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1.  Skin Autofluorescence, a Non-Invasive Marker for AGE Accumulation, Is Associated with the Degree of Atherosclerosis 
PLoS ONE  2013;8(12):e83084.
Introduction
Advanced glycation endproducts (AGEs) may be involved in the development of atherosclerosis, beyond diabetes and renal disease. Skin autofluorescence (AF) is a non-invasive marker for AGEs. We examined whether skin AF is increased in (subclinical) atherosclerosis and associated with the degree of atherosclerosis independent of diabetes and renal function.
Methods
A cross-sectional study of 223 patients referred for primary (n = 163) or secondary (n = 60) prevention between 2006 and 2012 was performed. Skin AF was measured using the AGE-Reader. Ultrasonography was used to assess plaques in carotid and femoral arteries and computed tomography for the calculation of the coronary artery calcium score (CACS; in primary prevention only). Primary prevention patients were divided into a group with subclinical atherosclerosis defined as >1 plaque or CACS>100 (n = 67; age 53 year [interquartile range 48–56]; 49% male) and without (controls; 96; 43 [38–51]; 55%). Secondary prevention were patients with peripheral arterial disease (60; 64 [58–70]; 73%).
Results
Skin AF was higher in subclinical and clinical atherosclerosis compared with controls (skin AF 2.11 [interquartile range 1.83–2.46] and 2.71 [2.15–3.27] vs. 1.87 [1.68–2.12] respectively; P = 0.005 and <0.001). In a multivariate analysis, the association of skin AF with the atherosclerosis categories was independent of age, sex, diabetes, presence of the metabolic syndrome, Framingham Risk Score, and renal function. Skin AF correlated with most cardiovascular risk factors, Framingham risk score, and IMT and CACS.
Conclusions
Skin AF is increased in documented subclinical and clinical atherosclerosis, independent of known risk factors such as diabetes and renal disease. These data suggest that AGEs may be associated with the burden of atherosclerosis and warrant a prospective study to investigate its clinical usability as a risk assessment tool for primary prevention.
doi:10.1371/journal.pone.0083084
PMCID: PMC3871581  PMID: 24376641
2.  Which patient and treatment factors are related to successful cardiovascular risk score reduction in general practice? Results from a randomized controlled trial 
BMC Family Practice  2013;14:123.
Background
Cardiovascular disease is a leading cause of death. It is important to identify patient and treatment factors that are related to successful cardiovascular risk reduction in general practice. This study investigates which patient and treatment factors are related to changes in cardiovascular risk estimation, expressed as the Systematic Coronary Risk Evaluation (SCORE) 10 year risk of cardiovascular mortality.
Methods
179 general practice patients with mild-moderately elevated cardiovascular risk followed a one-year programme which included structured lifestyle and medication treatment by practice nurses, with or without additional self-monitoring. From the patient and treatment data collected as part of the “Self-monitoring and Prevention of RIsk factors by Nurse practitioners in the region of Groningen” randomized controlled trial (SPRING-RCT), the contribution of patient and treatment factors to the change in SCORE was analysed with univariate and multivariate analyses.
Results
In multivariate analyses with multiple patient and treatment factors, only SCORE at baseline, and addition of or dose change in lipid lowering or antihypertensive medications over the course of the study were significantly related to change in SCORE.
Conclusions
Our analyses support the targeting of treatment at individuals with a high SCORE at presentation. Lipid lowering medication was added or changed in only 12% of participants, but nevertheless was significantly related to ΔSCORE in this study population. Due to the effect of medication in this practice-based project, the possible additional effect of the home monitoring devices, especially for individuals with no indication for medication, may have been overshadowed.
Trial registration
trialregister.nl NTR2188
doi:10.1186/1471-2296-14-123
PMCID: PMC3765386  PMID: 23968366
Primary health care; Arteriosclerosis; Cardiovascular diseases; Prevention and control; Self-management; Risk factors
3.  Skin Autofluorescence Based Decision Tree in Detection of Impaired Glucose Tolerance and Diabetes 
PLoS ONE  2013;8(6):e65592.
