (2·8 g/d) or placebo, for 4 weeks each, in random order. After each intervention, circulating biomarkers of endothelial function and inflammation were measured. Brachial artery flow-mediated dilation (FMD) and skin microvascular vasomotion were assessed in sub-groups of twenty-two to twenty-four subjects. Of thirty-seven randomised subjects, thirty-six completed the study. Following Na supplementation, serum endothelin-1 was increased by 0·24 pg/ml (95 % CI 0·03, 0·45), but no change was seen in other endothelial or inflammatory biomarkers. FMD and microvascular vasomotion were unaffected by Na supplementation. K supplementation reduced IL-8 levels by 0·28 pg/ml (95 % CI 0·03, 0·53), without affecting other circulating biomarkers. FMD was 1·16 % (95 % CI 0·37, 1·96) higher after K supplementation than after placebo. Microvascular vasomotion was unaffected. In conclusion, a 4-week increase in Na intake increased endothelin-1, but had no effect on other endothelial or inflammatory markers. Increased K intake had a beneficial effect on FMD and possibly IL-8, without affecting other circulating endothelial or inflammatory biomarkers. [ABSTRACT FROM AUTHOR]

The complement system, particularly the alternative complement pathway, may contribute to vascular damage and development of cardiovascular disease (CVD). We investigated the association of factor D, the rate-limiting protease in alternative pathway activation, with adverse cardiovascular outcomes. In 2947 participants (50.6% men, 59.9 ± 8.2 years, 26.5% type 2 diabetes [T2D], oversampled) we measured markers of low-grade inflammation (LGI, composite score, in SD) and, endothelial dysfunction (ED, composite score, in SD), carotid intima-media thickness (cIMT, μm), ankle-brachial index (ABI), CVD (yes/no) and plasma concentrations of factor D (in SD). Associations were estimated using multiple linear and logistic regression, adjusting for demographic, lifestyle, and dietary factors. Factor D (per SD) significantly associated with LGI (0.171 SD [0.137; 0.205]), ED (0.158 SD [0.123; 0.194]) and CVD (OR 1.15 [1.04; 1.27]) but not significantly with cIMT (−6.62 μm [-13.51; 0.27]) or ABI (−0.003 [-0.007; 0.001]). Interaction analyses show that factor D more strongly associated with ED in non-diabetes (0.237 SD [0.189; 0.285] than in T2D (0.095 SD [0.034; 0.157]), p interaction <0.05. These results were largely corroborated by additional analyses with C3 and C3a. In contrast, factor D inversely associated with cIMT in non-diabetes (−13.37 μm [-21.84; −4.90]), but not in T2D (4.49 [-7.91; 16.89]), p interaction <0.05. Plasma factor D is independently associated with LGI, ED, and prevalent CVD but not with ABI or cIMT. Hence, greater plasma factor D concentration in CVD may potentially induce complement activation which, in turn, might contribute to further disease progression via a process that may involve inflammation and endothelial dysfunction but was not directly related to atherosclerosis or arterial injury. The observation that, in participants without diabetes, factor D associated with worse ED but smaller cIMT warrants further investigation. [Display omitted] • Greater plasma concentration of factor D significantly associates with multiple markers of low-grade inflammation and endothelial dysfunction. • Greater plasma concentration of factor D significantly associates with more cardiovascular disease. • These observations for factor D were largely corroborated in analyses with complement C3 and C3a. • The association of factor D with cardiovascular disease manifested particularly as cerebral cardiovascular disease in men. • Factor D was not positively associated with either a marker of subclinical atherosclerosis or a marker of arterial injury. [ABSTRACT FROM AUTHOR]

Rationale: Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and DLCO, and with different circulating AGEs. Methods: Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV1 (%predicted) and FEV1/VC (%) were measured in both groups; DLCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE Nϵ-(carboxymethyl) lysine (CML) was decreased, Nϵ- (carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls. Results: Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p=0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV1 (r = 0.235, p = 0.032), FEV1/VC (r = 0.218, p = 0.047), and DLCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003). Conclusion: Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV1, FEV1/VC and DLCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice. Methods: Thereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n = 9–10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation. Results: Vehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice. Conclusions: Collectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling. [ABSTRACT FROM AUTHOR]

