Search

Background: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases.Methods: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status.Results: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 +/- 11.77 years, mean +/- SD) and had significantly lower SAF (1.90 +/- 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 +/- 12.07 years; SAF: 2.27 +/- 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (beta= -0.002, 95% confidence interval (95%CI): -0.002 to -0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (beta= 3.2 x 10(-5), 95%CI: 0.000-0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (beta= 4.2 x 10(-4), 95%CI: 0.000-0.001, p < 0.001), but this association was not found in the chronic disease population (beta = -3.2 x 10(-4), 95%CI: -0.001 to 0.000, p = 0.347).Conclusion: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

Background: We investigated the causality of IL-8 on carotid intima-media thickness (c-IMT), a measure of sub-clinical atherosclerosis. Methods: The IMPROVE is a multicenter European study (n = 3,711). The association of plasma IL-8 with c-IMT (mm) was estimated by quantile regression. Genotyping was performed using the Illumina CardioMetabo and Immuno chips. Replication was attempted in three independent studies and a meta-analysis was performed using a random model. Results: In IMPROVE, each unit increase in plasma IL-8 was associated with an increase in median c-IMT measures (all p

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.

Objective: Follow-up of patients with treatment-resistant Raynaud's phenomenon (RP) one-year after single-port thoracoscopic sympathicotomy (SPTS).Methods: Eight patients (six males, two females, median age of 45 years) with treatment-resistant RP underwent left-sided SPTS at the third rib (R3), unilaterally. Questionnaires were taken, and number and duration of RP attacks were reported over a 2-week period. Perfusion was assessed with a cooling and recovery procedure at baseline and one year after SPTS. Furthermore, laser speckle contrast analysis, pulse wave velocity, heart rate variability and nailfold capillary microscopy were performed.Results: One year after SPTS the duration of the attacks of was reduced with 1.9 h in the left hand versus 0.3 h in the right hand. Furthermore, three aspects of the questionnaire showed a significant improvement (role limitations due to physical health (p = 0.017), pain (p = 0.027) and physical functioning (p = 0.025)). The total area under the curve of the total cooling and recovery procedure of the left hand was larger one year after surgery (101 (75–140) at baseline versus 118 (95–190) one year post-operatively, p = 0.012), implying a better perfusion in the fingers. This was mainly due to the improvement during the recovery phase (21 (1–41) at baseline versus 38 (24–43) one year post-operatively, p = 0.028).Conclusion: One year after unilateral R3 SPTS the benefit with regard to the majority of outcome variables persisted, though some effects seem to attenuate. Long-term effects and long-term follow-up results will be investigated in an on-going study.Clinical trial registration number: NCT02680509.

Objective To assess the minimally invasive single-port thoracoscopic sympathicotomy feasibility and efficacy in patients with treatment-resistant RP. Methods Single-port thoracoscopic sympathicotomy was performed unilaterally on the left side in eight patients with RP (six males, two females, with a median age of 45.2 years). Five patients had primary and three had secondary RP. Perfusion effects in the hands were assessed at baseline and after 1 month by using a cooling and recovery procedure, and by using laser speckle contrast analysis. Number and duration of RP attacks were reported over a 2-week period. Results Patient satisfaction was 100% after surgery. After surgery, a unilateral improvement in perfusion was observed in the left hand compared with the right hand, with cooling and recovery (P = 0.008) and with laser speckle contrast analysis (P = 0.023). In addition, the number and duration of the attacks in the left hand decreased compared with the right hand (both P = 0.028). No serious adverse events occurred in a follow-up period of at least 10 months. Conclusion Single-port thoracoscopic sympathicotomy is feasible and can be effective in improving hand perfusion in patients with RP. However, long-term efficacy needs to be established. Clinical trial registration number NCT02680509.

CADM2 has been associated with a range of behavioural and metabolic traits, including physical activity, risk-taking, educational attainment, alcohol and cannabis use and obesity. Here, we set out to determine whether CADM2 contributes to mechanisms shared between mental and physical health disorders. We assessed genetic variants in the CADM2 locus for association with phenotypes in the UK Biobank, IMPROVE, PROCARDIS and SCARFSHEEP studies, before performing meta-analyses. A wide range of metabolic phenotypes were meta-analysed. Psychological phenotypes analysed in UK Biobank only were major depressive disorder, generalised anxiety disorder, bipolar disorder, neuroticism, mood instability and risk-taking behaviour. In UK Biobank, four, 88 and 172 genetic variants were significantly (p −5) associated with neuroticism, mood instability and risk-taking respectively. In meta-analyses of 4 cohorts, we identified 362, 63 and 11 genetic variants significantly (p −5) associated with BMI, SBP and CRP respectively. Genetic effects on BMI, CRP and risk-taking were all positively correlated, and were consistently inversely correlated with genetic effects on SBP, mood instability and neuroticism. Conditional analyses suggested an overlap in the signals for physical and psychological traits. Many significant variants had genotype-specific effects on CADM2 expression levels in adult brain and adipose tissues. CADM2 variants influence a wide range of both psychological and metabolic traits, suggesting common biological mechanisms across phenotypes via regulation of CADM2 expression levels in adipose tissue. Functional studies of CADM2 are required to fully understand mechanisms connecting mental and physical health conditions.

