Publications by authors named "Pieter C Dagnelie"

189 Publications

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 May 15. 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
May 2021

Habitual Intake of Dietary Advanced Glycation End Products Is Not Associated with Arterial Stiffness of the Aorta and Carotid Artery in Adults: The Maastricht Study.

J Nutr 2021 May 12. Epub 2021 May 12.

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

Background: Advanced glycation end products (AGEs), a heterogeneous group of bioactive compounds, are thought to contribute to arterial stiffness, which in turn is a causal factor in the pathogenesis of stroke, myocardial infarction, and heart failure. Whether AGEs derived from food also contribute to arterial stiffness is not clear.

Objectives: We investigated whether higher intake of dietary AGEs is associated with arterial stiffness.

Methods: In this cross-sectional observational study in 2255 participants of The Maastricht Study (mean ± SD age: 60 ± 8 y, 51% male, mean ± SD BMI: 26.9 ± 4.4 kg/m2, n = 1326 normal glucose metabolism, n = 341 prediabetes, and n = 585 type 2 diabetes mellitus), we estimated intake of 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) by a validated FFQ coupled to our ultra-performance liquid chromatography tandem mass spectrometry dietary AGE database. Arterial stiffness was determined using carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC), and carotid Young's elastic modulus (YEM). We performed multiple linear regression analyses adjusting for potential confounders (demographic, hemodynamic, cardiovascular, and dietary factors).

Results: In the fully adjusted models we observed no statistically significant associations between intake of the dietary AGEs CML, CEL, and MG-H1 and arterial stiffness expressed as cfPWV, carotid DC, and carotid YEM.

Conclusions: In adults aged 40-75 y, habitual intake of the dietary AGEs CML, CEL, and MG-H1 is not associated with arterial stiffness measured as cfPWV, carotid DC, or carotid YEM.
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http://dx.doi.org/10.1093/jn/nxab097DOI Listing
May 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

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

Microcirculation 2021 Apr 27:e12702. Epub 2021 Apr 27.

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
April 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

Towards precision medicine in diabetes? A critical review of glucotypes.

PLoS Biol 2021 Mar 11;19(3):e3000890. Epub 2021 Mar 11.

Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.

In response to a study previously published in PLOS Biology, this Formal Comment thoroughly examines the concept of 'glucotypes' with regard to its generalisability, interpretability and relationship to more traditional measures used to describe data from continuous glucose monitoring.
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http://dx.doi.org/10.1371/journal.pbio.3000890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951846PMC
March 2021

The relation of depression with structural brain abnormalities and cognitive functioning: the Maastricht study.

Psychol Med 2021 Feb 26:1-10. Epub 2021 Feb 26.

Alzheimer Centrum Limburg, Maastricht, the Netherlands.

Background: Individuals with depression often experience widespread and persistent cognitive deficits, which might be due to brain atrophy and cerebral small vessel disease (CSVD). We therefore studied the associations between depression, markers of brain atrophy and CSVD, and cognitive functioning.

Methods: We used cross-sectional data from the population-based Maastricht study (n = 4734; mean age 59.1 ± 8.6 years, 50.2% women), which focuses on type 2 diabetes. A current episode of major depressive disorder (MDD, n = 151) was assessed by the Mini-International Neuropsychiatric Interview. Volumes of cerebral spinal fluid, white matter, gray matter and white matter hyperintensities, presence of lacunar infarcts and cerebral microbleeds, and total CSVD burden were assessed by 3 T magnetic resonance imaging. Multiple linear and logistic regression analyses tested the associations between MDD, brain markers and cognitive functioning in memory, information processing speed, and executive functioning & attention, and presence of cognitive impairment. Structural equation modeling was used to test mediation.

Results: In fully adjusted models, MDD was associated with lower scores in information processing speed [mean difference = -0.18(-0.28;-0.08)], executive functioning & attention [mean difference = -0.13(-0.25;-0.02)], and with higher odds of cognitive impairment [odds ratio (OR) = 1.60(1.06;2.40)]. MDD was associated with CSVD in participants without type 2 diabetes [OR = 1.65(1.06;2.56)], but CSVD or other markers of brain atrophy or CSVD did not mediate the association with cognitive functioning.