Aim
Diabetes (DM) and impaired glucose tolerance (IGT) detection are conventionally based on glycemic criteria. Skin autofluorescence (SAF) is a noninvasive proxy of tissue accumulation of advanced glycation endproducts (AGE) which are considered to be a carrier of glycometabolic memory. We compared SAF and a SAF-based decision tree (SAF-DM) with fasting plasma glucose (FPG) and HbA1c, and additionally with the Finnish Diabetes Risk Score (FINDRISC) questionnaire±FPG for detection of oral glucose tolerance test (OGTT)- or HbA1c-defined IGT and diabetes in intermediate risk persons.
Methods
Participants had ≥1 metabolic syndrome criteria. They underwent an OGTT, HbA1c, SAF and FINDRISC, in adition to SAF-DM which includes SAF, age, BMI, and conditional questions on DM family history, antihypertensives, renal or cardiovascular disease events (CVE).
Results
218 persons, age 56 yr, 128M/90F, 97 with previous CVE, participated. With OGTT 28 had DM, 46 IGT, 41 impaired fasting glucose, 103 normal glucose tolerance. SAF alone revealed 23 false positives (FP), 34 false negatives (FN) (sensitivity (S) 68%; specificity (SP) 86%). With SAF-DM, FP were reduced to 18, FN to 16 (5 with DM) (S 82%; SP 89%). HbA1c scored 48 FP, 18 FN (S 80%; SP 75%). Using HbA1c-defined DM-IGT/suspicion ≥6%/42 mmol/mol, SAF-DM scored 33 FP, 24 FN (4 DM) (S76%; SP72%), FPG 29 FP, 41 FN (S71%; SP80%). FINDRISC≥10 points as detection of HbA1c-based diabetes/suspicion scored 79 FP, 23 FN (S 69%; SP 45%).
Conclusion
SAF-DM is superior to FPG and non-inferior to HbA1c to detect diabetes/IGT in intermediate-risk persons. SAF-DM’s value for diabetes/IGT screening is further supported by its established performance in predicting diabetic complications.
doi:10.1371/journal.pone.0065592
PMCID: PMC3672176  PMID: 23750268
4.  Cost-effectiveness of cardiovascular risk management by practice nurses in primary care 
BMC Public Health  2013;13:148.
Background
Cardiovascular disease (CVD) is largely preventable and prevention expenditures are relatively low. The randomised controlled SPRING-trial (SPRING-RCT) shows that cardiovascular risk management by practice nurses in general practice with and without self-monitoring both decreases cardiovascular risk, with no additional effect of self-monitoring. For considering future approaches of cardiovascular risk reduction, cost effectiveness analyses of regular care and additional self-monitoring are performed from a societal perspective on data from the SPRING-RCT.
Methods
Direct medical and productivity costs are analysed alongside the SPRING-RCT, studying 179 participants (men aged 50–75 years, women aged 55–75 years), with an elevated cardiovascular risk, in 20 general practices in the Netherlands. Standard cardiovascular treatment according to Dutch guidelines is compared with additional counselling based on self-monitoring at home (pedometer, weighing scale and/ or blood pressure device) both by trained practice nurses. Cost-effectiveness is evaluated for both treatment groups and patient categories (age, sex, education).
Results
Costs are €98 and €187 per percentage decrease in 10-year cardiovascular mortality estimation, for the control and intervention group respectively. In both groups lost productivity causes the majority of the costs. The incremental cost-effectiveness ratio is approximately €1100 (95% CI: -5157 to 6150). Self-monitoring may be cost effective for females and higher educated participants, however confidence intervals are wide.
Conclusions
In this study population, regular treatment is more cost effective than counselling based on self-monitoring, with the majority of costs caused by lost productivity.
Trial registration
Trialregister.nl identifier: http://NTR2188
doi:10.1186/1471-2458-13-148
PMCID: PMC3599815  PMID: 23418958
Cost-effectiveness; Arteriosclerosis; Cardiovascular diseases; Primary health care; Prevention and control; Self-management
5.  A gene-centric study of common carotid artery remodelling 
Atherosclerosis  2013;226(2):440-446.
Background
Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized.
Methods
Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA).
Results
rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling.
Conclusions
Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
Highlights
► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.
doi:10.1016/j.atherosclerosis.2012.11.002
PMCID: PMC3573227  PMID: 23246012
Abdominal aortic aneurysm; Genome-wide association studies; Vascular remodelling; Carotid artery
6.  Cardiovascular screening in general practice in a low SES area 
BMC Family Practice  2012;13:117.