Objective.To assess the presence of a systemic sclerosis (SSc) pattern on nailfold capillary microscopy (NCM) in patients with Raynaud phenomenon (RP) and to explore its association with abnormal pulmonary function tests (PFT).Methods.NCM patterns were assessed in 759 consecutive patients with RP. Patterns were classified as normal (n = 354), nonspecific (n = 159), or SSc pattern (n = 246). Abnormal PFT was defined as forced vital or diffusion capacity < 70%. Patients were classified as primary RP (n = 245), or secondary: no definite diagnosis (n = 391), SSc (n = 40), primary Sjögren syndrome (pSS; n = 30), systemic lupus erythematosus (SLE; n = 30), mixed connective tissue disease (MCTD; n = 7), rheumatoid arthritis (RA; n = 15).Results.An SSc pattern on NCM was frequently observed in most patients with a definite diagnosis: SSc (88%), pSS (33%), SLE (17%), MCTD (71%), and RA (13%). In patients without definite diagnosis, 17% had a normal NCM pattern, 35% nonspecific, and 48% SSc pattern. Abnormal PFT was more frequent in patients with an SSc pattern (35.9% vs 19.5%, p = 0.002), even when corrected for SSc diagnosis (p = 0.003). Absence of an SSc pattern had high negative predictive value (88%); positive predictive values were low.Conclusion.SSc pattern on NCM is common in patients with RP, and in those with connective tissue diseases other than SSc. It is associated with a higher prevalence of abnormal PFT, independent of the presence of an SSc diagnosis. Although these data need validation in a prospective setting, they underline the importance of NCM in RP and putative value to stratify the risk of pulmonary involvement in early stages of disease.

Aims Advanced glycation endproducts (AGEs) are sugar modified adducts which arise during non-enzymatic glycoxidative stress. These compounds may become systemically elevated in disease states, and accumulate in tissue, especially on long-lived proteins. AGEs have been implicated in various acute, and chronic diseases, stressing the need for reliable and comprehensive measuring techniques. Measurement of AGEs in tissue such as skin requires skin biopsies, which is an invasive procedure. The AGE Reader has been developed to assess skin autofluorescence (SAF) non-invasively by the fluorescent properties of several AGEs. Results/Conclusion Various studies have shown that SAF is a useful marker of disease processes associated with oxidative stress. It is prospectively associated with development of cardiovascular events in patients with diabetes, renal or cardiovascular disease, and it predicts diabetes, cardiovascular disease and mortality in the general population. However, when measuring SAF in individual subjects, several factors may limit the reliability of the measurement, and hamper its use as a systemic biomarker for AGEs. These include endogenous factors present in the skin that absorb emission light such as melanin in dark-skinned subjects, but also factors that lead to temporal changes in SAF such as acute diseases and strenuous physical exercise associated with glycoxidative stress. Also, exogenous factors could potentially influence SAF levels inadvertently such as nutrition, and for example the application of skin care products. This review will give an overview of the AGE Reader functionality and the intrinsic, and exogenous factors which potentially influence the SAF assessment in individual subjects.

Background Advanced glycation end products (AGEs) are associated with aging, diabetes mellitus (DM), and other chronic diseases. Recently, the accumulation of AGEs can be evaluated by skin autofluorescence (SAF). However, the relationship between SAF levels and exercise capacity in patients with cardiovascular disease (CVD) remains unclear. This study aimed to investigate the association between the tissue accumulation of AGEs and clinical characteristics, including exercise capacity, in patients with CVD. Methods We enrolled 319 consecutive CVD patients aged ≥40 years who underwent early phase II cardiac rehabilitation (CR) at our university hospital between November 2015 and September 2017. Patient background, clinical data, and the accumulation of AGEs assessed by SAF were recorded at the beginning of CR. Characteristics were compared between two patient groups divided according to the median SAF level (High SAF and Low SAF). Results The High SAF group was significantly older and exhibited a higher prevalence of DM than the Low SAF group. The sex ratio did not differ between the two groups. AGE levels showed significant negative correlations with peak oxygen uptake and ventilator efficiency (both P P P = 0.02). Conclusion High levels of tissue accumulated AGEs, as assessed by SAF, were significantly and independently associated with reduced exercise capacity. These data suggest that measuring the tissue accumulation of AGEs may be useful in patients who have undergone CR, irrespective of whether they have DM.

Background: Decline in physical activity and functioning is commonly observed in the older population and might be associated with biomarkers such as advanced glycation end products (AGEs). AGEs contribute to age-related decline in the function of cells and tissues in normal aging and have been found to be associated with motor function decline. The aim of this study is to investigate the association between the levels of AGEs, as assessed by skin autofluorescence, and the amount of physical activity and loss of physical functioning in older participants.Methods: Cross-sectional data of 5,624 participants aged 65 years and older from the LifeLines Cohort Study were used. Linear regression analyses were utilized to study the associations between skin autofluorescence/AGE levels (AGE Reader), the number of physically active days (SQUASH), and physical functioning (RAND-36). A logistic regression analysis was used to study the associations between AGE levels and the compliance with the Dutch physical activity guidelines (SQUASH).Results: A statistical significant association between AGE levels and the number of physically active days (beta = -0.21, 95% confidence interval: -0.35 to -0.07,p = .004), physical functioning (beta = -1.60, 95% confidence interval: -2.64 to -0.54, p = .003), and compliance with the Dutch physical activity guidelines (odds ratio = 0.76, 95% confidence interval: 0.62 to 0.94, p = .010) was revealed.Conclusions: This study indicates that high AGE levels may be a contributing factor as well as a biomarker for lower levels of physical activity and functioning in the older population.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide, particularly in individuals with diabetes. The current study objective was to determine the circulating metabolite profiles associated with the risk of future cardiovascular events, with emphasis on diabetes status. Nontargeted metabolomics analysis was performed by LC-HRMS in combination with targeted quantification of eicosanoids and endocannabinoids. Plasma from 375 individuals from the IMPROVE pan-European cohort was included in a case-control study design. Following data processing, the three metabolite data sets were concatenated to produce a single data set of 267 identified metabolites. Factor analysis identified six factors that described 26.6% of the variability in the given set of predictors. An association with cardiovascular events was only observed for one factor following adjustment (p = 0.026). From this factor, we identified a free fatty acid signature (n = 10 lipids, including saturated, monounsaturated, and polyunsaturated fatty acids) that was associated with lower risk of future cardiovascular events in nondiabetics only (OR = 0.65, 0.27-0.80 95% CI, p = 0.030), whereas no association was observed among diabetic individuals. These observations support the hypothesis that increased levels of circulating omega-6 and omega-3 fatty acids are associated with protective effects against future cardiovascular events. However, these effects were only observed in the nondiabetic population, further highlighting the need for patient stratification in clinical investigations.