Conclusions: MDD is associated with more impaired information processing speed and executive functioning & attention, and overall cognitive impairment. Furthermore, MDD was associated with CSVD in participants without type 2 diabetes, but this association did not explain an impaired cognitive profile.
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http://dx.doi.org/10.1017/S0033291721000222DOI Listing
February 2021

Interplay of White Matter Hyperintensities, Cerebral Networks, and Cognitive Function in an Adult Population: Diffusion-Tensor Imaging in the Maastricht Study.

Radiology 2021 02 22;298(2):384-392. Epub 2020 Dec 22.

From the Department of Radiology & Nuclear Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, 6229 HX Maastricht, the Netherlands (L.W.M.V., J.F.A.J., S.K., M.P.J.v.B., J.J.A.d.J., W.H.B.); MHeNs School for Mental Health and Neuroscience (L.W.M.V., J.F.A.J., S.K., M.P.J.v.B., J.J.A.d.J., M.T.S., W.H.B.), Department of Internal Medicine (T.T.v.S., C.D.A.S., N.C.S., P.C.D., A.A.K., M.T.S.), School for Cardiovascular Disease (CARIM) (L.W.M.V., T.T.v.S., C.D.A.S., N.C.S., P.C.D., A.A.K., M.T.S., W.H.B.), Care and Public Health Institute (CAPHRI) (N.C.S.), School of Nutrition and Translational Research in Metabolism (NUTRIM) (A.W., M.T.S.), and Department of Complex Genetics & Epidemiology (A.W.), Maastricht University, Maastricht, the Netherlands; and Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands (J.F.A.J.).

Background Lesions of cerebral small vessel disease, such as white matter hyperintensities (WMHs) in individuals with cardiometabolic risk factors, interfere with the trajectories of the white matter and eventually contribute to cognitive decline. However, there is no consensus yet about the precise underlying topological mechanism. Purpose To examine whether WMH and cognitive function are associated and whether any such association is mediated or explained by structural connectivity measures in an adult population. In addition, to investigate underlying local abnormalities in white matter by assessing the tract-specific WMH volumes and their tract-specific association with cognitive function. Materials and Methods In the prospective type 2 diabetes-enriched population-based Maastricht Study, structural and diffusion-tensor MRI was performed (December 2013 to February 2017). Total and tract-specific WMH volumes; network measures; cognition scores; and demographic, cardiovascular, and lifestyle characteristics were determined. Multivariable linear regression and mediation analyses were used to investigate the association of WMH volume, tract-specific WMH volumes, and network measures with cognitive function. Associations were adjusted for age, sex, education, diabetes status, and cardiovascular risk factors. Results A total of 5083 participants (mean age, 59 years ± 9 [standard deviation]; 2592 men; 1027 with diabetes) were evaluated. Larger WMH volumes were associated with stronger local (standardized β coefficient, 0.065; < .001), but not global, network efficiency and lower information processing speed (standardized β coefficient, -0.073; < .001). Moreover, lower local efficiency (standardized β coefficient, -0.084; < .001) was associated with lower information processing speed. In particular, the relationship between WMHs and information processing speed was mediated (percentage mediated, 7.2% [95% CI: 3.5, 10.9]; < .05) by the local network efficiency. Finally, WMH load was larger in the white matter tracts important for information processing speed. Conclusion White matter hyperintensity volume, local network efficiency, and information processing speed scores are interrelated, and local network properties explain lower cognitive performance due to white matter network alterations. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2021202634DOI Listing
February 2021

Vascular risk factors for optical coherence tomography-detected macular cysts: The Maastricht Study.

Acta Ophthalmol 2020 Nov 30. Epub 2020 Nov 30.

University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, The Netherlands.

Purpose: To investigate whether higher blood pressure and greater arterial stiffness are associated with the presence of macular cysts and whether this association is already present in the absence of micro-aneurysms in individuals with and without type 2 diabetes.

Methods: Using spectral domain optical coherence tomography (OCT), we performed a macular volume scan in 2647 individuals (mean age 60 ± 8 years, 50% men, 27% type 2 diabetes). The association between macular cysts and 24-hour systolic and diastolic blood pressure, pulse pressure, mean arterial blood pressure, carotid-femoral pulse wave velocity and carotid distensibility was assessed by use of logistic regression.