Background
Lower social economic status (SES) is related to an elevated cardiovascular (CV) risk. A pro-active primary prevention CV screening approach in general practice (GP) might be effective in a region with a low mean SES. This approach, supported by a regional GP laboratory, was investigated on feasibility, attendance rate and proportion of persons identified with an elevated risk.
Methods
In a region with a low mean SES, men and women aged ≥50/55 years, respectively, were invited for cardiovascular risk profiling, based on SCORE 10-year risk of fatal cardiovascular disease and additional risk factors (family history, weight and end organ damage). Screening was performed by laboratory personnel, at the GP practice. Treatment advice was based on Dutch GP guidelines for cardiovascular risk management. Response rates were compared to those in five other practices, using the same screening method.
Results
521 persons received invitations, 354 (68%) were interested, 33 did not attend and 43 were not further analysed because of already known diabetes/cardiovascular disease. Eventually 278 risk profiles were analysed, of which 60% had a low cardiovascular risk (SCORE-risk <5%). From the 40% participants with a SCORE-risk ≥5%, 60% did not receive medication yet for hypertension/hypercholesterolemia. In the other five GPs response rates were comparable to the currently described GP.
Conclusion
Screening in GP in a low SES area, performed by a laboratory service, was feasible, resulted in high attendance, and identification and treatment advice of many new persons at risk for cardiovascular disease.
doi:10.1186/1471-2296-13-117
PMCID: PMC3564938  PMID: 23228012
General practice; Socio-economic status (SES); Cardiovascular risk management; Screening
7.  Randomized controlled trial on cardiovascular risk management by practice nurses supported by self-monitoring in primary care 
BMC Family Practice  2012;13:90.
Background
Treatment goals for cardiovascular risk management are generally not achieved. Specialized practice nurses are increasingly facilitating the work of general practitioners and self-monitoring devices have been developed as counseling aid. The aim of this study was to compare standard treatment supported by self-monitoring with standard treatment without self-monitoring, both conducted by practice nurses, on cardiovascular risk and separate risk factors.
Methods
Men aged 50–75 years and women aged 55–75 years without a history of cardiovascular disease or diabetes, but with a SCORE 10-year risk of cardiovascular mortality ≥5% and at least one treatable risk factor (smoking, hypertension, lack of physical activity or overweight), were randomized into two groups. The control group received standard treatment according to guidelines, the intervention group additionally received pro-active counseling and self-monitoring (pedometer, weighing scale and/ or blood pressure device). After one year treatment effect on 179 participants was analyzed.
Results
SCORE risk assessment decreased 1.6% (95% CI 1.0–2.2) for the control group and 1.8% (1.2–2.4) for the intervention group, difference between groups was .2% (−.6–1.1). Most risk factors tended to improve in both groups. The number of visits was higher and visits took more time in the intervention group (4.9 (SD2.2) vs. 2.6 (SD1.5) visits p < .001 and 27 (P25 –P75:20–33) vs. 23 (P25 –P75:19–30) minutes/visit p = .048).
Conclusions
In both groups cardiovascular risk decreased significantly after one year of treatment by practice nurses. No additional effect of basing the pro-active counseling on self-monitoring was found, despite the extra time investment.
Trial registration
trialregister.nl NTR2188
doi:10.1186/1471-2296-13-90
PMCID: PMC3503756  PMID: 22947269
Primary health care; Arteriosclerosis; Cardiovascular diseases; Prevention and control; Self-management; Risk factors
8.  Skin Autofluorescence: A Pronounced Marker of Mortality in Hemodialysis Patients 
Nephron Extra  2012;2(1):184-191.
Background
Accelerated formation and tissue accumulation of advanced glycation endproducts (AGEs), reflecting cumulative glycemic and oxidative stress, occur in age-related and chronic diseases like diabetes mellitus (DM) and renal failure, and contribute to vascular damage. Skin autofluorescence (AF), a noninvasive measurement method, reflects tissue accumulation of AGEs. The aim of our study was to determine the predictive value of skin AF on overall and cardiovascular mortality in hemodialysis patients.
Methods
Baseline skin AF was measured in 105 patients on hemodialysis, 23 had DM. Survival status was assessed after a mean follow-up period of 4.9 years (interquartile range 2.3–6.9 years).