AIMS: To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on aortic pulse wave velocity (PWV) as a surrogate marker of arterial stiffness and early atherosclerosis in people with early type 2 diabetes.METHODS: A total of 45 people with type 2 diabetes (median [interquartile range] age 63 [54-66] years, 61% men, mean ± standard deviation glycated haemoglobin [HbA1c] 6.3% ± 0.4% [45 ± 4.6 mmol/mol]), without cardiovascular disease and naïve to antidiabetic treatment, were randomized (1:1) to treatment with linagliptin 5 mg once daily or placebo for 26 weeks in a double-blind fashion. PWV was assessed at baseline, 4 and 26 weeks of treatment, and again at 30, 4 weeks after treatment. The primary endpoint was between-group difference in PWV (corrected for systolic blood pressure [SBP]) at week 26. Secondary endpoints included differences in central SBP and augmentation index (AIx).RESULTS: Compared with placebo, 26 weeks of linagliptin decreased PWV by an average of 0.91 m/s (95% confidence interval -1.76 to -0.06; P = .035). PWV returned to baseline after 4 weeks washout. Differences in central SBP and AIx were not different between linagliptin and placebo. Linagliptin decreased HbA1c (-0.4%; P CONCLUSIONS: Linagliptin decreased aortic PWV in people with early-stage type 2 diabetes as compared with placebo after 26 weeks of treatment. These results suggest that linagliptin has a favourable effect on arterial stiffness.

Objective: HIV-1 infection is associated with an increased cardiovascular disease (CVD) risk. Advanced glycation end products are formed as stable markers of glycaemic and oxidative stress. Skin autofluorescence (SAF) as marker of accumulated advanced glycation end products is increased and predictive of CVD events in diabetes mellitus, chronic kidney disease (CKD), and preexisting CVD. We determined SAF levels in HIV-1 infected patients, testing the hypothesis that SAF predicts CVD events in HIV infection.Design: Single-centre prospective cohort study.Methods: In 2010-2011, SAF was measured in 91 patients. Development of CVD events was monitored during a median follow-up of 4.8 years. SAF values of the patients were expressed as a ratio (rSAF) to expected SAF levels in age-matched healthy volunteers.Results: Seventy-nine men and 12 women were included, mean age 47 years; 81 patients were on combination antiretroviral therapy. With a mean rSAF of 1.155, SAF levels in patients were 15.5% higher than predicted for their age (95% confidence interval, 10.0-20.0; PConclusion: SAF is increased in HIV-infected patients, and related with smoking, low nadir CD4(+) cell count, and MSM. Larger studies are needed to confirm whether SAF is an independent predictor of CVD events. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin‐2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin‐2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan‐European cohort of high‐risk individuals where carotid intima‐media thickness has been assessed was adopted. Human primary monocyte‐derived macrophages were prepared from whole blood from individuals recruited by perilipin‐2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin‐2 is associated with decreased intima‐media thickness at baseline and over 30 months of follow‐up. Using human primary monocyte‐derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver‐X‐receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed‐forward loop, regulated by CYP27A1 and 27OH‐cholesterol. Conclusions For the first time, we show that perilipin‐2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin‐2 modulates levels of the LXR ligand 27OH‐cholesterol and initiates a feed‐forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin‐2 exerts its beneficial effects on subclinical atherosclerosis.

Background Systemic sclerosis (SSc) is a progressive fibro-inflammatory autoimmune disease of which the pathogenetic pathways are incompletely understood. Advanced glycation endproducts (AGEs) are oxidative stress derived compounds with potential proinflammatory effects. Their exact role in fibrosis remains unknown. The receptor for AGEs is RAGE, which is also the receptor for high mobility group box 1 (HMGB1), a nuclear protein, which is proinflammatory when released from activated or apoptotic cells. We hypothesize that AGEs and HMGB1 may promote inflammation and profibrotic processes, presumably mediated by RAGE. Objectives To study the role of the HMGB1/AGE-RAGE axis in the pathogenesis of SSc. Methods Distribution of NƐ-(carboxymethyl)lysine (CML) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) was assessed by immunohistochemistry in skin biopsies of 12 SSc patients [median age 56 years (IQR 52-61); 6 of affected, 6 of unaffected skin]. The intensity was assessed semi-quantitatively on endothelium and fibroblasts. In vitro experiments were performed on healthy human dermal fibroblasts, which were stimulated by HMGB1, AGE-BSA or TGF-β1 as control. Inflammatory and profibrotic markers were measured by ELISA and rt-PCR. Differentiation to myofibroblasts was assessed by staining of α-smooth muscle actin (α-SMA). In an additional clinical study, we included 20 SSc patients [51 years (44-58)] and 20 age- and sex-matched healthy controls [(HC) 52 years (45-62)]. Sera were obtained to determine CRP, ESR, HMGB1 and soluble RAGE (sRAGE) levels. AGE accumulation in skin was assessed as skin autofluorescence (SAF) by the AGE Reader. Results MG-H1 staining was more intense on all skin structures in SSc patients, compared to HC, while CML staining showed no differences. MG-H1 was more pronouncedly detected on endothelium and fibroblasts in affected compared to unaffected skin. In vitro stimulation of fibroblasts with AGE-BSA resulted in increased expression of IL-6, collagen-1α and connective tissue growth factor. Finally, HMGB1 and AGE-BSA induced myofibroblast differentiation and formation of SMA fibers (Fig. 1, 2). In regards to the clinical study CRP (SSc: median 1.8 mg/l (IQR 0.8-3.5), HC: 0.7 (0.4-1.8), p=0.04), ESR (SSc: 8.5 mm/h (5.3-15.5), HC: 5.0 (3.0-7.0), p=0.02), HMGB1 (SSc: 3.4 ng/ml (1.6-6.1), HC: 1.6 (0.8-2.8), p=0.03), sRAGE (SSc: 956.3 pg/ml (717.9-1670.0), HC: 684.9 (517.0-890.5), p=0.02) and SAF (SSc: 2.2 AU (1.8-2.5), HC: 1.8 (1.4-2.1), p=0.02) were significantly increased in SSc patients, compared to HC. Conclusion This is the first translational study that might indicate a prominent role of the HMGB1/AGE-RAGE axis in systemic sclerosis by promoting inflammation and fibrosis. Further studies investigating this pathway are ongoing. Acknowledgement Actelion, for co-funding the clinical study. Disclosure of Interests Isabella Atzeni: None declared, Amaal Eman Abdulle : None declared, Anniek van Roon: None declared, Gilles Diercks: None declared, Harry van Goor: None declared, Andries Smit Shareholder of: Has been co-founder, and is still shareholder of Diagnoptics Technologies, the company which developed the AGE reader., Johanna Westra: None declared, Douwe J Mulder Grant/research support from: My University has received research grants for my research from: Boehringer Ingelheim and Actelion, Speakers bureau: My University has received speakers fee from: Sanofi

