Publications by authors named "Coen D A Stehouwer"

586 Publications

High vitamin K status is prospectively associated with decreased left ventricular mass in women: the Hoorn Study.

Nutr J 2021 Oct 19;20(1):85. Epub 2021 Oct 19.

Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC-location VUmc, Amsterdam, The Netherlands.

Background: Vitamin K is associated with reduced cardiovascular disease risk such as heart failure, possibly by carboxylation of matrix-gla protein (MGP), a potent inhibitor of vascular calcification. The relationship of vitamin K intake or status with cardiac structure and function is largely unknown. Therefore this study aims to investigate the prospective association of vitamin K status and intake with echocardiographic measures.

Methods: This study included 427 participants from the Hoorn Study, a population-based cohort. Vitamin K status was assessed at baseline by plasma desphospho-uncarboxylated MGP (dp-ucMGP) with higher concentrations reflecting lower vitamin K status. Vitamin K intake was assessed at baseline with a validated food-frequency questionnaire. Echocardiography was performed at baseline and after a mean follow-up time of 7.6, SD=±0.7 years. We used linear regression for the association of vitamin K status and intake with left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and left ventricular mass index (LVMI), adjusted for potential confounders.

Results: The mean age was 66.8, SD=±6.1 years (51% were male). A high vitamin K status was prospectively associated with decreased LVMI (change from baseline to follow-up: -5.0, 95% CI: -10.5;0.4 g/m) for the highest quartile compared to the lowest in women (P-interaction sex=0.07). No association was found in men. Vitamin K status was not associated with LVEF or LAVI. Vitamin K intake was not associated with any of the echocardiographic measures.

Conclusions: This study showed a high vitamin K status being associated with decreased LVMI only in women, while intakes of vitamin K were not associated with any cardiac structure or function measures. These results extend previous findings for a role of vitamin K status to decrease heart failure risk.
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http://dx.doi.org/10.1186/s12937-021-00742-0DOI Listing
October 2021

Retinal Microvascular Calibers and Incident Depressive Symptoms: The Multi-Ethnic Study of Atherosclerosis.

Am J Epidemiol 2021 Oct 15. Epub 2021 Oct 15.

Department of Internal Medicine, School for Cardiovascular Diseases CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.

Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. The retina allows for visualisation of a microvascular bed that shares similarities with the cerebral microvasculature. We investigated the association between baseline retinal arteriolar and venular calibers (CRAE and CRVE) and incident depressive symptoms in the Multi-Ethnic Study of Atherosclerosis (MESA). We used longitudinal data of 4,366 participants (63.2 years/48.5% women/28.4% black) without baseline depressive symptoms. Depressive symptoms, defined as Center for Epidemiological Studies Depression Scale score ≥16 and/or antidepressant medication use, were determined between 2002-2004 (baseline, MESA visit 2) and at three follow-up examinations every 1.5-2 years thereafter. Fundus photography was performed at baseline. After a mean follow-up of 6.1 years, 21.9% (n=958) had incident depressive symptoms. After adjustment for socio-demographic, lifestyle and cardiovascular factors, one standard deviation (SD) larger baseline CRVE was associated with a higher risk of depressive symptoms (hazard ratio:1.10; 95% confidence interval:1.02,1.17), and one SD larger baseline CRAE was not statistically significantly associated with incident depressive symptoms (1.04;0.97,1.11). In conclusion, larger baseline CRVE, but not CRAE, is associated with a higher incidence of depressive symptoms.
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http://dx.doi.org/10.1093/aje/kwab255DOI Listing
October 2021

Higher habitual intake of dietary dicarbonyls is associated with higher corresponding plasma dicarbonyl concentrations and skin autofluorescence: The Maastricht Study.

Am J Clin Nutr 2021 Oct 8. Epub 2021 Oct 8.

Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation endproducts (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously, but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.

Objective: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.

Design: In 2566 individuals of the population based Maastricht Study (age: 60±8 yrs, 50% males, 26% type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), by combining Food Frequency Questionnaires with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in >200 commonly-consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by UPLC-MS/MS. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE-Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardio-metabolic risk factors and lifestyle.

Results: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/day, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (β = 0.08, 95%CI [0.02,0.13]) and SAF (β = 0.12 [0.07,0.17]). Dietary GO was associated with plasma GO (β = 0.10 [0.04,0.16]) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.

Conclusions: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined.Clinical Trial Registry number: The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).
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http://dx.doi.org/10.1093/ajcn/nqab329DOI Listing
October 2021

Association of Type 2 Diabetes, According to the Number of Risk Factors Within Target Range, With Structural Brain Abnormalities, Cognitive Performance, and Risk of Dementia.

Diabetes Care 2021 Nov 29;44(11):2493-2502. Epub 2021 Sep 29.

Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands

Objective: Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes.

Research Design And Methods: Prospective data were from UK Biobank of 87,856 individuals ( = 10,663 diabetes, = 77,193 control subjects; baseline 2006-2010), with dementia follow-up until February 2018. Individuals with diabetes were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking; guideline-recommended levels of glycated hemoglobin, blood pressure, BMI, albuminuria, physical activity, and diet). Outcomes were incident dementia, domain-specific cognitive performance, white matter hyperintensities, and total brain volume.

Results: After a mean follow-up of 9.0 years, 147 individuals (1.4%) with diabetes and 412 control subjects (0.5%) had incident dementia. Among individuals with diabetes, excess dementia risk decreased stepwise for a higher number of risk factors on target. Compared with control subjects (incidence rate per 1,000 person-years 0.62 [95% CI 0.56; 0.68]), individuals with diabetes who had five to seven risk factors on target had no significant excess dementia risk (absolute rate difference per 1,000 person-years 0.20 [-0.11; 0.52]; hazard ratio 1.32 [0.89; 1.95]). Similarly, differences in processing speed, executive function, and brain volumes were progressively smaller for a higher number of risk factors on target. These results were replicated in the Maastricht Study.