Results
Multivariate Cox regression analysis showed skin AF (hazard ratio (HR) 1.83; 95% confidence interval (CI) 1.32–2.54), preexisting cardiovascular disease (CVD) (HR 2.77; 95% CI 1.48–5.18), renal replacement therapy duration (HR 1.10; 95% CI 1.01–1.19), age (HR 1.03; 95% CI 1.01–1.06), serum albumin (HR 0.90; 95% CI 0.85–0.95), hematocrit (HR 0.92; 95% CI 0.86–0.98), phosphorus (HR 2.01; 95% CI 1.15–3.49), and parathyroid hormone (HR 0.99; 95% CI 0.98–0.996) to be predictors of mortality, whereas DM was not. Preexisting CVD and serum phosphorus were the only predictors of cardiovascular mortality.
Conclusion
Skin AF showed to be an independent predictor of overall mortality in hemodialysis patients, but it had no predictive value for cardiovascular mortality.
doi:10.1159/000339282
PMCID: PMC3398816  PMID: 22811692
Autofluorescence; Diabetes mellitus; Hemodialysis; Mortality
9.  Elevated skin autofluorescence is strongly associated with foot ulcers in patients with diabetes: a cross-sectional, observational study of Chinese subjects 
Objective: This study was designed to evaluate the association between skin autofluorescence (AF), an indicator of advanced glycation end-products (AGEs), and foot ulcers in subjects with diabetes. Methods: In this study, 195 Chinese diabetic subjects were examined. Their feet were examined regardless of whether an ulcer was present or not. Skin AF was measured with an AGE reader. Demographic characteristics and blood data were recorded. Results: The mean values of skin AF were 2.29±0.47 for subjects without foot ulcers, and 2.80±0.69 for those with foot ulcers, a significant difference (P<0.05). Skin AF was strongly correlated with age and duration of diabetes. After adjusting for these factors, multivariate logistic regression showed that skin AF was independently associated with foot ulcerations. Conclusions: Skin AF is independently associated with diabetic foot ulcerations. It might be a useful screening method for foot ulceration risk of diabetic patients.
doi:10.1631/jzus.B1100249
PMCID: PMC3348228  PMID: 22556175
Advanced glycation end-products (AGEs); Diabetic foot ulcerations; Screening
10.  Advanced glycation endproducts are increased in rheumatoid arthritis patients with controlled disease 
Arthritis Research & Therapy  2011;13(6):R205.
Introduction
Advanced glycation end products (AGEs) are produced and can accumulate during chronic inflammation, as might be present in patients with rheumatoid arthritis (RA). AGEs are involved in the development of cardiovascular disease. The aim of this study is to evaluate whether AGEs are increased in patients with long-standing RA and whether AGE accumulation is related to disease activity, disease severity and measures of (premature) atherosclerosis, such as endothelial activation, endothelial dysfunction and intima media thickness (IMT).
Methods
In a cross-sectional study, 49 consecutive RA patients with longstanding disease (median disease duration of 12.3 years (range 9.3 to 15.1)), receiving standard of care, were included and compared with 49 age- and sex-matched healthy controls (HC). AGEs were determined by skin autofluorescence. Disease activity was evaluated by the Disease Activity Score of 28 joints (DAS-28) score and joint damage by modified Sharp-v.d. Heijde score. Endothelial activation (soluble vascular cellular adhesion molecule-1) sVCAM-1, von Willebrand factor (vWF), thrombomodulin), endothelial dysfunction (determined by small artery elasticity (SAE)) and IMT were measured and related to AGE accumulation.
Results
AGEs were increased in RA patients (median 2.4 arbitrary units (a.u.), range 1.6 to 4.2) compared to HC (2.2, 1.3 to 3.8). RA patients had a DAS-28 score of 2.9 (0.8 to 6.9) and a modified Sharp-v.d. Heijde score of 19 (0 to 103). sVCAM-1 and vWF levels were higher in RA patients. SAE was significantly decreased in RA (3.9 ml/mmHg (1.4 to 12.2) vs. 6.1 in HC (1.7 to 12.9). IMT did not differ between the two groups. Combining both groups' AGEs correlated with vWF, sVCAM-1 and IMT, and was inversely related to SAE. In RA, AGEs had an inverse relation with SAE, but did not relate to disease activity or radiological damage. In multivariate analysis for both groups, smoking, glucose levels, vWF, SAE and male gender were significantly related to the formation of AGEs.