Background: In some patients, Raynaud’s Phenomenon (RP) symptoms prove resistant to conventional vasodilatory treatment. Thoracic sympathectomy is shown to be effective as treatment of RP, but is associated with surgical burden. During this procedure, the sympathetic nerve traversing to the upper extremity is dissected, subsequently leading to vasodilatation. In our centre, single-port thoracoscopic sympathicotomy (SPTS) has been developed, a minimally invasive technique, extensively limiting surgical burden. [1] Objectives: To evaluate SPTS feasibility and efficacy after one month in patients with treatment resistant RP. Methods: In this study RP patients were their own controls, as they received an unilaterally left sided sympathicotomy. The effects of the SPTS was assessed at baseline and one month after the procedure. Perfusion of the hand was assessed using a cooling and recovery procedure, and laser speckle contrast analysis (LASCA) at room temperature of 23 degrees Celsius. The number and duration of RP attacks was reported over a two week period prior to reassessment by standard questionnaire. Results: Eight patients were included in the study, 6 male/2 female, with a median (IQR) age of 45.2 (30.2–55.3) years, body mass index of 23.9 (23.4–26.8) kg/m2, and RP duration of 7.0 (2.5–14.3) years. Five patients suffered from primary RP, and three patients had RP secondary to connective tissue disease (CTD) [mixed CTD (n=2) and limited cutaneous systemic sclerosis (n=1)]. All patients were very satisfied with the results and the number of attacks in the left hand decreased (p=0.018). After surgery an unilateral improvement in left hand perfusion was observed during the cooling and recovery procedure (p=0.008, figure 1), and in the fingertips with LASCA (p=0.023). No serious adverse events occurred. Conclusion: SPTS, a minimally invasive technique, appears to be feasible and effective in improving hand perfusion in patients with RP after one month. Although these results are promising, long-term efficacy needs to be established and therefore follow-up is on-going. Reference [1] Kuijpers M, Klinkenberg TJ, Bouma W, DeJongste MJ, Mariani MA. Single-port one-stage bilateral thoracoscopic sympathicotomy for severe hyperhidrosis: prospective analysis of a standardized approach. J Cardiothorac Surg2013;8:216-8090-8-216. Disclosure of Interests: Anniek van Roon: None declared, Michiel Kuijpers: None declared, Saskia van de Zande: None declared, Amaal Eman Abdulle : None declared, Arie Van Roon: None declared, Reinhard Bos Grant/research support from: SUN Pharma, Wobbe Bouma: None declared, Theo Klinkenberg: None declared, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant for: Roche, Bristol-Myers Squibb, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Bristol-Myers Squibb, Novartis, Mike DeJongste: None declared, Massimo Mariani: None declared, Andries Smit Shareholder of: Has been co-founder, and is still shareholder of Diagnoptics Technologies, the company which developed the AGE reader., Douwe J Mulder Grant/research support from: My University has received research grants for my research from: Boehringer Ingelheim and Actelion, Speakers bureau: My University has received speakers fee from: Sanofi

Background Distinguishing primary Raynaud’s phenomenon (PRP) from Raynaud’s phenomenon secondary to systemic sclerosis (SSc) is crucial in the early detection of SSc. Recently we reported that patients with more severe vasculopathy suffer from a prolonged ischemia time during Raynaud’s attack. [1] additionally, it appears that the thumb is more frequently involved in SSc, where it seems to be spared in PRP. [2] these two characteristics are easily recognized by patients and physicians, and can help rising awareness for SSc. Objectives The aim was to study if the recovery of a Raynaud’s attack and involvement of the thumb are differentiators for SSc in patients with Raynaud’s phenomenon (RP). Methods A stepwise cooling and recovery procedure was performed, provoking an RP attack, in patients with PRP and SSc. One hand was submerged up till the radiocarpal joint in water. The water temperature was lowered in steps of 3 degrees Celsius every four minutes, from 33 until at least 9 degrees Celsius. Afterwards ten minutes of recovery in room air of 23 degrees Celsius was observed. During the procedure perfusion of the fingertips was assessed by photo-electric plethysmography. Results In total 18 patients with SSc and 68 patients with PRP underwent the procedure. Seventeen (94%) SSc patients had no restoration of perfusion after ten minutes in one or more fingers, compared to 28 (41%) PRP patients (figure 1), with a negative predictive value of 98%. During cooling, 17 (94%) SSc patients developed abnormal perfusion in the thumb compared to 48 (71%) PRP patients (p=0.036), with a negative predictive value of 95%. There was no difference in involvement of the other fingers during cooling (all p>0.05). Positive predictive values were low. Conclusion In patients with RP, when there is restoration of perfusion in all fingers after ten minutes or when the thumb is spared, the presence of an underlying SSc is very unlikely. Although this objective measurement needs to be verified with patient’s reports, these results suggest that these simple signs can help physicians to assess if the patient needs to be referred for additional tests. References [1] van Roon aM, Smit aJ, van Roon aM, Bootsma H, Mulder DJ. Digital ischaemia during cooling is independently related to nailfold capillaroscopic pattern in patients with Raynaud’s phenomenon. Rheumatology (Oxford)2016;55:1083-1090. [2] Chikura B, Moore T, Manning J, Vail a, Herrick aL. Thumb involvement in Raynaud’s phenomenon as an indicator of underlying connective tissue disease. J Rheumatol2010;37:783-786. Disclosure of interests Anniek van Roon: None declared, arie Van Roon: None declared, alja J. Stel: None declared, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant for: Roche, Bristol-Myers Squibb, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Bristol-Myers Squibb, Novartis, andries Smit Shareholder of: Has been co-founder, and is still shareholder of Diagnoptics Technologies, the company which developed the aGE reader., Douwe J Mulder Grant/research support from: My University has received research grants for my research from: Boehringer ingelheim and actelion, Speakers bureau: My University has received speakers fee from: Sanofi