Conclusions: Among individuals with diabetes, excess dementia risk, lower cognitive performance, and brain abnormalities decreased stepwise for a higher number of risk factors on target.
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http://dx.doi.org/10.2337/dc21-0149DOI Listing
November 2021

Habitual intake of dietary advanced glycation end products is not associated with generalized microvascular function-the Maastricht Study.

Am J Clin Nutr 2021 Sep 28. Epub 2021 Sep 28.

Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands.

Background: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat.

Objectives: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort.

Methods: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors.

Results: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned.

Conclusions: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.
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http://dx.doi.org/10.1093/ajcn/nqab302DOI Listing
September 2021

Causal relationship between polycystic ovary syndrome and coronary artery disease: A Mendelian randomisation study.

Clin Endocrinol (Oxf) 2021 Sep 15. Epub 2021 Sep 15.

Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.

Objective: Polycystic ovary syndrome (PCOS) has been associated with an increased risk of coronary artery disease (CAD). However, it remains uncertain whether this increased risk is the result of PCOS per se or, alternatively, is explained by obesity, a common feature of PCOS. The aim of this study was to assess the causal association between PCOS and CAD and the role of obesity herein.

Design And Methods: We conducted two-sample Mendelian randomisation analyses in large-scale, female-specific datasets to study the association between genetically predicted (1) risk of PCOS and risk of CAD, (2) body mass index (BMI) and risk of PCOS and (3) BMI and risk of CAD. Primary analyses were conducted with the inverse-variance weighted (IVW) method. Simple median, penalized weighted median and contamination mixture analyses were performed to assess the robustness of the outcomes.

Results: IVW analyses did not show a statistically significant association between PCOS and CAD (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.89, 1.11). In contrast, genetically predicted BMI was statistically significantly associated with an increased odds of PCOS (OR: 3.21, 95% CI: 2.26, 4.56) and CAD (OR: 1.38, 95% CI: 1.14, 1.67). Similar results were obtained when secondary analyses were performed.

Conclusion: These sex-specific analyses show that the genetically predicted risk of PCOS is not associated with the risk of CAD. Instead, the genetically predicted risk of obesity (and its downstream metabolic effects) is the common denominator of both PCOS and CAD risk.
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http://dx.doi.org/10.1111/cen.14593DOI Listing
September 2021

The role of serum and dietary advanced glycation endproducts in relation to cardiac function and structure: The Hoorn Study.

Nutr Metab Cardiovasc Dis 2021 Jul 27. Epub 2021 Jul 27.

Department of Epidemiology & Data Science, Amsterdam UMC-location VUmc, Amsterdam Cardiovascular Sciences Research Institute, Amsterdam, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

Background And Aims: This study aims to investigate the relationship of serum and dietary advanced glycation endproducts (AGEs) with cardiac function and structure after eight years of follow-up.

Methods And Results: We included 370 Hoorn Study participants (aged 66.4 ± 6.1, 47% women). Serum protein-bound AGEs [N-(carboxymethyl)lysine, N-(carboxyethyl)lysine, and pentosidine], as well as echocardiography to assess left atrium volume index (LAVI), left ventricle ejection fraction (LVEF), and left ventricle mass index (LVMI), were measured at baseline and after 8 years of follow-up. Dietary AGEs [N-(carboxymethyl)lysine and N-(carboxyethyl)lysine] were estimated at baseline with a validated food-frequency questionnaire and an AGEs database. Increased pentosidine [-1.4% (-2.6;-0.2)] and overall serum AGEs Z-scores over time [-2.1% (-3.8;-0.5)] were associated with decreased LVEF at follow-up, adjusted for confounders. Glucose metabolism status was an effect modifier (P-for-interaction = 0.04). In participants with impaired glucose metabolism, but not type 2 diabetes, increased pentosidine was associated with decreased LVEF [-4.2 (-8.0;-0.3)%]. Higher dietary N-(carboxyethyl)lysine [1.9 (0.1; 3.7)%] and overall dietary AGEs Z-scores [2.1 (0.1; 4.2)%] were associated with higher LVEF at follow-up. However, prior cardiovascular disease (CVD) was an effect modifier (P = 0.02). We found a stronger, non-significant, association of higher dietary (carboxyethyl)lysine with higher LVEF at follow-up in participants without CVD [2.3 (-0.1; 4.7)%] compared to participants with CVD [0.6 (-2.1; 3.4)%].

Conclusion: Overall serum AGEs were longitudinally associated with impaired systolic function. Future research should focus on including changes in dietary AGEs intake over time and the relation of dietary AGEs with cardiac measures needs to be established in intervention studies using low AGEs diets.
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http://dx.doi.org/10.1016/j.numecd.2021.07.020DOI Listing
July 2021

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 09 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 2021

Relationship between Central Obesity and the incidence of Cognitive Impairment and Dementia from Cohort Studies Involving 5,060,687 Participants.

Neurosci Biobehav Rev 2021 11 28;130:301-313. Epub 2021 Aug 28.

Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands.

Central obesity, measured by the waist circumference (WC) or waist-to-hip ratio, has been linked with metabolic dysfunction and structural abnormalities in the brain, two risk factors for cognitive impairment and dementia. The current analysis was performed to understand the influence of central obesity on the incidence of cognitive impairment and dementia. It included 21 studies involving 5,060,687 participants and showed that a high WC was associated with a greater risk of cognitive impairment and dementia (HR = 1.10, 95 % CI: 1.05-1.15), compared with a low WC. Sub-group analysis showed that a high WC increased the likelihood of developing cognitive impairment and dementia in individuals older than 65 years of age (HR = 1.13, 95 % CI: 1.08-1.19), whereas no association was observed in individuals younger than 65 years of age (HR = 1.04, 95 % CI: 0.93-1.16). Furthermore, dose-response meta-analysis confirmed that a high WC was a risk factor for cognitive impairment and dementia. In conclusion, central obesity, as measured by WC, was associated with a risk of cognitive impairment and dementia.
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http://dx.doi.org/10.1016/j.neubiorev.2021.08.028DOI Listing
November 2021

Associations of the Lifestyle for Brain Health Index With Structural Brain Changes and Cognition: Results From the Maastricht Study.