Results: Twenty-four hours systolic blood pressure was associated with the presence of macular cysts [OR = 1.03 (95% CI 1.00-1.05) per 1 mmHg, p = 0.03]. 24 hr pulse pressure [OR = 1.61 (95% CI 1.11-2.34) per 10 mmHg, p = 0.01] and carotid-femoral pulse wave velocity [OR = 1.16 (95% CI 1.02-1.32) per 1 m/s, p = 0.02] were associated with macular cysts, while carotid distensibility was not [OR = 1.03 (95% CI 0.96-1.11) per 1.0*10 /kPa, p = 0.45]. Associations were similar in individuals with and without type 2 diabetes and were already present in the absence of micro-aneurysms.

Conclusion: Twenty-four hours systolic blood pressure, 24 hr pulse pressure and carotid-femoral pulse wave velocity are associated with the presence of OCT-detected macular cysts in individuals with and without type 2 diabetes, even in the absence of micro-aneurysms. Therefore, blood pressure and aortic stiffness are potential factors contributing to macular cysts.
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http://dx.doi.org/10.1111/aos.14677DOI Listing
November 2020

Exercise SBP response and incident depressive symptoms: The Maastricht Study.

J Hypertens 2021 Mar;39(3):494-502

Department of Internal Medicine, Maastricht University Medical Centre.

Objective: : An exaggerated exercise SBP, which is potentially modifiable, may be associated with incident depressive symptoms via an increased pulsatile pressure load on the brain. However, the association between exaggerated exercise SBP and incident depressive symptoms is unknown. Therefore, we examined whether exaggerated exercise SBP is associated with a higher risk of depressive symptoms over time.

Methods: : We used longitudinal data from the population-based Maastricht Study, with only individuals free of depressive symptoms at baseline included (n = 2121; 51.3% men; age 59.5 ± 8.5 years). Exercise SBP was measured at baseline with a submaximal exercise cycle test. We calculated a composite score of exercise SBP based on four standardized exercise SBP measures: SBP at moderate workload, SBP at peak exercise, SBP change per minute during exercise and SBP 4 min after exercise. Clinically relevant depressive symptoms were determined annually at follow-up and defined as a Patient Health Questionnaire score of at least 10.

Results: : After a mean follow-up of 3.9 years, 175 participants (8.3%) had incident clinically relevant depressive symptoms. A 1 SD higher exercise SBP composite score was associated with a higher incidence of clinically relevant depressive symptoms [hazard ratio: 1.27 (95% confidence interval: 1.04-1.54)]. Results were adjusted for age, sex, education level, glucose metabolism status, lifestyle, cardiovascular risk factors, resting SBP and cardiorespiratory fitness.

Conclusion: : A higher exercise SBP response is associated with a higher incidence of clinically relevant depressive symptoms.
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http://dx.doi.org/10.1097/HJH.0000000000002657DOI Listing
March 2021

Association of the Amount and Pattern of Physical Activity With Arterial Stiffness: The Maastricht Study.

J Am Heart Assoc 2020 10 15;9(20):e017502. Epub 2020 Oct 15.

CAPHRI Care and Public Health Research Institute Maastricht University Maastricht the Netherlands.

Background Arterial stiffness is an independent risk factor for cardiovascular disease and can be beneficially influenced by physical activity. However, it is not clear how an individual's physical activity pattern over a week is associated with arterial stiffness. Therefore, we examined the associations of the amount and pattern of higher intensity physical activity with arterial stiffness. Methods and Results Data from the Maastricht Study (n=1699; mean age: 60±8 years, 49.4% women, 26.9% type 2 diabetes mellitus) were used. Arterial stiffness was assessed by carotid-to-femoral pulse wave velocity and carotid distensibility. The amount (continuous variable as h/wk) and pattern (categorical variable) of higher intensity physical activity were assessed with the activPAL3. Activity groups were: inactive (<75 min/wk), insufficiently active (75-150 min/wk), weekend warrior (>150 min/wk in ≤2 sessions), and regularly active (>150 min/wk in ≥3 sessions). In the fully adjusted model (adjusted for demographic, lifestyle, and cardiovascular risk factors), higher intensity physical activity was associated with lower carotid-to-femoral pulse wave velocity (amount: β = -0.05, 95% CI, -0.09 to -0.01; insufficiently active: β = -0.33, 95% CI, -0.55 to -0.11; weekend warrior: β = -0.38, 95% CI, -0.64 to -0.12; and regularly active: β = -0.46, 95% CI, -0.71 to -0.21 [reference: inactive]). These associations were stronger in those with type 2 diabetes mellitus. There was no statistically significant association between higher intensity physical activity with carotid distensibility. Conclusions Participating in higher intensity physical activity was associated with lower carotid-to-femoral pulse wave velocity, but there was no difference between the regularly actives and the weekend warriors. From the perspective of arterial stiffness, engaging higher intensity physical activity, regardless of the weekly pattern, may be an important strategy to reduce the risk of cardiovascular disease, particularly in individuals with type 2 diabetes mellitus.
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http://dx.doi.org/10.1161/JAHA.120.017502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763372PMC
October 2020