Background Systemic sclerosis (SSc)-related vasculopathy is generally thought to occur on a microvascular level. However, some observations also suggest involvement of arterial vessels. Macrovascular involvement (e.g., aorta or upper extremity) can be non-invasively assessed by measuring pulse wave velocity (PWV). Although, several studies have assessed aortic and upper extremity PWV in SSc, studies have not reached a consensus regarding this matter. Furthermore, we hypothesized that the endothelin antagonist bosentan may improve arterial stiffness by its direct endothelial and potential anti-fibrotic effects. Objectives The aim of this exploratory study was two-fold. First, we aimed to compare arterial stiffness in patients with SSc and age and sex-matched healthy controls (HC). Secondly, we will investigate the effect of bosentan on both short-term (three month) and long-term (one year) PWV. Methods Baseline differences between HC and SSc patients were studied in a case-control design. The follow-up of SSc patients was a randomized, prospective, 2-arm parallel group, open-label, (usual care with bosentan versus usual care only), blinded endpoint, intervention study. PWV (Sphygmocor) in meters/second, was measured to assess arterial stiffness in the aorta (carotid-femoral PWV), upper arm (carotid-brachial PWV), and forearm (brachial-radial PWV), adjusted for mean arterial pressure. Results Baseline characteristics are shown in table 1. No significant differences were observed in PWV (at all sites) between HC and SSc patients. No effect of bosentan on aortic, and upper arm PWV was found. The change in forearm PWV was different between the groups, with a decrease (e.g. lowering arterial stiffness) in the bosentan group (figure 1). Conclusion This small study shows that aortic, upper arm, and forearm arterial stiffness does not appear to be increased in patients with SSc, as compared to age- and sex-matched healthy controls. To the best of our knowledge, this is the first study to investigate the concept of potential effects of an endothelin receptor antagonist on macrovascular involvement in SSc. Although the results demonstrate no effects on aorta and upper arm arterial stiffness, they may indicate a beneficial effect on the stiffness of the smaller arteries of the forearm. Future studies are needed to further investigate the potential effect of bosentan on these smaller arteries. Acknowledgement Actelion for co-funding the study Disclosure of Interests Anniek van Roon: None declared, Amaal Eman Abdulle : None declared, Saskia van de Zande: None declared, Arie Van Roon: None declared, Dan Zhang: None declared, Reinhard Bos Grant/research support from: SUN Pharma, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant for: Roche, Bristol-Myers Squibb, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Bristol-Myers Squibb, Novartis, Andries Smit Shareholder of: Has been co-founder, and is still shareholder of Diagnoptics Technologies, the company which developed the AGE reader., Douwe J Mulder Grant/research support from: My University has received research grants for my research from: Boehringer Ingelheim and Actelion, Speakers bureau: My University has received speakers fee from: Sanofi

Raynaud's phenomenon (RP) is often the first sign of systemic sclerosis (SSc). Molecular mechanisms involved are incompletely understood, but reactive oxygen, nitrogen, and sulfur species are thought to play an important role in the pathogenesis of SSc. Free thiol groups play a protective role against oxidative stress and may represent an attractive therapeutic target. We aimed to investigate the effects of hypothermia‐induced vasoconstriction on the responsiveness of redox‐related markers. Thirty participants (n = 10/group [SSc, primary Raynaud's phenomenon (PRP), healthy controls (HC)]) were included in this study. Fingertip photoelectric plethysmography was performed during a standardized cooling and recovery experiment. Venous blood was collected at four predetermined time points. Free thiols, NO‐derived species (nitros(yl)ated species, nitrite, nitrate), sulfate and endothelin‐1 were measured. Lower baseline concentrations of free thiols were observed in PRP and SSc patients (HC: 5.87 [5.41–5.99] μmol/g; PRP: 5.17 [4.74–5.61]; SSc 5.28 [4.75–5.80], P = 0.04). Redox‐related markers remained unchanged during cooling. However, an unexpected increase in systemic free thiol concentrations was observed in all groups during the recovery phase. The response of this marker differed between groups, with a higher increase found in SSc patients (HC Δ = 1.30 [1.48–1.17]; PRP Δ = 1.04 [1.06–1.03]; SSc Δ = 1.72 [1.13–1.49], P = 0.04). NO‐derived species, sulfate and endothelin‐1 levels remained unchanged throughout the recovery phase. This exploratory study sheds light on the rapid responsiveness of systemic free thiol concentrations following reperfusion, which may reflect overall redox balance. The robust response to reperfusion in SSc patients suggests that reductive systems involved in this response are functionally intact in these patients.