Neurology 2021 Sep 25;97(13):e1300-e1312. Epub 2021 Aug 25.

From the School for Mental Health and Neuroscience (I.S.H., K.D., M.T.S., J.F.A.J., F.R.J.V., M.P.J.v.B., S.K.), Department of Psychiatry and Neuropsychology (I.S.H., K.D., F.R.J.V., M.P.J.v.B., S.K.), School for Cardiovascular Diseases (M.T.S., C.D.A.S., P.C.D., C.J.H.v.d.K., S.J.P.M.E.), Care and Public Health Research Institute (A.K.), Department of Social Medicine (A.K.), and Department of Epidemiology (S.J.P.M.E.), Maastricht University; and Heart and Vascular Center (M.T.S.), Department of Internal Medicine (M.T.S., C.D.A.S., P.C.D., C.J.H.v.d.K.), and Department of Radiology (J.F.A.J.), Maastricht University Medical Center+, the Netherlands.

Background And Objectives: Observational research has shown that a substantial proportion of all dementia cases worldwide are attributable to modifiable risk factors. Dementia risk scores might be useful to identify high-risk individuals and monitor treatment adherence. The objective of this study was to investigate whether a dementia risk score, the Lifestyle for Brain Health (LIBRA) index, is associated with MRI markers and cognitive functioning/impairment in the general population.

Methods: Cross-sectional data were used from the observational population-based cohort of The Maastricht Study. The weighted compound score of LIBRA (including 12 dementia risk and protective factors, e.g., hypertension, physical inactivity) was calculated, with higher scores indicating higher dementia risk. Standardized volumes of white matter, gray matter, and CSF (as proxy for general brain atrophy), white matter hyperintensities, and presence of cerebral small vessel disease were derived from 3T MRI. Cognitive functioning was tested in 3 domains: memory, information processing speed, and executive function and attention. Values ≤1.5 SDs below the average were defined as cognitive impairment. Multiple regression analyses and structural equation modeling were used, adjusted for age, sex, education, intracranial volume, and type 2 diabetes.

Results: Participants (n = 4,164; mean age 59 years; 49.7% men) with higher LIBRA scores (mean 1.19, range -2.7 to 9.2), denoting higher dementia risk, had higher volumes of white matter hyperintensities (β = 0.051, = 0.002) and lower scores on information processing speed (β = -0.067, = 0.001) and executive function and attention (β = -0.065, = 0.004). Only in men, associations between LIBRA score and volumes of gray matter (β = -0.093, < 0.001) and CSF (β = 0.104, < 0.001) and memory (β = -0.054, = 0.026) were found. White matter hyperintensities and CSF volume partly mediated the association between LIBRA score and cognition.

Discussion: Higher health- and lifestyle-based dementia risk is associated with markers of general brain atrophy, cerebrovascular pathology, and worse cognition, suggesting that LIBRA meaningfully summarizes individual lifestyle-related brain health. Improving LIBRA factors on an individual level might improve population brain health. Sex differences in lifestyle-related pathology and cognition need to be further explored.

Classification Of Evidence: This study provides Class II evidence that higher LIBRA scores are significantly associated with lower scores in some cognitive domains and a higher risk of cognitive impairment.
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http://dx.doi.org/10.1212/WNL.0000000000012572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480401PMC
September 2021

Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study.

Diabetologia 2021 Nov 19;64(11):2445-2457. Epub 2021 Aug 19.

MHeNs School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.

Aims/hypothesis: Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes.

Methods: Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders.

Results: Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism.

Conclusions/interpretation: Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies.
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http://dx.doi.org/10.1007/s00125-021-05521-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494700PMC
November 2021

Sleep Apnea is Associated With Accelerated Vascular Aging: Results From 2 European Community-Based Cohort Studies.

J Am Heart Assoc 2021 08 26;10(15):e021318. Epub 2021 Jul 26.

INSERM UMR 970 Integrative Epidemiology of Cardiovascular Diseases University of Paris Paris France.

Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community-based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima-media thickness, Young's elastic modulus, carotid-femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid-femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5±6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9±8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima-media thickness (β=0.21; 0.17-0.26), Young's elastic modulus (β=0.21; 0.17-0.25), carotid-femoral pulse wave velocity (β=0.24; 0.14-0.34), carotid pulse wave velocity (β=0.31; 0.26-0.35), and carotid diameter (β=0.43; 0.38-0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.
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http://dx.doi.org/10.1161/JAHA.120.021318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475690PMC
August 2021

The relationships of sex hormone-binding globulin, total testosterone, androstenedione and free testosterone with metabolic and reproductive features of polycystic ovary syndrome.

Endocrinol Diabetes Metab 2021 Jul 24;4(3):e00267. Epub 2021 May 24.

Division of Endocrinology and Metabolic Diseases Department of Internal Medicine Maastricht University Medical Centre Maastricht The Netherlands.

Objective: A recent Mendelian randomization study has suggested a causal role for sex hormone-binding globulin (SHBG), total testosterone and free testosterone in the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to assess the relationships of SHBG, androstenedione, total and free testosterone with the individual metabolic and reproductive features of PCOS.

Design: Cross-sectional data in PCOS patients (n=96) prospectively collected in a secondary/tertiary clinic for menstrual cycle disorders.