Conclusions
AGEs were increased in RA patients with long-standing disease and without signs of premature atherosclerosis. AGEs were related to endothelial activation and endothelial dysfunction. This supports the hypothesis that in RA AGEs may be an early marker of cardiovascular disease.
doi:10.1186/ar3538
PMCID: PMC3334658  PMID: 22168993
rheumatoid arthritis; endothelial cell activation; endothelial dysfunction; intima media thickness; advanced glycation end products; atherosclerosis
11.  Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease 
Advanced glycation end products (AGEs) have a pivotal role in atherosclerosis. We evaluated skin autofluorescence (SAF), a non-invasive measurement of tissue AGE accumulation, in patients with carotid artery stenosis with and without coexisting peripheral artery occlusive disease (PAOD). SAF was measured using the AGE Reader™ in 56 patients with carotid artery stenosis and in 56 age- and sex-matched healthy controls without diabetes, renal dysfunction or known atherosclerotic disease. SAF was higher in patients with carotid artery stenosis compared to the control group: mean 2.81 versus 2.46 (P = 0.002), but especially in the younger age group of 50–60 years old: mean 2.82 versus 1.94 (P = 0.000). Patients with carotid artery stenosis and PAOD proved to have an even higher SAF than patients with carotid artery stenosis only: mean 3.28 versus 2.66 (P = 0.003). Backward linear regression analysis showed that age, smoking, diabetes mellitus, renal function and the presence of PAOD were the determinants of SAF, but carotid artery stenosis was not. SAF is increased in patients with carotid artery stenosis and PAOD. The univariate and multivariate associations of SAF with age, smoking, diabetes, renal insufficiency and PAOD suggest that increased SAF can be seen as an indicator of widespread atherosclerosis.
doi:10.1007/s10554-011-9805-6
PMCID: PMC3288376  PMID: 21336554
Carotid artery stenosis; Peripheral vascular disease; Advanced glycation end products; Skin autofluorescence
12.  Small artery elasticity is decreased in patients with systemic lupus erythematosus without increased intima media thickness 
Arthritis Research & Therapy  2010;12(5):R181.
Introduction
The objectives of this study were to determine small arterial elasticity (SAE) in systemic lupus erythematosus (SLE) and to investigate its relationship with intima media thickness (IMT), accumulation of advanced glycation end products (AGEs), endothelial activation and inflammation.
Methods
Thirty SLE patients with inactive disease and 30 age- and sex-matched healthy controls were included. Twenty patients with essential hypertension (EH) served as positive control. SAE was assessed by pulse-wave analysis using tonometric recordings of the radial artery. IMT of the carotid arteries was measured by ultrasound. AGE accumulation was assessed with an AGE-reader. Endothelial activation markers and C-reactive protein (CRP) were determined by enzyme-linked immunosorbent assay (ELISA).
Results
SAE was decreased in SLE (P = 0.01) and further decreased in EH (P < 0.01) compared to healthy controls. IMT was increased in EH (P < 0.05), but not in SLE. AGE accumulation was increased in SLE (P < 0.05) and further increased in EH (P < 0.01) compared to healthy controls. Endothelial activation markers and CRP were increased in SLE but not in EH. SAE related to AGE accumulation (r = -0.370, P < 0.05), CRP (r = -0.429, P < 0.05) and creatinine clearance (r = 0.440, P < 0.05), but not to IMT and endothelial activation markers. In multivariate analysis SLE was an independent predictor of SAE.
Conclusions
SAE is decreased in SLE patients without increased IMT, independently of traditional cardiovascular risk factors. Longitudinal studies are needed to investigate whether SAE, endothelial activation and AGE accumulation are early markers for cardiovascular disease in SLE.
doi:10.1186/ar3145
PMCID: PMC2991012  PMID: 20920173
13.  Life Expectancy in a Large Cohort of Type 2 Diabetes Patients Treated in Primary Care (ZODIAC-10) 
PLoS ONE  2009;4(8):e6817.
Background
Most longitudinal studies showed increased relative mortality in individuals with type 2 diabetes mellitus until now. As a result of major changes in treatment regimes over the past years, with more stringent goals for metabolic control and cardiovascular risk management, improvement of life expectancy should be expected. In our study, we aimed to assess present-day life expectancy of type 2 diabetes patients in an ongoing cohort study.