Aims/hypothesis Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4 year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population. Methods For this prospective analysis, we included 72,880 participants of the Dutch Lifelines Cohort Study, who underwent baseline investigations between 2007 and 2013, had validated baseline skin autofluorescence values available and were not known to have diabetes or CVD. Individuals were diagnosed with incident type 2 diabetes by self-report or by a fasting blood glucose ≥7.0 mmol/l or HbA1c ≥48 mmol/mol (≥6.5%) at follow-up. Participants were diagnosed as having incident CVD (myocardial infarction, coronary interventions, cerebrovascular accident, transient ischaemic attack, intermittent claudication or vascular surgery) by self-report. Mortality was ascertained using the Municipal Personal Records Database. Results After a median follow-up of 4 years (range 0.5–10 years), 1056 participants (1.4%) had developed type 2 diabetes, 1258 individuals (1.7%) were diagnosed with CVD, while 928 (1.3%) had died. Baseline skin autofluorescence was elevated in participants with incident type 2 diabetes and/or CVD and in those who had died (all p

Publisher's version (útgefin grein), Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans., The work was supported by the following grants: National Institute of Health grants: R21HL123677, R21-HL140385, DK104806-01A1, R01-MD012765-01A1 (NF), National Institutes of Health awards R01HG009120, R01HG006399, U01CA194393, T32NS048004 (CG), the American Heart Association Grant #17POST33350042 (PV), the British Heart Foundation (RG/13/5/30112) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (RCL and RPH), the British Heart Foundation FS/14/55/30806 (JCH), the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed), the DFG as part of the CRC 1123 (B3), and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456). We thank Li-Ming Gan for assistance with the STARNET study and Jon White for assistance with UCLEB analyses. Additional acknowledgements are included in Supplementary Note 2.

Background: Microvascular disease, with rarefaction of nailfold capillaries, is the hallmark of systemic sclerosis (SSc). Obliteration of the ulnar and radial artery is regularly observed, implicating involvement of the forearm arteries. Pulse wave velocity (PWV) may serve as early biomarker of forearm artery involvement, before occurrence of irreversible arterial obliteration. Objectives: The aim was to investigate arterial stiffness of the aorta and the upper extremities in SSc patients and to correlate these findings with nailfold capillary count and extent of disease. Methods: Aortic PWV was defined as carotid-femoral (cf). Upper extremity PWV was measured as carotid-brachial (cb) and carotid-radial (cr), the ratio between cbPWV/crPWV was used as an indication of the relative PWV change in the forearm. Capillary count was the mean capillary count per 3 mm of 8 fingers. The number of SSc classification criteria was used as surrogate for extent of disease. [1] Results: In total, 19 SSc patients (median age 51 years, 68% female) were included. CbPWV/crPWV ratio correlated strongly with capillary count (r = −0.55, p = 0.022, figure 1) in SSc patients, with a trend in regards to its relation with the extent of disease (r=0.48, p=0.053). Conclusions: Our findings demonstrate that arterial stiffness of the forearm has a relationship with nailfold capillary count and tends to be associated with the extent of disease in patients with SSc. These may suggest that vascular damage also occurs in larger arteries of the forearm, which potentially serves as novel tool for assessing early vascular involvement in SSc.

Background: Raynaud’s phenomenon of the hands is a great burden and reduces quality of life. In some patients, complaints may be resistant to vasodilatory treatment, for which additional options are very limited. Previously thoracic sympathectomy has been shown effective, but with great surgical burden. In our centre, single-port thoracoscopic sympathicotomy (SPTS) was developed, a new minimally invasive endoscopic technique extensively limiting surgical burden. Objectives: The aim of this pilot study was to evaluate feasibility and efficacy of SPTS in patients with treatment resistant Raynaud’s. Methods: In the current study, we aim to include 10 patients with treatment resistant Raynaud’s. SPTS was performed on the left side and the effects were compared contralateral after 1 and 12 months. To assess perfusion of the hands a cooling fingertip plethysmography (PPG) and laser Doppler imaging (LDI) were used. Pulse wave velocity (PWV) of the carotis-femoralis and carotis-radialis was measured. Results: During this interim report, 7 patients are included so far (age 42 ± 13 years, 5/2 male/female, 5/2 primary/secondary Raynaud’s). All 7 patients were satisfied. A clear improvement in hand perfusion was observed with LDI and PPG during cooling, as compared to the contralateral side. A trend in decrease of PWV carotis-radialis left was seen, while PWV at the other sites did not change significantly (figure 1). Conclusions: SPTS is a novel minimally invasive technique which appears to be safe and feasible in patients with treatment resistant Raynaud’s and increases hand perfusion. However, this study is on-going and long-term efficacy needs to be established.

Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe−/− cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

Background: Metastatic testicular cancer (TC) can be cured with bleomycin, etoposide and cisplatin (BEP) chemotherapy. This comes at the price of an increased cardiovascular disease risk, not only years afterwards, but also during and shortly after chemotherapy. To prevent cardiovascular events, high-risk patients should be identified. The aim of this study was to assess BEP-chemotherapy induced vascular damage and to find risk factors for early vascular events.Patients and methods: A prospective cohort study was performed in (B) EP treated TC patients. Development of venous and arterial vascular events was assessed. Vascular damage markers (von Willebrand factor [vWF], coagulation factor VIII [FVIII], intima media thickness [IMT]) and cardiovascular risk factors were assessed before and until 1 year after chemotherapy. Before start of chemotherapy a vascular fingerprint was estimated. Presence of >= 3 risk factors was defined as high-risk vascular fingerprint: body mass index >25 kg/m(2), current smoking, blood pressure >140/90 mm Hg, total cholesterol >5.1 and/or low-density lipoprotein >2.5 mmol/L or glucose >= 7 mmol/L.Results: Seventy-three patients were included. Eight (11%) developed vascular events (four arterial events, four pulmonary embolisms). vWF and FVIII increased during chemotherapy, especially in patients with vascular events. Sixteen patients (22%) had a high-risk vascular fingerprint before start of chemotherapy. These patients had arterial events more often (3/16 [19%] versus 1/57 [2%]; p = 0.031) and higher vWF levels and IMT.Conclusions: Endothelial activation and upregulation of procoagulant activity seem important mechanisms involved in early (B) EP-chemotherapy-induced vascular events. Before chemotherapy, a quarter already had cardiovascular risk factors. A vascular fingerprint could identify patients at risk for arterial events. This vascular fingerprint, when validated, can be used as a tool to select patients who may benefit from preventive strategies. (C) 2016 Elsevier Ltd. All rights reserved.