Background: Diet may be associated with the development of type 2 diabetes through its effects on low-grade inflammation. Objectives: We investigated whether an adapted dietary inflammatory index (ADII) is associated with a summary score for low-grade inflammation and markers of glucose metabolism. In addition, we investigated the mediating role of inflammation in the association between ADII and markers of glucose metabolism. Design: We performed cross-sectional analyses of 2 Dutch cohort studies (n= 1024). An ADII was obtained by multiplying standardized energy-adjusted intakes of dietary components by literaturebased dietary inflammatory weights that reflected the inflammatory potential of components. Subsequently, these multiplications were summed. Six biomarkers of inflammation were compiled in a summary score. Associations of the ADII (expressed per SD) with the summary score for inflammation and markers of glucose metabolism were investigated by using multiple linear regression models. Inflammation was considered a potential mediator in the analysis with markers of glucose metabolism. Results: A higher ADII was associated with a higher summary score for inflammation [b-adjusted = 0.04 per SD (95% CI: 0.01, 0.07 per SD)]. The ADII was also adversely associated with insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR): b-adjusted = 3.5% per SD (95% CI: 0.6%, 6.3% per SD)]. This association was attenuated after the inclusion of the summary score for inflammation [b-adjusted+inflammation = 2.2% (95% CI: 20.6%, 5.0%)]. The ADII was also adversely associated with fasting glucose and postload glucose but not with glycated hemoglobin. Conclusion: The significant mediating role of low-grade inflammation in the association between the ADII and HOMA-IR suggests that inflammation might be one of the pathways through which diet affects insulin resistance. [ABSTRACT FROM AUTHOR]

Background The complement system may be involved in the pathogenesis of alcoholic and nonalcoholic liver disease, although studies in humans are scarce. For this reason, we investigated whether circulating levels of activated complement factor 3 (C3a) were associated with hepatic steatosis and hepatocellular damage. Materials and methods Plasma C3a, aspartate aminotransferase ( AST), alanine aminotransferase ( ALT) and gamma-glutamyl transferase ( GGT) were determined in 523 individuals (61% men, age 59 ± 7 years). Liver enzymes ( LEs) were standardized and compiled into a LE score. Liver fat content was estimated using a predictive equation that has recently been validated with magnetic resonance spectrometry. Cross-sectional associations between C3a and liver fat or LE s were investigated with multiple linear regression analyses, stratified in no-to-moderate vs. heavy alcohol consumers (men: > 30 g/day; women: > 20 g/day). Results C3a was associated with liver fat percentage both in the no-to-moderate (β = 0·223; 95%CI 0·036; 0·409) and in the heavy alcohol consumers (β = 0·632; 95%CI 0·259-1·004; P-interactio n = 0·047). C3a was also associated with the LE score in heavy alcohol consumers (β = 0·917; 95%CI 0·443-1·392), but not in no-to-moderate alcohol consumers (β = 0·042; 95%CI −0·198 to 0·281; P-interaction = 0·001). Conclusions C3a levels, as a marker of complement activation, were associated with liver fat content and hepatocellular injury, at least in subjects who consume considerable amounts of alcohol daily. [ABSTRACT FROM AUTHOR]