Methodology and Principal Findings
We included 973 primary care type 2 diabetes patients in a prospective cohort study, who were all participating in a shared care project in The Netherlands. Vital status was assessed from May 2001 till May 2007. Main outcome measurement was life expectancy assessed by transforming actual survival time to standardised survival time allowing adjustment for the baseline mortality rate of the general population. At baseline, mean age was 66 years, mean HbA1c 7.0%. During a median follow-up of 5.4 years, 165 patients died (78 from cardiovascular causes), and 17 patients were lost to follow-up. There were no differences in life expectancy in subjects with type 2 diabetes compared to life expectancy in the general population. In multivariate Cox regression analyses, concentrating on the endpoints ‘all-cause’ and cardiovascular mortality, a history of cardiovascular disease: hazard ratio (HR) 1.71 (95% confidence interval (CI) 1.23–2.37), and HR 2.59 (95% CI 1.56–4.28); and albuminuria: HR 1.72 (95% CI 1.26–2.35), and HR 1.83 (95% CI 1.17–2.89), respectively, were significant predictors, whereas smoking, HbA1c, systolic blood pressure and diabetes duration were not.
Conclusions
This study shows a normal life expectancy in a cohort of subjects with type 2 diabetes patients in primary care when compared to the general population. A history of cardiovascular disease and albuminuria, however, increased the risk of a reduction of life expectancy. These results show that, in a shared care environment, a normal life expectancy is achievable in type 2 diabetes patients.
doi:10.1371/journal.pone.0006817
PMCID: PMC2729379  PMID: 19714245
14.  Skin Advanced Glycation End Product Accumulation Is Poorly Reflected by Glycemic Control in Type 2 Diabetic Patients (ZODIAC-9) 
Background
Glycemic memory can be reflected by tissue accumulation of advanced glycation end products (AGEs). In type 1 diabetes mellitus (T1DM) patients, hemoglobin A1c (HbA1c) levels over various time periods poorly predicted the accumulation of different AGEs in skin biopsies. Our aim was to investigate whether HbA1c assessments can predict the change in skin AGEs during time in type 2 diabetes mellitus (T2DM).
Methods
We included 452 T2DM patients participating in a shared-care setting, who are screened annually for HbA1c and diabetic complications. Baseline and follow-up levels of skin AGEs were assessed with a validated noninvasive autofluorescence (AF) method, which is based on the fluorescence characteristics of certain AGEs.
Results
Our study population had a mean age of 65 years and 54% were female. After a mean follow-up duration of 3.3 years, linear regression analyses showed weak relationships among different assessments of HbA1c (baseline, maximum, mean, and variance of HbA1c) and skin AF at follow-up. Baseline skin AF and age were predictors of skin AF at follow-up, but diabetes duration, smoking, and creatinine were of less or no predictive value for skin AF at follow-up.
Conclusions
In our T2DM population, integrated HbA1c assessments over years poorly predict the change in skin AGE level measured by skin AF. These findings agree with results in patients with T1DM. This suggests either the need for longer exposure to glucose disturbances to change tissue AGEs or other mechanisms, such as oxidative stress, leading to AGE accumulation.
PMCID: PMC2769771  PMID: 19885232
advanced glycosylation end products; fluorescence; hemoglobin A1c; type 2 diabetes mellitus; ZODIAC-9
15.  No effects of bosentan on microvasculature in patients with limited cutaneous systemic sclerosis 
Clinical Rheumatology  2009;28(7):825-833.
The endothelium-derived vasoconstrictor molecule endothelin-1 (ET-1) has been suggested to play a role in the pathogenesis of Raynaud’s phenomenon (RP) and systemic sclerosis (SSc). We studied the effect of bosentan on microvascular structure and function in patients with RP secondary to limited cutaneous SSc in a mechanistic pilot study. In this single center, open study, 15 patients with limited cutaneous SSc were treated with bosentan for 16 weeks with a follow-up period of 4 weeks. Changes in microvascular structure and function were studied with assessment of vasodilatory microvascular responses using laser Doppler fluxmetry combined with iontophoresis, capillary permeability using fluorescence videomicroscopy, nailfold capillary microscopy, and serological markers of endothelial activation. No significant changes were seen in vasodilator responses to acetylcholine and sodium nitroprusside following bosentan treatment. No effect was noted on capillary permeability during treatment. The number of nailfold capillaries remained unchanged. The endothelial activation marker vascular cell adhesion molecule did not change during treatment, but levels of thrombomodulin significantly decreased after 12 weeks of treatment. Bosentan did not induce significant changes in vasodilator responses, capillary permeability, and capillary density during treatment, so no evidence was obtained for structural improvement of microvascular structure and function in this short-time mechanistic pilot study in patients with lcSSc.