The association of hyperglycaemia and insulin resistance with incident depressive symptoms over 4 years of follow-up: The Maastricht Study.

Diabetologia 2020 11 5;63(11):2315-2328. Epub 2020 Aug 5.

Department of Psychiatry and Neuropsychology, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands.

Aims/hypothesis: Depression is twice as common in individuals with type 2 diabetes as in the general population. However, it remains unclear whether hyperglycaemia and insulin resistance are directly involved in the aetiology of depression. Therefore, we investigated the association of markers of hyperglycaemia and insulin resistance, measured as continuous variables, with incident depressive symptoms over 4 years of follow-up.

Methods: We used data from the longitudinal population-based Maastricht Study (n = 2848; mean age 59.9 ± 8.1 years, 48.8% women, 265 incident depression cases, 10,932 person-years of follow-up). We assessed hyperglycaemia by fasting and 2 h post-load OGTT glucose levels, HbA and skin autofluorescence (reflecting AGEs) at baseline. We used the Matsuda insulin sensitivity index and HOMA-IR to calculate insulin resistance at baseline. Depressive symptoms (nine-item Patient Health Questionnaire score ≥10) were assessed at baseline and annually over 4 years. We used Cox regression analyses, and adjusted for demographic, cardiovascular and lifestyle risk factors.

Results: Fasting plasma glucose, 2 h post-load glucose and HbA levels were associated with an increased risk for incident depressive symptoms after full adjustment (HR 1.20 [95% CI 1.08, 1.33]; HR 1.25 [1.08, 1.44]; and HR 1.22 [1.09, 1.37] per SD, respectively), while skin autofluorescence, insulin sensitivity index and HOMA-IR were not (HR 0.99 [0.86, 1.13]; HR 1.02 [0.85, 1.25]; and HR 0.93 [0.81, 1.08], per SD, respectively).

Conclusions/interpretation: The observed temporal association between hyperglycaemia and incident depressive symptoms in this study supports the presence of a mechanistic link between hyperglycaemia and the development of depressive symptoms. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05247-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527373PMC
November 2020

Blood pressure variability and microvascular dysfunction: the Maastricht Study.

J Hypertens 2020 08;38(8):1541-1550

Department of Internal Medicine, Maastricht University Medical Centre.

Background: Microvascular dysfunction (MVD) contributes to stroke, dementia, depression, retinopathy and chronic kidney disease. However, the determinants of MVD are incompletely understood. Greater blood pressure variability (BPV) may be one such determinant.

Methods And Results: We used cross-sectional data of The Maastricht Study (n = 2773, age 59.9 years; 51.9% men) to investigate whether greater very short- to mid-term BPV is associated with various MVD measures. We standardized and averaged within-visit, 24-h and 7-day BPV into a systolic and a diastolic BPV composite score. MVD measures included a composite score of MRI cerebral small vessel disease (CSVD) features (total brain parenchymal volume, white matter hyperintensity volume, lacunar infarcts and cerebral microbleeds), a composite score of flicker light-induced retinal arteriolar and venular dilation response, albuminuria, heat-induced skin hyperemia and a composite score of plasma biomarkers of MVD (sICAM-1, sVCAM-1, sE-selectin and von Willebrand Factor). We used linear regression adjusted for age, sex, glucose metabolism status, mean 24-h systolic or DBP, cardiovascular risk factors and antihypertensive medication. We found that higher systolic and diastolic BPV composite scores (per SD) were associated with higher albuminuria [higher ratio, 1.04 (95% CI 1.00-1.08) and 1.07 (1.03-1.11), respectively], but not with other measures of MVD tested.