Background: Heart failure is associated with abnormalities of myocardial structure, and plasma levels of the advanced glycation end-product (AGE) Ne-(carboxymethyl)lysine (CML) correlate with the severity and prognosis of heart failure. Aging is associated with diastolic dysfunction and increased risk of heart failure, and we investigated the hypothesis that diastolic dysfunction of aging humans is associated with altered myocardial structure and plasma AGE levels. Methods: We performed histological analysis of non-ischemic left ventricular myocardial biopsies and measured plasma levels of the AGEs CML and low molecular weight fluorophores (LMWFs) in 26 men undergoing coronary artery bypass graft surgery who had transthoracic echocardiography before surgery. None had previous cardiac surgery, myocardial infarction, atrial fibrillation, or heart failure. Results:The patients were aged 43-78 years and increasing age was associated with echocardiographic indices of diastolic dysfunction, with higher mitral Doppler flow velocity A wave (r = 0.50, P = 0.02), lower mitral E/A wave ratio (r = 0.64, P = 0.001), longer mitral valve deceleration time (r = 0.42, P = 0.03) and lower early diastolic peak velocity of the mitral septal annulus, e' (r = 0.55, P = 0.008). However, neither mitral E/A ratio nor mitral septal e' was correlated with myocardial total, interstitial or perivascular fibrosis (picrosirius red), immunostaining for collagens I and III, CML, and receptor for AGEs (RAGE), cardiomyocyte width, capillary length density, diffusion radius or arteriolar dimensions. Plasma AGE levels were not associated with age. However, plasma CML levels were associated with E/A ratio (r = 0.44, P = 0.04) and e' (r = 0.51, P = 0.02) and LMWF levels were associated with E/A ratio (r = 0.49, P = 0.02). Moreover, the mitral E/A ratio remained correlated with plasma LMWF levels in all patients (P = 0.04) and the mitral septal e' remained correlated with plasma CML levels in non-diabetic patients (P = 0.007) when age was a covariate. Conclusions: Diastolic dysfunction of aging was independent of myocardial structure but was associated with plasma AGE levels. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Frequent episodes of severe hypoglycemia may increase the risk of cardiovascular disease (CVD) in people with diabetes. Our aim was to study the relationship between severe hypoglycemic episodes and CVD incidence in subjects with type 1 diabetes, and further, to assess if markers of inflammation/endothelial injury were enhanced in individuals who experienced hypoglycemic episodes. RESEARCH DESIGN AND METHODS--The prospective study included 2,181 type 1 diabetic patients from the EURODIAB Prospective Complications Study. At baseline, frequency of self-reported severe hypoglycemia, defined as episodes serious enough to require the help of another person, was assessed based on responses to a patient questionnaire. Both fatal/nonfatal CVD was assessed 7.3 years after baseline examination. At the follow-up visit, data on both severe and nonsevere hypoglycemic episodes in the previous year were collected through a questionnaire and markers of inflammation/stress response/endothelial injury measured by enzyme-linked immunosorbent assays in the 531 subjects of the nested case-control study, including 363 case subjects with one or more complications of diabetes and 168 control subjects with no evidence of any complication. RESULTS--During the follow-up period, 176 patients had incident CVD. Logistic regression analysis showed that severe hypoglycemia at the baseline examination was not associated with incidence of CVD (adjusted odds ratios [95%CI]: one to two episodes, 0.87 [0.55--1.37]; three or more episodes, 1.09 [0.68--1.75]). Furthermore, follow-up serum levels of markers of endothelial damage/inflammation were not cross-sectionally associated with the frequency of hypoglycemic episodes. CONCLUSIONS--Taken together our data do not support the hypothesis that in type 1 diabetes, severe hypoglycemia increases the risk of CVD. [ABSTRACT FROM AUTHOR]

Background. Plasma and urinary levels of D-lactate have been linked to the presence of diabetes. Previously developed techniques have shown several limitations to further evaluate D-lactate as a biomarker for this condition. Methods. D- and L-lactate were quantified using ultraperformance liquid chromatography tandem mass spectrometry with labelled internal standard. Samples were derivatized with diacetyl-L-tartaric anhydride and separated on a C18-reversed phase column. D- and L-lactate were analysed in plasma and urine of controls, patients with inflammatory bowel disease (IBD), and patients with type 2 diabetes (T2DM). Results. Quantitative analysis of D- and L-lactate was achieved successfully. Calibration curves were linear (r ²0 99) over the physiological and pathophysiological ranges. Recoveries for urine and plasma were between 96% and 113%. Inter- and intra-assay variations were between 2% and 9%. The limits of detection of D-lactate and L-lactate in plasma were 0.7 μmol/L and 0.2 μmol/L, respectively. The limits of detection of D-lactate and L-lactate in urine were 8.1 nmol/mmol creatinine and 4.4 nmol/mmol creatinine, respectively. Plasma and urinary levels of D- and L-lactate were increased in patients with IBD and T2DMas compared with controls. Conclusion. The presented method proved to be suitable for the quantification of D- and L-lactate and opens the possibility to explore the use of D-lactate as a biomarker. [ABSTRACT FROM AUTHOR]