Glycation is important in the development of complications of diabetes mellitus and may have a central role in the well-described glycaemic memory effect in developing these complications. Skin fluorescence has emerged over the last decade as a non-invasive method for assessing accumulation of advanced glycation endproducts. Skin fluorescence is independently related to micro- and macrovascular complications in both type 1 and type 2 diabetes mellitus and is associated with mortality in type 2 diabetes. The relation between skin fluorescence and cardiovascular disease also extends to other conditions with increased tissue AGE levels, such as renal failure. Besides cardiovascular complications, skin fluorescence has been associated, more recently, with other prevalent conditions in diabetes, such as brain atrophy and depression. Furthermore, skin fluorescence is related to past long-term glycaemic control and clinical markers of cardiovascular disease. This review will discuss the technique of skin fluorescence, its validation as a marker of tissue AGE accumulation, and its use as a clinical tool for the prediction of long-term complications in diabetes mellitus.

Objective. The aim of the study was to assess the association between plethysmographically measured vasospasms during stepwise cooling and recovery, as an index for digital ischaemia, and nailfold capillaroscopic pattern (NCP) severity in patients with primary or secondary RP, including SSc.Methods. In 381 consecutive patients with suspected RP without a history of digital ulcers, NCP (assessed by widefield videocapillaroscopy), fingertip photoelectric plethysmography during cooling and recovery and clinical characteristics were analysed. NCPs were graded as follows: normal, non-specific, early and active. The mean ischaemic time was defined as the mean time of perfusion loss during cooling and recovery of five fingers.Results. In the patients with loss of perfusion during cooling and recovery, the NCP was normal in 152, non-specific in 96, early in 61 and active in 39 patients. The mean ischaemic time was positively associated with the severity of NCP, with P Conclusion. We demonstrate that the degree of vasospasm and ischaemia provoked by stepwise cooling and recovery are positively associated with NCP in patients with RP of different aetiologies and without a history of digital ulcers.

AIM: The aim of the present study was to investigate whether skin autofluorescence would improve the Finnish Diabetes Risk Score (FINDRISC) in detecting undiagnosed diabetes in a large population-based cohort.METHODS: Included were participants from the Dutch LifeLines Cohort Study. Skin autofluorescence was assessed in an unselected subset of participants using the AGE Reader. After the exclusion of participants with previously diagnosed diabetes (n=1635), pregnant women (n=58) and those using corticosteroids (n=345), 79,248 subjects were eligible for analysis. Diabetes was defined as fasting plasma glucose ≥7.0mmol/L, non-fasting plasma glucose ≥11.1mmol/L or HbA1c ≥6.5% (48mmol/mol).RESULTS: Diabetes was detected in 1042 participants (aged 55±12 years; 54% male). Skin autofluorescence improved the area under the receiver operating characteristic (AUROC) curve of the FINDRISC model from 0.802 to 0.811 (P30%) in the intermediate (1% to CONCLUSION: Skin autofluorescence is a non-invasive tool that can be used to further improve the FINDRISC for diabetes detection. The new resultant model is especially useful for reclassifying people in the intermediate-risk categories, where additional blood glucose testing is needed to confirm the presence of diabetes.

Background and aims: Non-LDL dyslipidemia (NLD) confers cardiovascular risk, and prevalence rates appear to be high in elderly populations. Small cohorts have identified several lifestyle, anthropometric, and medical factors associated with NLD. We aimed to assess sex-and age-specific prevalence of NLD in a contemporary population cohort (n = 167 729), and to identify independent determinants of NLD, focusing on lifestyle, anthropometric, and medical factors.Methods: The prevalence of NLD was assessed per 10-year age intervals in adults without cardiovascular disease not using lipid-modifying drugs from the Dutch LifeLines cohort. NLD was defined as low HDL-cholesterol or high triglycerides or high remnant cholesterol as per guideline cut-off values. Multivariable regression was used to identify factors independently associated with NLD. Determinants included age, smoking, alcohol use, physical activity, diet, BMI, diabetes mellitus (DM), chronic kidney disease, and in women, menopausal state and oral contraceptive use.Results: NLD occurred in 15-19% of women and 13-30% of men in this cohort, with the highest prevalence of 30% in 35-55 year old men. In most age groups, the prevalence in women was lower than in men. Obesity (both sexes: Odds ratio (OR) 5.3, 95% confidence interval (95% CI) 5.0-5.7), current smoking (men: OR 1.8, 95% CI 1.7-1.9; women OR 2.2, 95% CI 2.1-2.3), and DM (men: OR 2.2, 95% CI 1.8-2.6; women: OR 2.7, 95% CI 2.3-3.1) were strongly associated with NLD.Conclusions: NLD already occurs frequently at an early age. Modifiable lifestyle choices, obesity, and DM were strong determinants of NLD. Public health efforts could substantially contribute to decrease NLD. (C) 2018 Elsevier B.V. All rights reserved.