Conclusion: Greater systolic and diastolic BPV was associated with higher albuminuria, but not with CSVD features, flicker light-induced retinal arteriolar and venular dilation response, heat-induced skin hyperemia and plasma biomarkers of MVD. This suggests that the microvasculature of the kidneys is most vulnerable to the detrimental effects of greater BPV.
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http://dx.doi.org/10.1097/HJH.0000000000002444DOI Listing
August 2020

Associations of 24-Hour Urinary Sodium and Potassium Excretion with Cardiac Biomarkers: The Maastricht Study.

J Nutr 2020 06;150(6):1413-1424

Division of Nephrology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, Netherlands.

Background: It is a matter of debate whether sodium and potassium intake are associated with heart disease. Further, the mechanisms underlying associations of sodium and potassium intake with cardiac events, if any, are not fully understood.

Objectives: We examined cross-sectional associations of 24-h urinary sodium excretion (UNaE) and potassium excretion (UKE), as estimates of their intakes, with high-sensitivity cardiac troponins T (hs-cTnT) and I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), which are markers of cardiomyocyte injury and cardiac dysfunction.

Methods: We included 2961 participants from the population-based Maastricht Study (mean ± SD age 59.8 ± 8.2 y, 51.9% men), who completed the baseline survey between November 2010 and September 2013. Associations were examined with restricted cubic spline linear regression analyses and ordinary linear regression analyses, adjusted for demographics, lifestyle, and cardiovascular disease (CVD) risk factors.

Results: Median [IQR] 24-h UNaE and UKE were 3.7 [2.8-4.7] g/24 h and 3.0 [2.4-3.6] g/24 h, respectively. After adjustment for potential confounders, 24-h UNaE was not associated with hs-cTnT, hs-cTnI, and NT-proBNP concentrations. In contrast, after adjustment for potential confounders, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. For example, as compared with the third/median quintile of 24-h UKE (range: 2.8-3.2 g/24 h), participants in the first quintile (range: 0.5-2.3 g/24 h) had 1.05 (95% CI: 0.99, 1.11) times higher hs-cTnT and 1.14 (95% CI: 1.03, 1.26) times higher NT-proBNP. Associations were similar after further adjustment for estimated glomerular filtration rate, albuminuria, blood pressure, and serum potassium.

Conclusions: Twenty-four-hour UNaE was not associated with the studied cardiac biomarkers. In contrast, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. This finding supports recommendations to increase potassium intake in the general population. In addition, it suggests that cardiac dysfunction and/or cardiomyocyte injury may underlie previously reported associations of lower potassium intake with CVD mortality.
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http://dx.doi.org/10.1093/jn/nxaa080DOI Listing
June 2020

Associations of Arterial Stiffness With Cognitive Performance, and the Role of Microvascular Dysfunction: The Maastricht Study.

Hypertension 2020 06 10;75(6):1607-1614. Epub 2020 Apr 10.

From the CARIM School for Cardiovascular Diseases (S.P.R., C.D.A.S., A.J.H.M.H., C.G.S., A.A.K., R.M.A.H., P.C.D., S.J.P.M.E., K.D.R., M.T.S., T.T.v.S.).