A healthy diet rich in fish, fruit, and vegetables, moderate in alcoholic beverages, and low in dairy products has been associated with lower circulating concentrations of biomarkers of endothelial dysfunction (ED) and low-grade inflammation (LGI). It is, however, unknown how consumption of these food groups affects ED and/or LGI over time. We measured diet by the computer-assisted crosscheck dietary history method at 36 ± 0.63 y of age )n = 301, women = 161). At 36 and 42 y of age, we measured von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble endothelial selectin, soluble vascular cell adhesion molecule 1 and soluble thrombomodulin (circulating biomarkers of ED); and C-reactive protein, serum amyloid A, lL-6, IL-8, TNFα, and sICAM-1 (circulating biomarkers of LGII. We investigated the associations between food groups and changes in combined biomarker Z-scores of ED and LGI [higher scores associated with greater risk of (incident) cardiovascular disease]. After adjustment for sex, energy intake, SMI, physical activity, alcohol consumption, smoking behavior, and other food groups, consumption of fish (per 100 g/wkl, but none of the other food groups, was inversely associated with changes in ED [β )95%Cl) = -0.06 (-0.10; -0.021; P = 0.003] and LGI [-0.05 1-0.09; -0.003); P = 0.0361. Additionally, EPA+DHA intake was inversely associated with changes in ED [β (95%Cl) = -0.13 (-0.19; -0.07); P ≤ 0.001] and LGI [-0.09 (-0.16; -0.02); P= 0.013] and explained 83 and 40% of theassociation between fish and changes in ED and LGI. In conclusion, fish consumption, but not fruit, vegetable, alcoholic beverage, or dairy product consumption, was associated with decreased ED and LG( in healthy adults. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness. RESEARCH DESIGN AND METHODS--We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of Nε(carboxymethyl)lysine, Nε(carboxyethyl) lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6-12.5) years. RESULTS--During the course of follow-up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all-cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03-1.66) and HR = 1.27 (1.00-1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness. CONCLUSIONS--Higher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients. [ABSTRACT FROM AUTHOR]

Objective . To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides). Methods . IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n = 269, 68 %). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-β) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information. Results . In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28 % increase ( = 1 SD) in Z-score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75 % increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p = 0.038). Conclusion . Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915. [ABSTRACT FROM AUTHOR]

The impact of irbesartan treatment on biomarkers of low-grade inflammation, endothelial dysfunction, growth factors, and advanced glycation end products (AGEs) during the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study was evaluated. IRMA 2 was a 2-year multicenter, randomized, double-blind trial in patients comparing irbesartan (150 or 300 mg once daily) versus placebo. The primary end point was onset of overt nephropathy. A subgroup (n = 269, 68%) was analyzed for biomarkers at baseline and after 1 and 2 years. High-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, fibrinogen, adhesion molecules, transforming growth factor-β and AGE peptides were assessed. Irbesartan treatment yielded significant changes in hs-CRP (based on generalized estimating equation regression coefficient) with a 5.4% decrease per year versus a 10% increase per year in the placebo group (P < 0.001). Fibrinogen decreased 0.059 g/l per year from baseline versus placebo's 0.059 g/l increase per year (P = 0.027). IL-6 showed a 1.8% increase per year compared with placebo's 6.5% increase per year (P = 0.005). Changes in IL-6 were associated with changes in albumin excretion (P = 0.04). There was no treatment effect on the other biomarkers. Irbesartan (300 mg once daily) reduces low-grade inflammation in this high-risk population, and this may reduce the risk of micro-and macrovascular disease. Diabetes 55:3550-3555, 2006 [ABSTRACT FROM AUTHOR]