Background Although the exact etiology of systemic sclerosis (SSc) remains unknown, a current hypothesis is that reactive species (including reactive oxygen species (ROS), reactive nitrogen species (RNS and reactive sulfur species (RSS)) play an important role in the pathogenesis. In addition, the chemical interactions between these molecules, also known as the reactive species interactome, may lead to the formation of more harmful free radicals, thus leading to more damage. We have previously shown a rapid free thiol increase in SSc patients during a cooling and recovery experiment, however the implications of RNS and RSS in this process remain uncharacterized. Objectives The aim of the current study was to explore nitric oxide and sulfate response, as a measure of the unified reactive species interactome, during hypothermia induced Raynaud’s attack in systemic sclerosis (SSc), primary Raynaud’s phenomenon (PRP) and healthy controls (HC). Methods Healthy controls (n=10), PRP patients (n=10) and SSc patients (n=10), all aged ≥18 years, were included. All SSc patients fulfilled the ACR/EULAR 2013 criteria. Fingertip photoelectric plethysmography was performed during a standardised cooling and recovery experiment. Patient characteristics were obtained and blood was drawn at four predetermined time points (T0, T1, T2 and T3). In addition to the previously mentioned free thiols, the following markers were also measured: nitros(yl)ated species, nitrite, nitrate, sulfate and the vascular leakage related molecules angiopoietin-1 and angiopoietin-2). Results Our results revealed a significantly longer median duration of hypoperfusion and longer recovery time in SSc patients compared to PRP patients and HC. This coincided with stable levels of angiopoietin-1/angiopoietin-2 throughout the experiment. In regards to the thiol modification related molecules, (nitrate, nitrite and RXNO) an increased median level of nitrate (T2: median 29.6 µmol, range 21.99–41.70 µmol, p=0.041) was found in SSc patients. Correspondingly, the same trend was observed for the median plasma concentrations of sulfate (p>0.05 at all time points). Conclusions We have previously shown an increase of free thiols in all patients during the reperfusion phase. This finding sheds new light on the possibility that processes related to oxidative thiol modification, are rapidly reversible. The current findings revealed also a trend in increased levels of nitrate and sulfate in SSc patients. Therefore, it is plausible that these markers of the redox system interact with one another through the same pathway, underlining the complexity of the redox interactome and suggesting potential novel approaches for therapeutic intervention. Disclosure of Interest None declared

AIM The United Kingdom Prospective Diabetes Study (UKPDS) study showed that glycaemic control (HbA1c ) can predict vascular complications in Type 2 diabetes mellitus. The Diabetes Control and Complications Trial (DCCT) study showed that accumulation of advanced glycation end products (AGEs) from skin biopsies predicts vascular complications in Type 1 diabetes. Previously, we showed that tissue AGEs can be measured non-invasively using skin autofluorescence (SAF). The aim of this study was to compare the predictive value of HbA1c and SAF for new macrovascular events and microvascular complications in people with Type 2 diabetes. METHODS A prospective cohort study of 563 participants, median age 64 years [interquartile range (IQR) 57-72], diabetes duration of 13 years, from five Dutch hospitals was performed. RESULTS After a median follow-up of 5.1 (IQR 4.3-5.9) years, 79 (15%) participants had died and 49 (9%) were lost to follow-up. Some 133 (26%) developed a microvascular complication and 189 (37%) a macrovascular event. Tertiles of HbA1c were significantly associated with development of microvascular complications (log rank P = 0.022), but not with macrovascular events. Tertiles of SAF were significantly associated with macrovascular events (log rank P = 0.003). Cox regression analysis showed SAF was associated with macrovascular events: crude hazard ratio (HR) 1.53 (P

Objective. The incidence of cardiovascular disease (CVD) is increased in RA. This study was designed to evaluate whether a reduction in disease activity influences early markers of CVD.Methods. In a prospective longitudinal study, 58 newly diagnosed RA patients and 58 age- and sex-matched healthy controls (HCs) were included. Endothelial dysfunction was measured by small artery elasticity (SAE) and endothelial cell activation was assessed by measuring soluble vascular cellular activation molecule 1(sVCAM-1) and von Willebrand factor (vWF). Advanced glycation end products (AGEs) were quantified by skin autofluorescence. After 1 year, measurements were repeated in all RA patients.Results. At entry, SAE was decreased in RA vs HCs [median 3.4 ml/mmHg100 (range 1.2-9.0) vs 6.1 (range 5.0-15.3), P Conclusion. Endothelial dysfunction is present in newly diagnosed RA patients, independently of traditional risk factors and is inversely correlated with disease activity. By reducing disease activity, endothelial dysfunction improves, although not to normal values. Also, a reduction in disease activity targeting traditional risk factors remains important in preventing CVD in RA.

Objective— Patients with peripheral artery disease are at risk for critical limb ischemia and amputation. Accumulation of advanced glycation end products is increased and predictive for coronary and cerebrovascular events in several high cardiovascular risk groups. We hypothesized that accumulation of tissue advanced glycation end products, measured by skin autofluorescence (SAF), predicts amputation in patients with peripheral artery disease. Approach and Results— Between October 2007 and June 2008, 252 patients with peripheral artery disease were included at the outpatient clinic. During a 5-year follow-up, 22 (9%) had an amputation because of critical limb ischemia. Competing risks regression analysis showed a subproportional hazard ratio of 3.05 (95% confidence interval [CI], 1.87–4.96); P P =0.004. In patients with Fontaine stage I and II only (n=215), SAF was the only predictor for amputation, subproportional hazard ratio 4.05 (95% CI, 2.09–7.83); P P =0.003. Conclusions— Skin autofluorescence, as a measure of tissue advanced glycation end products deposition, predicts amputation in patients with peripheral artery disease during a 5-year follow-up, independent from the presence of diabetes mellitus and Fontaine stage. Even at lower Fontaine stage (I or II), SAF is a strong predictor of amputation. The multiplication of Fontaine stage by SAF results in a good prediction model of amputation.