The mechanisms underlying cognitive impairment are incompletely understood but may include arterial stiffness and microvascular dysfunction. In the population-based Maastricht Study, we investigated the association between arterial stiffness and cognitive performance, and whether any such association was mediated by microvascular dysfunction. We included cross-sectional data of 2544 participants (age, 59.7 years; 51.0% men; 26.0% type 2 diabetes mellitus). We used carotid-femoral pulse wave velocity and carotid distensibility coefficient as measures of aortic and carotid stiffness, respectively. We calculated a composite score of microvascular dysfunction based on magnetic resonance imaging features of cerebral small vessel disease, flicker light-induced retinal arteriolar and venular dilation response, albuminuria, and plasma biomarkers of microvascular dysfunction (sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [von Willebrand factor]). Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the average of these domains. Higher aortic stiffness (per m/s) was associated with lower cognitive function (β, -0.018 SD [95% CI, -0.036 to -0.000]) independent of age, sex, education, and cardiovascular risk factors, but higher carotid stiffness was not. Higher aortic stiffness (per m/s) was associated with a higher microvascular dysfunction score (β, 0.034 SD [95% CI, 0.014 to 0.053]), and a higher microvascular dysfunction score (per SD) was associated with lower cognitive function (β, -0.089 SD [95% CI, -0.124 to -0.053]). Microvascular dysfunction significantly explained 16.2% of the total effect of aortic stiffness on cognitive function. The present study showed that aortic stiffness, but not carotid stiffness, is independently associated with worse cognitive performance, and that this association is in part explained by microvascular dysfunction.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14307DOI Listing
June 2020

Reduced corneal nerve fibre length in prediabetes and type 2 diabetes: The Maastricht Study.

Acta Ophthalmol 2020 Feb 3. Epub 2020 Feb 3.

University Eye Clinic Maastricht, Maastricht University Medical Center +, Maastricht, the Netherlands.

Purpose: In individuals with diabetes, injury to the corneal nerve fibres predisposes to delayed corneal epithelial healing, reduced corneal sensitivity and corneal erosion. We investigated to what extent a reduction in corneal nerve fibre length (CNFL) is present in individuals with prediabetes or type 2 diabetes (DM2) compared with individuals with normal glucose metabolism (NGM).

Methods: Using composite images acquired by corneal confocal microscopy, we assessed total CNFL per mm in the subbasal nerve plexus of the cornea in 134 participants (mean age 59 ± 8 years, 49% men, 87 NGM, 20 prediabetes, 27 DM2). Multivariable linear regression was used to assess the association between CNFL and glucose metabolism status, adjusted for age and sex.

Results: In individuals with type 2 diabetes, the mean CNFL was significantly reduced [β = -1.86 mm/mm (95% CI -3.64 to -0.08), p = 0.04], as compared with individuals with normal glucose metabolism after adjustment for age and sex. Part of the reduction was present in individuals with prediabetes [β = -0.96 mm/mm (95% CI -2.91 to 0.99), p = 0.34], with a linear trend of corneal nerve fibre reduction with severity of glucose metabolism status (p trend = 0.04).

Conclusions: A significant reduction in CNFL was found in individuals with DM2 compared with individuals with NGM. A trend of reduction in CNFL was observed between individuals with NGM and prediabetes. The reduction in corneal nerve fibre length could contribute to a delayed corneal healing and an increased risk for corneal complications after surgery.
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http://dx.doi.org/10.1111/aos.14359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496813PMC
February 2020

Drug utilization in the Maastricht Study: A comparison with nationwide data.

Medicine (Baltimore) 2020 Jan;99(1):e18524

Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center.

Within the southern region of the Netherlands, the Maastricht Study is an on-going observational prospective population-based cohort study that focuses on the etiology of Type 2 diabetes mellitus (T2DM). Representativeness of the participating population is a crucial but often an unknown factor in population-based cohort studies such as the Maastricht Study. We therefore aimed to assess the representativeness of the study population by comparing drug utilization of the participants of the Maastricht Study with the general population of the Netherlands.Since T2DM patients were oversampled in this study, a sampling method was applied in order to ensure a similar distribution of T2DM over the study population. Drug use in the study population was compared with drug use in the population of the Netherlands, using a Z-test to compare 2 independent proportions.In general, drug use in the study was similar compared with national data. However, in the age group 65 to 74 years total drug use was lower in the study population (833/1000 persons) versus nationwide data (882/1000 persons). The use of pulmonary medications was lower (104/1000 persons vs 141/1000 persons) and the use of hypnotics/anxiolytics was higher (90/1000 persons vs 36/1000 persons) in the Maastricht Study as compared with national data.Drug use in the Maastricht Study population is largely comparable to that in the total Dutch population aged 45 to 74. Therefore, data on drug use by participants in the Maastricht Study can be used to perform studies assessing outcomes associated with drug use.
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http://dx.doi.org/10.1097/MD.0000000000018524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946313PMC
January 2020

Adverse differences in cardiometabolic risk factor levels between individuals with pre-diabetes and normal glucose metabolism are more pronounced in women than in men: the Maastricht Study.