Cholesterol Efflux Capacity (CEC) is considered to be a key atheroprotective property of high-density lipoproteins (HDL). However, the role of HDL-CEC in atherosclerosis and cardiovascular (CV) risk is still controversial, and data in individuals with diabetes are limited. In this study, we have investigated the relationship of CEC and other HDL characteristics with clinical and subclinical atherosclerosis in subjects with elevated cardiovascular diseases (CVD) risk and Type 2 Diabetes Mellitus (T2DM). Using multiple linear regression analyses, we determined the relationship of HDL-CEC with carotid intima-media thickness (cIMT, Z-Score), an endothelial dysfunction (EnD) Score (Z-Score), prevalent CVD (n = 150 cases) and history of CV events (CVE, n = 85 cases) in an observational cohort (CODAM, n = 574, 59.6 ± 0.3 yr, 61.3% men, 24.4% T2DM). Stratified analyses were performed to determine if the associations differed between individuals with normal glucose metabolism (NGM) and those with disturbed glucose metabolism. HDL-CEC was not associated with either marker of atherosclerosis (cIMT, EnD Score) nor with CVD or CVE. In contrast, other HDL characteristics that is, HDL-Cholesterol (HDL-C, Z-Score), apolipoprotein A-I (apoA-I, Z-Score), HDL size (Z-Score) and HDL particle number (HDL-P, Z-Score) were inversely and significantly associated with the EnD Score (s −0.226 to −0.097, P <.05) and CVE (ORs 0.61 to 0.68, P <.05). In stratified analyses, HDL size and HDL-P were significantly associated with the EnD Score in individuals with NGM (P interaction.039 and.005, respectively), but not in those with (pre)diabetes. HDL-C and apoA-I were inversely associated with prevalent CVD in individuals with (pre)diabetes (P interaction =.074 and.034, respectively), but not in those with NGM. HDL-CEC is not associated with clinical or subclinical atherosclerosis, neither in the whole population nor in individuals with (pre)diabetes, while other HDL characteristics show atheroprotective associations. The atheroprotective associations of HDL-size and HDL-P are lost in (pre)diabetes, while higher concentrations of HDL-C and apoA-I are associated with a lower prevalence of CVD in (pre)diabetes. • HDL-CEC is not associated with subclinical or clinical atherosclerosis • HDL-C, apoA-I, HDL size, and HDL-P show atheroprotective associations • Atheroprotective associations of HDL-size and HDL-P are lost with (pre)diabetes [ABSTRACT FROM AUTHOR]

Background: Vascular calcifications are associated with a three- to fourfold increased risk of cardiovascular disease (CVD) and are highly prevalent in type 2 diabetes patients. Emerging evidence indicates that vascular calcification is a process of active bone formation regulated by stimulators and inhibitors of calcification. Therefore, this study aimed to evaluate whether six bone markers are associated with CVD risk in patients with type 2 diabetes. Methods: We used data of a case-cohort study, nested in the EPIC-NL cohort, comprising 134 CVD cases and a random subcohort of 218 participants, all with type 2 diabetes at baseline. Six bone markers (osteocalcin, osteopontin, osteonectin, osteoprotegerin, alkaline phosphatase and sclerostin) were measured in baseline plasma samples with multiplex assays and information on CVD events was obtained. The association of bone makers with CVD risk was evaluated using Cox proportional hazard analyses. Results: Higher concentrations of plasma osteopontin were associated (ptrend < 0.01) with an increased CVD risk with a hazard ratio of 2.00 (95%-CI 1.20–3.35) for the highest versus the lowest quartile in a multivariable adjusted model. The other bone markers were not associated with CVD risk. Conclusions: Higher osteopontin concentrations were associated with an increased CVD risk in type 2 diabetes patients. No consistent associations were found for the other five bone markers and risk of CVD in type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