Methods: Multivariable regression analyses were conducted to study the associations between SHBG, androstenedione, total and free testosterone with metabolic (BMI, waist circumference, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and homeostatic model assessment for insulin resistance [HOMA2-IR]) and reproductive features (menstrual cycle length, antral follicle count, anti-Müllerian hormone, luteinizing hormone, follicle-stimulating hormone and Ferriman-Gallwey score) of PCOS.

Results: Serum SHBG and free testosterone, but not total testosterone or androstenedione, were significantly associated with BMI, waist circumference, serum triglycerides, HDL cholesterol, LDL cholesterol and HOMA2-IR. The strength of the associations with serum lipids was reduced after adjustment for BMI, but not for HOMA2-IR. Total testosterone was significantly associated with antral follicle count. SHBG, total testosterone and androstenedione were significantly associated with serum AMH. Only the strength of the association for SHBG was reduced after adjustment for BMI.

Conclusions: Serum SHBG is associated with primarily metabolic features, whereas total testosterone and androstenedione are associated with reproductive features of PCOS. These results suggest a differential underlying pathophysiology for the metabolic and reproductive features of PCOS.
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http://dx.doi.org/10.1002/edm2.267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279613PMC
July 2021

Quantification of the B6 vitamers in human plasma and urine in a study with pyridoxamine as an oral supplement; pyridoxamine as an alternative for pyridoxine.

Clin Nutr 2021 07 10;40(7):4624-4632. Epub 2021 Jun 10.

Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht, the Netherlands. Electronic address:

Background And Aims: Vitamin B6 is involved in a large spectrum of physiological processes and comprises of the vitamers pyridoxamine (PM), pyridoxal (PL), pyridoxine (PN), and their phosphorylated derivatives including the biological active pyridoxal 5'-phosphate (PLP). While PN toxicity is known to complicate several treatments, PM has shown promise in relation to the treatment of metabolic and age-related diseases by blocking oxidative degradation and scavenging toxic dicarbonyl compounds and reactive oxygen species. We aimed to assess the metabolization of oral PM supplements in a single and three daily dose.

Materials And Methods: We optimized and validated a method for the quantification of the B6 vitamers in plasma and urine using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Five healthy volunteers were recruited to study PM metabolization after a single oral dose of 200 mg PM or a three daily dose of 67 mg PM. A third protocol was implemented as control for dietary intake. Venous blood samples, 24 h urine and fasted second void urine samples were collected.

Results: After a single oral dose of 200 mg PM, plasma PM increased in the first 3 h to a maximum of 2324 ± 266 nmol/L. While plasma PM levels returned to baseline after ~10 h of PM intake, PLP increased to a maximum of 2787 ± 329 nmol/L and reached a plateau. We found a small increase of PN to a maximum of 13.5 ± 2.1 nmol/L; it was nearly undetectable after ~12 h. With a three daily dose of 67 mg PM we observed an increase and decline of plasma PM, PL, and PN concentrations after each PM intake. PLP showed a similar increase as in the single dose protocol and accumulated over time.

Conclusion: In this study we showed high plasma levels of PM after oral PM supplementation. We found steadily increasing levels of the biologically active PLP, with minimal formation of PN. The B6 vitamer PM is an interesting supplement as an inhibitor of harmful processes in metabolic diseases and for the treatment of vitamin B6 deficiency.

Clinical Trial Registry: The study was approved by the Medical Ethics Committee of Maastricht University (NL) and was registered at ClinicalTrials.gov as NCT02954588.
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http://dx.doi.org/10.1016/j.clnu.2021.05.028DOI Listing
July 2021

Low-grade inflammation and endothelial dysfunction predict four-year risk and course of depressive symptoms: The Maastricht study.

Brain Behav Immun 2021 10 26;97:61-67. Epub 2021 Jun 26.

MHeNs School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands; CARIM Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Heart and Vascular Center, Maastricht University Medical Center+, Maastricht, the Netherlands. Electronic address:

Background: Low-grade inflammation (LGI) and endothelial dysfunction (ED) might play a key role in the development of depression. We investigated the associations and mediation of LGI and ED with four-year incidence and course of depressive symptoms (remitted, recurrent or persistent).

Design, Setting, Participants, Measurements: In this prospective cohort study (mean age 59.6 ± 8.2 years, 48.9% women, 26.6% diabetes by design), Cox and multinomial regression analyses, adjusted for age, sex, educational level and diabetes status were used to investigate the associations of LGI and ED with onset and course of depressive symptoms as assessed by the PHQ-9 questionnaire.

Results: During 10,847 person-years of follow-up, 264 participants developed incident depression. Higher levels of LGI (OR [95%CI] per SD 1.32[1.16-1.49], p < 0.001) and ED (1.26[1.11-1.43], p < 0.001) were associated with incident depressive symptoms. In mediation analysis, 60% of the total effect of ED with incident depressive symptoms could be attributed to LGI. 76 out of 2637 participants had a persistent course of depressive symptoms. Higher levels of LGI (1.75[1.40-2.19], p < 0.001) and ED (1.33[1.04-1.71], p = 0.021) were associated with a persistent course of depressive symptoms. Higher ED was more strongly associated with persistent depressive symptoms (1.33[1.04-1.71], p = 0.021), while LGI was associated with remission of depression symptoms.

Conclusions: LGI and ED were both associated with incident depressive symptoms, where the latter association was substantially mediated by LGI. ED was further associated with a persistent course of depressive symptoms, while LGI was not. These results suggest a temporal, vascular contribution of both LGI and ED to the etiology and chronicity of depressive symptoms.
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http://dx.doi.org/10.1016/j.bbi.2021.06.013DOI Listing
October 2021

Machine learning-based glucose prediction with use of continuous glucose and physical activity monitoring data: The Maastricht Study.

PLoS One 2021 24;16(6):e0253125. Epub 2021 Jun 24.

CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.