BMJ Open Diabetes Res Care 2019 15;7(1):e000787. Epub 2019 Nov 15.

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

Objective: To investigate whether adverse differences in levels of cardiovascular risk factors in women than men, already established when comparing individuals with and without diabetes, are also present before type 2 diabetes onset.

Research Design And 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 associations with cardiometabolic and lifestyle risk factors of (1) pre-diabetes and type 2 diabetes (reference category: normal glucose metabolism) and (2) among non-diabetic individuals, of continuous levels of hemoglobin A1c (HbA1c). Age-adjusted sex differences were analyzed using linear and logistic regression models with sex interaction terms.

Results: In pre-diabetes, adverse differences in cardiometabolic risk factors were greater in women than men for systolic blood pressure (difference, 3.02 mm Hg; 95% CI:-0.26 to 6.30), high-density lipoprotein (HDL) cholesterol (difference, -0.10 mmol/L; 95% CI: -0.18 to -0.02), total-to-HDL cholesterol ratio (difference, 0.22; 95% CI: -0.01 to 0.44), triglycerides (ratio: 1.11; 95% CI: 1.01 to 1.22), and inflammation markers Z-score (ratio: 1.18; 95% CI: 0.98 to 1.41). In type 2 diabetes, these sex differences were similar in direction, and of greater magnitude. Additionally, HbA1c among non-diabetic individuals was more strongly associated with several cardiometabolic risk factors in women than men: per one per cent point increase, systolic blood pressure (difference, 3.58 mm Hg; 95% CI: -0.03 to 7.19), diastolic blood pressure (difference, 2.10 mm Hg; 95% CI: -0.02 to 4.23), HDL cholesterol (difference, -0.09 mmol/L; 95% CI: -0.19 to 0.00), and low-density lipoprotein cholesterol (difference, 0.26 mmol/L; 95% CI: 0.05 to 0.47). With regard to lifestyle risk factors, no consistent pattern was observed.

Conclusion: Our results are consistent with the concept that the more adverse changes in cardiometabolic risk factors in women (than men) arise as a continuous process before the onset of type 2 diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2019-000787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861068PMC
September 2020

Initial Imaging-Guided Strategy Versus Routine Care in Patients With Non-ST-Segment Elevation Myocardial Infarction.

J Am Coll Cardiol 2019 11;74(20):2466-2477

Department of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands. Electronic address:

Background: Patients with non-ST-segment elevation myocardial infarction and elevated high-sensitivity cardiac troponin levels often routinely undergo invasive coronary angiography (ICA), but many do not have obstructive coronary artery disease.

Objectives: This study investigated whether cardiovascular magnetic resonance imaging (CMR) or computed tomographic angiography (CTA) may serve as a safe gatekeeper for ICA.

Methods: This randomized controlled trial (NCT01559467) in 207 patients (age 64 years; 62% male patients) with acute chest pain, elevated high-sensitivity cardiac troponin T levels (>14 ng/l), and inconclusive electrocardiogram compared a CMR- or CTA-first strategy with a control strategy of routine clinical care. Follow-up ICA was recommended when initial CMR or CTA suggested myocardial ischemia, infarction, or obstructive coronary artery disease (≥70% stenosis). Primary efficacy and secondary safety endpoints were referral to ICA during hospitalization and 1-year outcomes (major adverse cardiac events and complications), respectively.

Results: The CMR- and CTA-first strategies reduced ICA compared with routine clinical care (87% [p = 0.001], 66% [p < 0.001], and 100%, respectively), with similar outcome (hazard ratio: CMR vs. routine, 0.78 [95% confidence interval: 0.37 to 1.61]; CTA vs. routine, 0.66 [95% confidence interval: 0.31 to 1.42]; and CMR vs. CTA, 1.19 [95% confidence interval: 0.53 to 2.66]). Obstructive coronary artery disease after ICA was found in 61% of patients in the routine clinical care arm, in 69% in the CMR-first arm (p = 0.308 vs. routine), and in 85% in the CTA-first arm (p = 0.006 vs. routine). In the non-CMR and non-CTA arms, follow-up CMR and CTA were performed in 67% and 13% of patients and led to a new diagnosis in 33% and 3%, respectively (p < 0.001).