doi:10.1007/s10067-009-1157-4
PMCID: PMC2686804  PMID: 19350343
Bosentan; Endothelial cell dysfunction; Raynaud’s phenomenon; Systemic sclerosis
16.  The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes 
Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs.
doi:10.1186/1475-2840-7-29
PMCID: PMC2569910  PMID: 18840258
17.  Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors 
Introduction
Several systemic autoimmune diseases are associated with an increased prevalence of atherosclerosis which could not be explained by traditional risk factors alone. In systemic sclerosis (SSc), microvascular abnormalities are well recognized. Previous studies have suggested an increased prevalence of macrovascular disease as well. We compared patients with SSc to healthy controls for signs of early atherosclerosis by measuring intima-media thickness (IMT) of the common carotid artery in relation to traditional risk factors and markers of endothelial activation.
Methods
Forty-nine patients with SSc, of whom 92% had limited cutaneous SSc, and 32 healthy controls were studied. Common carotid IMT was measured by using B-mode ultrasound. Traditional risk factors for cardiovascular disease were assessed and serum markers for endothelial activation were measured.
Results
In patients with SSc, the mean IMT (median 0.69 mm, interquartile range [IQR] 0.62 to 0.79 mm) was not significantly increased compared with healthy controls (0.68 mm, IQR 0.56 to 0.75 mm; P = 0.067). Also, after correction for the confounders age, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein cholesterol (P = 0.328) or using a different model taking into account the confounders age, HDL cholesterol, and history of macrovascular disease (P = 0.474), no difference in IMT was present between SSc patients and healthy controls. Plaques were found in three patients and not in healthy controls (P = 0.274). In patients, no correlations were found between maximum IMT, disease-related variables, and markers of endothelial activation. Endothelial activation markers were not increased in SSc patients compared with controls.
Conclusion
SSc is not associated with an increased prevalence of early signs of atherosclerosis.
doi:10.1186/ar2408
PMCID: PMC2453769  PMID: 18439295
18.  The Effect of Aggressive Versus Conventional Lipid-lowering Therapy on Markers of Inflammatory and Oxidative Stress 
Purpose
Recent trial results are in favor of aggressive lipid lowering using high dose statins in patients needing secondary prevention. It is unclear whether these effects are solely due to more extensive lipid lowering or the result of the potentially anti-inflammatory properties of statins. We aimed to determine whether aggressive compared with conventional statin therapy is more effective in reducing systemic markers of inflammation and oxidative stress.
Materials and methods
This was a multi-centre, double-blind, placebo-controlled trial. Patients with previous cardiovascular disease, who did not achieve low density lipoprotein (LDL) cholesterol levels <2.6 mmol/l on conventional statin therapy (simvastatin 40 mg) were randomized to continue with simvastatin 40 mg or to receive atorvastatin 40 mg for 8 weeks and thereafter atorvastatin 80 mg for the final 8 weeks (aggressive treatment). Lipids, C-reactive protein, soluble cellular adhesion molecules, neopterin, von Willebrand Factor, and antibodies against oxidized LDL were measured at baseline and after 16 weeks.
Results
Lipid levels decreased significantly in the aggressive treatment group (LDL-C reduction 20.8%; P < 0.001), whereas a slight increase was observed in the conventional group (LDL-C increase 3.7%; P = 0.037). A significant reduction in antibodies against oxidized LDL was seen in the aggressive (13.4%; P < 0.001) and the conventional (26.8%; P < 0.001) group, but there was no difference between groups (P = 0.25). Furthermore, no significant differences in change in other biomarkers was observed between both groups.
Conclusions
This study does not support the hypothesis that a more profound reduction in inflammatory and oxidative stress contributes to the benefits of aggressive statin therapy.
doi:10.1007/s10557-007-6010-x
PMCID: PMC1914252  PMID: 17342417
hydroxymethylglutaryl-CoA reductase inhibitors; atorvastatin; simvastatin; arteriosclerosis; C-reactive protein; neopterin; von Willebrand Factor; oxidized low density lipoprotein; soluble cellular adhesion molecules; inflammation

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