Background: Closed-loop insulin delivery systems, which integrate continuous glucose monitoring (CGM) and algorithms that continuously guide insulin dosing, have been shown to improve glycaemic control. The ability to predict future glucose values can further optimize such devices. In this study, we used machine learning to train models in predicting future glucose levels based on prior CGM and accelerometry data.

Methods: We used data from The Maastricht Study, an observational population-based cohort that comprises individuals with normal glucose metabolism, prediabetes, or type 2 diabetes. We included individuals who underwent >48h of CGM (n = 851), most of whom (n = 540) simultaneously wore an accelerometer to assess physical activity. A random subset of individuals was used to train models in predicting glucose levels at 15- and 60-minute intervals based on either CGM data or both CGM and accelerometer data. In the remaining individuals, model performance was evaluated with root-mean-square error (RMSE), Spearman's correlation coefficient (rho) and surveillance error grid. For a proof-of-concept translation, CGM-based prediction models were optimized and validated with the use of data from individuals with type 1 diabetes (OhioT1DM Dataset, n = 6).

Results: Models trained with CGM data were able to accurately predict glucose values at 15 (RMSE: 0.19mmol/L; rho: 0.96) and 60 minutes (RMSE: 0.59mmol/L, rho: 0.72). Model performance was comparable in individuals with type 2 diabetes. Incorporation of accelerometer data only slightly improved prediction. The error grid results indicated that model predictions were clinically safe (15 min: >99%, 60 min >98%). Our prediction models translated well to individuals with type 1 diabetes, which is reflected by high accuracy (RMSEs for 15 and 60 minutes of 0.43 and 1.73 mmol/L, respectively) and clinical safety (15 min: >99%, 60 min: >91%).

Conclusions: Machine learning-based models are able to accurately and safely predict glucose values at 15- and 60-minute intervals based on CGM data only. Future research should further optimize the models for implementation in closed-loop insulin delivery systems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253125PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224858PMC
June 2021

Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study.

Hepatology 2021 Nov 22;74(5):2467-2477. Epub 2021 Aug 22.

CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, the Netherlands.

Background And Aims: Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists.

Approach And Results: We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63).

Conclusions: Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings.
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http://dx.doi.org/10.1002/hep.32012DOI Listing
November 2021

Measures of Left Ventricular Diastolic Function and Cardiorespiratory Fitness According to Glucose Metabolism Status: The Maastricht Study.

J Am Heart Assoc 2021 07 14;10(13):e020387. Epub 2021 Jun 14.

Department of Cardiology Maastricht University Medical Centre+ Maastricht The Netherlands.

Background This cross-sectional study evaluated associations between structural and functional measures of left ventricular diastolic function and cardiorespiratory fitness (CRF) in a well-characterized population-based cohort stratified according to glucose metabolism status. Methods and Results Six hundred seventy-two participants from The Maastricht Study (mean±SD age, 61±9 years; 17.4% prediabetes and 25.4% type 2 diabetes mellitus) underwent both echocardiography to determine left atrial volume index, left ventricular mass index, maximum tricuspid flow regurgitation, average e' and E/e' ratio; and submaximal cycle ergometer test to determine CRF as maximum power output per kilogram body mass. Associations were examined with linear regression adjusted for cardiovascular risk and lifestyle factors, and interaction terms. After adjustment, in normal glucose metabolism but not (pre)diabetes, higher left atrial volume index (per 1 mL/m), left ventricular mass index (per 1 g/m), maximum tricuspid regurgitation flow (per 1 m/s) were associated with higher CRF (maximum power output per kilogram body mass; β in normal glucose metabolism 0.015 [0.008-0.023], (pre)diabetes <0.10; 0.007 [-0.001 to 0.015], type 2 diabetes mellitus <0.10; 0.129 [0.011-0.246], >0.10; for left atrial volume index, left ventricular mass index, maximum tricuspid regurgitation flow, respectively). Furthermore, after adjustment, in all individuals, higher average E/e' ratio (per unit), but not average e', was associated with lower CRF (normal glucose metabolism -0.044 [-0.071 to -0.016]), >0.10). Conclusions In this population-based study, structural and functional measures of left ventricular diastolic function were independently differentially associated with CRF over the strata of glucose metabolism status. This suggests that deteriorating left ventricular diastolic function, although of small effect, may contribute to the pathophysiological process of impaired CRF in the general population. Moreover, the differential effects in these structural measures may be the consequence of cardiac structural adaptation to effectively increase CRF in normal glucose metabolism, which is absent in (pre)diabetes.
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http://dx.doi.org/10.1161/JAHA.120.020387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403322PMC
July 2021

Sex hormone-binding globulin: biomarker and hepatokine?

Trends Endocrinol Metab 2021 08 26;32(8):544-553. Epub 2021 May 26.

Division of Endocrinology and Metabolic Diseases, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands. Electronic address:

Over the past decade, there have been important breakthroughs in our understanding of the regulation and function of sex hormone-binding globulin (SHBG). A recent genome-wide association and Mendelian randomization study has provided new insights at the population level. Thorough study of genetic variants affecting serum SHBG has identified de novo lipogenesis as one of the mechanistic links between the metabolic syndrome and reduced serum SHBG levels in humans. Furthermore, careful deduction of the Mendelian randomization results suggests a direct, causal role for SHBG in the pathogenesis of type 2 diabetes, as a hepatokine, in women. These findings prompt the development of SHBG-raising therapies as a means to prevent or treat disorders such as type 2 diabetes and polycystic ovary syndrome.
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http://dx.doi.org/10.1016/j.tem.2021.05.002DOI Listing
August 2021

Quality control strategies for brain MRI segmentation and parcellation: Practical approaches and recommendations - insights from the Maastricht study.

Neuroimage 2021 08 15;237:118174. Epub 2021 May 15.