Purpose: Coronary atherosclerosis is the leading cause of sudden death among athletes >35 yr old, but current cardiovascular risk prediction algorithms have not been validated for athletes. Advanced glycation end products (AGE) and dicarbonyl compounds have been associated with atherosclerosis and rupture-prone plaques in patients and ex vivo studies. The detection of AGE and dicarbonyl compounds might be a novel screening tool for high-risk coronary atherosclerosis in older athletes. Methods: Concentrations of three different AGE and the dicarbonyl compounds methylglyoxal, glyoxal, and 3-deoxyglucosone were measured in plasma with ultraperformance liquid chromatography tandem mass spectrometry in athletes from the Measuring Athletes' Risk of Cardiovascular Events 2 study cohort. Coronary plaques, plaque characteristics (calcified, noncalcified or mixed), and coronary artery calcium (CAC) scores were assessed with coronary computed tomography, and potential associations with AGE and dicarbonyl compounds were analyzed using linear and logistic regression. Results: A total of 289 men were included (60 [quartiles 1–3 = 56–66] yr old, body mass index = 24.5 [22.9–26.6] kg·m−2), with a weekly exercise volume of 41 (25–57) MET-hours. Coronary plaques were detected in 241 participants (83%), with a dominant plaque type of calcified plaques in 42%, noncalcified plaques in 12% and mixed plaques in 21%. No AGE or dicarbonyl compounds were associated with total number of plaques or any of the plaque characteristics in adjusted analyses. Similarly, AGE and dicarbonyl compounds were not associated with CAC score. Conclusions: Concentrations of plasma AGE and dicarbonyl compounds do not predict the presence of coronary plaques, plaque characteristics or CAC scores, in middle-age and older athletes. [ABSTRACT FROM AUTHOR]

Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified. [ABSTRACT FROM PUBLISHER]

Background The pathogenesis of depression may involve low-grade inflammation and endothelial dysfunction. We aimed to evaluate the independent associations of inflammation and endothelial dysfunction with depressive symptoms and depressive disorder, and the role of lifestyle factors in this association. Methods In The Maastricht Study, a population-based cohort study (n = 852, 55% men, m = 59.8 ± 8.5 years), depressive symptoms were assessed with the Patient Health Questionnaire-9 and (major and minor) depressive disorder with the Mini-International Neuropsychiatric Interview. Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) and endothelial dysfunction (sVCAM-1, sICAM-1, sE-selectin, vWF) were measured with sandwich immunoassays and combined into two standardized sum scores. Results Biomarkers of inflammation (hsCRP, TNF-α, SAA, sICAM-1) and endothelial dysfunction (sICAM-1, sE-Selectin) were univariately associated with depressive symptoms and depressive disorder. The sum scores of inflammation and endothelial dysfunction were associated with depressive disorder after adjustment for age, sex, type 2 diabetes, kidney function and prior cardiovascular disease (OR 1.54, p = 0.001 and 1.40, p = 0.006). Both sum scores remained significantly associated with depressive disorder after additional adjustment for lifestyle factors smoking, alcohol consumption and body mass index. The sum score of inflammation was also independently associated with depressive symptoms, while the sum score of endothelial dysfunction was not. Conclusions Inflammation and endothelial dysfunction are both associated with depressive disorder, independent of lifestyle factors. Our results might suggest that inflammation and endothelial dysfunction are involved in depression. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate whether an adverse body composition is associated with endothelial dysfunction (ED) and the extent to which any such association could be explained by low-grade inflammation (LGI) and/or insulin resistance (HOMA2-IR). Methods: We studied 475 individuals from the Hoorn Study [mean (range) age, 68.9 (60–87) years, 245 women). Body composition was assessed by whole body dual-energy absorptiometry. Endothelial dysfunction was measured functionally, by flow-mediated dilation (FMD) and by circulating biomarkers. Associations were examined with multiple linear regression models and mediation analyses according to the ab product of coefficients method. Results: After adjustment for age, sex, glucose metabolism status, prior cardiovascular disease and lifestyle factors, total and central fat mass were positively associated with the ED score [β = 0.16 (95% CI 0.04–0.29) and β = 0.18 (0.05–0.31), respectively] and inversely, although not statistically significantly, with FMD. Peripheral fat mass was not associated with the ED score or FMD. There was a significant favourable association between peripheral lean mass and FMD [β = 0.13 (0.00–0.26)], but not with the ED score. The association between total and central fat mass and the ED score was, to a great extent, mediated by LGI and HOMA2-IR. In contrast, LGI or HOMA2-IR did not mediate the association between peripheral lean mass and FMD. Conclusion: Higher levels of central, but not peripheral fat mass were adversely associated with ED, which was attributable to body composition-related LGI and insulin resistance. In contrast, peripheral lean mass was beneficially associated with ED, but this seemed to be unrelated to LGI or insulin resistance. [Copyright &y& Elsevier]