School for Mental Health & Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands; Department of Radiology & Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands. Electronic address:

Quality control of brain segmentation is a fundamental step to ensure data quality. Manual quality control strategies are the current gold standard, although these may be unfeasible for large neuroimaging samples. Several options for automated quality control have been proposed, providing potential time efficient and reproducible alternatives. However, those have never been compared side to side, which prevents consensus in the appropriate quality control strategy to use. This study aimed to elucidate the changes manual editing of brain segmentations produce in morphological estimates, and to analyze and compare the effects of different quality control strategies on the reduction of the measurement error. Structural brain MRI from 259 participants of The Maastricht Study were used. Morphological estimates were automatically extracted using FreeSurfer 6.0. Segmentations with inaccuracies were manually edited, and morphological estimates were compared before and after editing. In parallel, 12 quality control strategies were applied to the full sample. Those included: two manual strategies, in which images were visually inspected and either excluded or manually edited; five automated strategies, where outliers were excluded based on the tools "MRIQC" and "Qoala-T", and the metrics "morphological global measures", "Euler numbers" and "Contrast-to-Noise ratio"; and five semi-automated strategies, where the outliers detected through the mentioned tools and metrics were not excluded, but visually inspected and manually edited. In order to quantify the effects of each quality control strategy, the proportion of unexplained variance relative to the total variance was extracted after the application of each strategy, and the resulting differences compared. Manually editing brain surfaces produced particularly large changes in subcortical brain volumes and moderate changes in cortical surface area, thickness and hippocampal volumes. The performance of the quality control strategies depended on the morphological measure of interest. Overall, manual quality control strategies yielded the largest reduction in relative unexplained variance. The best performing automated alternatives were those based on Euler numbers and MRIQC scores. The exclusion of outliers based on global morphological measures produced an increase of relative unexplained variance. Manual quality control strategies are the most reliable solution for quality control of brain segmentation and parcellation. However, measures must be taken to prevent the subjectivity associated with these strategies. The detection of inaccurate segmentations based on Euler numbers or MRIQC provides a time efficient and reproducible alternative. The exclusion of outliers based on global morphological estimates must be avoided.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118174DOI Listing
August 2021

Greater daily glucose variability and lower time in range assessed with continuous glucose monitoring are associated with greater aortic stiffness: The Maastricht Study.

Diabetologia 2021 Aug 15;64(8):1880-1892. Epub 2021 May 15.

CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.

Aims: CVD is the main cause of morbidity and mortality in individuals with diabetes. It is currently unclear whether daily glucose variability contributes to CVD. Therefore, we investigated whether glucose variability is associated with arterial measures that are considered important in CVD pathogenesis.

Methods: We included participants of The Maastricht Study, an observational population-based cohort, who underwent at least 48 h of continuous glucose monitoring (CGM) (n = 853; age: 59.9 ± 8.6 years; 49% women, 23% type 2 diabetes). We studied the cross-sectional associations of two glucose variability indices (CGM-assessed SD [SD] and CGM-assessed CV [CV]) and time in range (TIR) with carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient, carotid intima-media thickness, ankle-brachial index and circumferential wall stress via multiple linear regression.

Results: Higher SD was associated with higher cf-PWV after adjusting for demographics, cardiovascular risk factors and lifestyle factors (regression coefficient [B] per 1 mmol/l SD [and corresponding 95% CI]: 0.413 m/s [0.147, 0.679], p = 0.002). In the model additionally adjusted for CGM-assessed mean sensor glucose (MSG), SD and MSG contributed similarly to cf-PWV (respective standardised regression coefficients [st.βs] and 95% CIs of 0.065 [-0.018, 0.167], p = 0.160; and 0.059 [-0.043, 0.164], p = 0.272). In the fully adjusted models, both higher CV (B [95% CI] per 10% CV: 0.303 m/s [0.046, 0.559], p = 0.021) and lower TIR (B [95% CI] per 10% TIR: -0.145 m/s [-0.252, -0.038] p = 0.008) were statistically significantly associated with higher cf-PWV. Such consistent associations were not observed for the other arterial measures.

Conclusions: Our findings show that greater daily glucose variability and lower TIR are associated with greater aortic stiffness (cf-PWV) but not with other arterial measures. If corroborated in prospective studies, these results support the development of therapeutic agents that target both daily glucose variability and TIR to prevent CVD.
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http://dx.doi.org/10.1007/s00125-021-05474-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245390PMC
August 2021

Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study.

Cardiovasc Diabetol 2021 05 7;20(1):102. Epub 2021 May 7.

Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.

Background: Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures.

Methods: In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders.

Results: Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation.

Conclusions: Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.
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http://dx.doi.org/10.1186/s12933-021-01290-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106227PMC
May 2021

Sex differences in the longitudinal relationship of low-grade inflammation and echocardiographic measures in the Hoorn and FLEMENGHO Study.

PLoS One 2021 4;16(5):e0251148. Epub 2021 May 4.

Department of Epidemiology & Data Science, Amsterdam UMC, Amsterdam Cardiovascular Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: This study aimed to determine the within-person and between-persons associations of low-grade inflammation (LGI) and endothelial dysfunction (ED) with echocardiographic measures related to diastolic dysfunction (DD) in two general populations and whether these associations differed by sex.

Methods: Biomarkers and echocardiographic measures were measured at both baseline and follow-up in the Hoorn Study (n = 383) and FLEMENGHO (n = 491). Individual biomarker levels were combined into either a Z-score of LGI (CRP, SAA, IL-6, IL-8, TNF-α and sICAM-1) or ED (sICAM-1, sVCAM-1, sE-selectin and sTM). Mixed models were used to determine within-person and between-persons associations of biomarker Z-scores with left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) and left atrial volume index (LAVI). These associations were adjusted for a-priori selected confounders.

Results: Overall Z-scores for LGI or ED were not associated with echocardiographic measures. Effect modification by sex was apparent for ED with LVEF in both cohorts (P-for interaction = 0.08 and 0.06), but stratified results were not consistent. Effect modification by sex was apparent for TNF-α in the Hoorn Study and E-selectin in FLEMENGHO with LVEF (P-for interaction≤0.05). In the Hoorn Study, women whose TNF-α levels increased with 1-SD over time had a decrease in LVEF of 2.2 (-4.5;0.01) %. In FLEMENGHO, men whose E-selectin levels increased with 1-SD over time had a decrease in LVEF of 1.6 (-2.7;-0.5) %.

Conclusion: Our study did not show consistent associations of LGI and ED with echocardiographic measures. Some evidence of effect modification by sex was present for ED and specific biomarkers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251148PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096104PMC
October 2021

Diet-induced weight loss reduces postprandial dicarbonyl stress in abdominally obese men: Secondary analysis of a randomized controlled trial.

Clin Nutr 2021 05 15;40(5):2654-2662. Epub 2021 Apr 15.

Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht, the Netherlands; Top Institute of Food and Nutrition (TIFN), Wageningen, the Netherlands. Electronic address:

Aims: Dicarbonyl compounds contribute to the formation of advanced glycation endproducts (AGEs) and the development of insulin resistance and vascular complications. Dicarbonyl stress may already be detrimental in obesity. We evaluated whether diet-induced weight loss can effectively reverse dicarbonyl stress in abdominally obese men.

Materials And Methods: Plasma samples were collected from lean (n = 25) and abdominally obese men (n = 52) in the fasting state, and during a mixed meal test (MMT). Abdominally obese men were randomized to 8 weeks of dietary weight loss or habitual diet, followed by a second MMT. The α-dicarbonyls methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG) and AGEs were measured by UPLC-MS/MS. Skin autofluorescence (SAF) was measured using the AGE reader. T-tests were used for the cross-sectional analysis and ANCOVA to assess the treatment effect.

Results: Postprandial glucose, MGO and 3-DG concentrations were higher in obese men as compared to lean men (p < 0.05 for all). Fasting dicarbonyls, AGEs, and SAF were not different between lean and obese men. After the weight loss intervention, fasting MGO levels tended to decrease by 25 nmol/L (95%-CI: -51-0.5; p = 0.054). Postprandial dicarbonyls were decreased after weight loss as compared to the control group: iAUC of MGO decreased by 57% (5280 nmol/L∙min; 95%-CI: 33-10526; p = 0.049), of GO by 66% (11,329 nmol/L∙min; 95%-CI: 495-22162; p = 0.041), and of 3-DG by 45% (20,175 nmol/L∙min; 95%-CI: 5351-35000; p = 0.009). AGEs and SAF did not change significantly after weight loss.

Conclusion: Abdominal obesity is characterized by increased postprandial dicarbonyl stress, which can be reduced by a weight loss intervention. Registered under ClinicalTrials.gov Identifier no. NCT01675401.
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http://dx.doi.org/10.1016/j.clnu.2021.03.042DOI Listing
May 2021

Carotid stiffness is associated with retinal microvascular dysfunction-The Maastricht study.

Microcirculation 2021 08 6;28(6):e12702. Epub 2021 May 6.

CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands.

Objective: This study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy.

Research Design And Methods: This study used cross-sectional data from the Maastricht Study, a type 2 diabetes-enriched population-based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid-femoral pulse wave velocity with retinal microvascular diameters and flicker light-induced dilation and adjusted for cardiovascular and lifestyle risk factors.

Results: The retinal microvascular diameter study population consisted of N = 2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years, and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e., lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light-induced dilation (per standard deviation, standardized beta [95% CI] 0.06 [0.00; 0.12]) and non-significantly, but directionally similarly, associated with greater retinal venular flicker light-induced dilation (0.04 [-0.02; 0.10]). Carotid-femoral pulse wave velocity (i.e., aortic stiffness) was not associated with retinal microvascular flicker light-induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light-induced dilation were two- to threefold stronger in individuals with type 2 diabetes than in those without.

Conclusion: In this population-based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light-induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction.
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http://dx.doi.org/10.1111/micc.12702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459287PMC
August 2021

Determinants of treatment modification before and after implementation of the updated 2015 NICE guideline on type 2 diabetes: A retrospective cohort study.

Diabetes Res Clin Pract 2021 Jun 21;176:108828. Epub 2021 Apr 21.

Department of Clinical Pharmacy, Maastricht University Medical Centre+, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre+, Maastricht, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands; NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.

Aims: To identify patient-specific factors associated with early metformin treatment modification among type 2 diabetes patients before and after implementation of the updated 2015 NICE (National Institute for Health and Care Excellence) guideline.

Methods: We conducted a population-based cohort study using data from the Clinical Practice Research Datalink GOLD database (2009-2016). Patients ≥ 18 years, newly treated with metformin only, during the period of valid data collection were included. The first prescription defined start of follow-up. Determinants of treatment modification in two cohorts (before and after implementation of the updated guideline) were studied by time-dependent Cox proportional hazards regression.

Results: After implementation of the updated guideline, patients were less likely to receive sulphonylureas (62.3% vs 41.3%) or thiazolidediones (4.7% vs 2.2%) and more likely to receive dipeptidyl peptidase-4 inhibitors (15.8% vs 27.1%) or sodium-glucose cotransporter-2 inhibitors (0.8% vs 9.9%). Some determinants influenced general practitioners' prescribing differently after implementation of the updated guideline compared to before, including a high body mass index and heart failure.

Conclusions: Our results indicate that a first step towards tailored prescribing has been made. However, not all determinants that are important to consider when prescribing second-line glucose-lowering agents were of influence on general practitioners' prescribing.
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http://dx.doi.org/10.1016/j.diabres.2021.108828DOI Listing
June 2021

Sex Disparities in Cardiovascular Risk Factor Assessment and Screening for Diabetes-Related Complications in Individuals With Diabetes: A Systematic Review.

Front Endocrinol (Lausanne) 2021 30;12:617902. Epub 2021 Mar 30.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Background: Insight in sex disparities in the detection of cardiovascular risk factors and diabetes-related complications may improve diabetes care. The aim of this systematic review is to study whether sex disparities exist in the assessment of cardiovascular risk factors and screening for diabetes-related complications.

Methods: PubMed was systematically searched up to April 2020, followed by manual reference screening and citations checks (snowballing) using Google Scholar. Observational studies were included if they reported on the assessment of cardiovascular risk factors (HbA1c, lipids, blood pressure, smoking status, or BMI) and/or screening for nephropathy, retinopathy, or performance of feet examinations, in men and women with diabetes separately. Studies adjusting their analyses for at least age, or when age was considered as a covariable but left out from the final analyses for various reasons (i.e. backward selection), were included for qualitative analyses. No meta-analyses were planned because substantial heterogeneity between studies was expected. A modified Newcastle-Ottawa Quality Assessment Scale for cohort studies was used to assess risk of bias.

Results: Overall, 81 studies were included. The majority of the included studies were from Europe or North America (84%).The number of individuals per study ranged from 200 to 3,135,019 and data were extracted from various data sources in a variety of settings. Screening rates varied considerably across studies. For example, screening rates for retinopathy ranged from 13% to 90%, with half the studies reporting screening rates less than 50%. Mixed findings were found regarding the presence, magnitude, and direction of sex disparities with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, with some evidence suggesting that women, compared with men, may be more likely to receive retinopathy screening and less likely to receive foot exams.

Conclusion: Overall, no consistent pattern favoring men or women was found with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, and screening rates can be improved for both sexes.
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http://dx.doi.org/10.3389/fendo.2021.617902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043152PMC
March 2021

Metformin and N-terminal pro B-type natriuretic peptide in type 2 diabetes patients, a post-hoc analysis of a randomized controlled trial.

PLoS One 2021 8;16(4):e0247939. Epub 2021 Apr 8.

Department of Internal Medicine, Care Group Treant, Location Bethesda Hoogeveen, Hoogeveen, The Netherlands.

Background: Beyond antihyperglycemic effects, metformin may improve cardiovascular outcomes. Patients with type 2 diabetes often have an elevated plasma level of N-terminal pro B-type as a marker of (sub) clinical cardiovascular disease. We studied whether metformin was associated with a reduction in the serum level of N-terminal pro B-type natriuretic peptide (NT-proBNP) in these patients.

Methods: In the HOME trial 390 insulin-treated patients with type 2 diabetes were randomized to 850 mg metformin or placebo three times daily. Plasma samples were drawn at baseline, 4, 17, 30, 43 and 52 months. In a post-hoc analysis we analyzed the change in NT-proBNP in both groups. We used a longitudinal mixed model analysis adjusting for age, sex and prior cardiovascular disease. In a secondary analysis we assessed a possible immediate treatment effect post baseline.

Results: Metformin did not affect NT-proBNP levels over time in the primary analysis (-1% [95%CI -4;3, p = 0.62]). In the secondary analysis there was also no sustained time independent immediate treatment effect (initial increase of 17% [95%CI 4;30, p = 0.006] followed by yearly decrease of -4% [95%CI -7;0, p = 0.07]).

Conclusions: Metformin as compared to placebo did not affect NT-proBNP plasma levels in this 4.3-year placebo-controlled trial. Potential cardioprotective effects of metformin cannot be explained by changes in cardiac pressures or volumes to the extent reflected by NT-proBNP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031400PMC
September 2021

Associations of Dietary Patterns with Incident Depression: The Maastricht Study.

Nutrients 2021 Mar 23;13(3). Epub 2021 Mar 23.

CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.

Our aim was to assess the association between defined dietary patterns and incident depressive symptoms. We used data from The Maastricht Study, a population-based cohort study ( = 2646, mean (SD) age 59.9 (8.0) years, 49.5% women; 15,188 person-years of follow-up). Level of adherence to the Dutch Healthy Diet (DHD), Mediterranean Diet, and Dietary Approaches To Stop Hypertension (DASH) were derived from a validated Food Frequency Questionnaire. Depressive symptoms were assessed at baseline and annually over seven-year-follow-up (using the 9-item Patient Health Questionnaire). We used Cox proportional hazards regression analyses to assess the association between dietary patterns and depressive symptoms. One standard deviation (SD) higher adherence in the DHD and DASH was associated with a lower hazard ratio (HR) of depressive symptoms with HRs (95%CI) of 0.78 (0.69-0.89) and 0.87 (0.77-0.98), respectively, after adjustment for sociodemographic and cardiovascular risk factors. After further adjustment for lifestyle factors, the HR per one SD higher DHD was 0.83 (0.73-0.96), whereas adherence to Mediterranean and DASH diets was not associated with incident depressive symptoms. Higher adherence to the DHD lowered risk of incident depressive symptoms. Adherence to healthy diet could be an effective non-pharmacological preventive measure to reduce the incidence of depression.
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http://dx.doi.org/10.3390/nu13031034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004955PMC
March 2021

Relationship between de novo lipogenesis and serum sex hormone binding globulin in humans.

Clin Endocrinol (Oxf) 2021 Jul 28;95(1):101-106. Epub 2021 Mar 28.

Division of Endocrinology and Metabolic Diseases, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.

Objective: Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans.

Design: A cross-sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex.

Participants: Healthy men (n = 34) and women (n = 21) were combined from two cross-sectional studies. Forty-two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%).

Results: DNL was inversely associated with SHBG in women (β: -0.015, 95% CI: -0.030; 0.000), but not in men (β: 0.007, 95% CI: -0.005; 0.019) (p for interaction = .068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin.

Conclusions: An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women.
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http://dx.doi.org/10.1111/cen.14459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287427PMC
July 2021
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