Conclusions: A novel strategy of implementing CMR or CTA first in the diagnostic process in non-ST-segment elevation myocardial infarction is a safe gatekeeper for ICA.
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http://dx.doi.org/10.1016/j.jacc.2019.09.027DOI Listing
November 2019

White Matter Connectivity Abnormalities in Prediabetes and Type 2 Diabetes: The Maastricht Study.

Diabetes Care 2020 01 10;43(1):201-208. Epub 2019 Oct 10.

Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+ (MUMC+), Maastricht, the Netherlands

Objective: Prediabetes and type 2 diabetes are associated with structural brain abnormalities, often observed in cognitive disorders. Besides visible lesions, (pre)diabetes might also be associated with alterations of the intrinsic organization of the white matter. In this population-based cohort study, the association of prediabetes and type 2 diabetes with white matter network organization was assessed.

Research Design And Methods: In the Maastricht Study, a type 2 diabetes-enriched population-based cohort study (1,361 subjects with normal glucose metabolism, 348 with prediabetes, and 510 with type 2 diabetes assessed by oral glucose tolerance test; 52% men; aged 59 ± 8 years), 3 Tesla structural and diffusion MRI was performed. Whole-brain white matter tractography was used to assess the number of connections (node degree) between 94 brain regions and the topology (graph measures). Multivariable linear regression analyses were used to investigate the associations of glucose metabolism status with network measures. Associations were adjusted for age, sex, education, and cardiovascular risk factors.

Results: Prediabetes and type 2 diabetes were associated with lower node degree after full adjustment (standardized [st]β = -0.055 [95% CI -0.172, 0.062], stβ = -0.256 [-0.379, -0.133], < 0.001). Prediabetes was associated with lower local efficiency (stβ = -0.084 [95% CI -0.159, -0.008], = 0.033) and lower clustering coefficient (stβ = -0.097 [95% CI -0.189, -0.005], = 0.049), whereas type 2 diabetes was not. Type 2 diabetes was associated with higher communicability (stβ = 0.148 [95% CI 0.042, 0.253], = 0.008).

Conclusions: These findings indicate that prediabetes and type 2 diabetes are associated with fewer white matter connections and weaker organization of white matter networks. Type 2 diabetes was associated with higher communicability, which was not yet observed in prediabetes and may reflect the use of alternative white matter connections.
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http://dx.doi.org/10.2337/dc19-0762DOI Listing
January 2020

Serum Phosphate and Microvascular Function in a Population-Based Cohort.

Clin J Am Soc Nephrol 2019 11 20;14(11):1626-1633. Epub 2019 Sep 20.

Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, California.

Background And Objectives: Higher serum phosphate is associated with cardiovascular events and all-cause mortality. Explanations of this association have focused on large vessel calcification and stiffness. Studies suggest that a higher serum phosphate induces microvascular dysfunction, but relationships in humans with direct measures of microvascular function are lacking.

Design, Setting, Participants, & Measurements: We performed a cross-sectional analysis of 3189 community-living participants that underwent skin capillaroscopy, laser-Doppler flowmetry, and flicker light-induced retinal vessel responses. We used linear regression to assess the association between serum phosphate and each microvascular outcome. The primary outcome was skin capillary recruitment during postocclusive peak reactive hyperemia by capillaroscopy. Secondary outcomes included capillary recruitment during venous congestion, heat-induced skin hyperemic response, flicker light-induced retinal arteriolar, and venular dilation.

Results: The mean age of the cohort was 59±8 years, 48% were women, 7% had an eGFR <60 ml/min per 1.73 m, and the mean serum phosphate concentration was 3.2±0.5 mg/dl. A 1 mg/dl higher serum phosphate was independently associated with a 5.0% lower postocclusive capillary recruitment (95% CI, -10.0% to -0.1%). Results were similar for capillary recruitment with venous congestion (-4.5%; 95% CI, -9.8% to 0.7%). A 1 mg/dl higher serum phosphate was also independently associated with a 0.23% lower retinal venular dilation in response to flicker light (95% CI, -0.44% to -0.02%). A higher serum phosphate was not associated with change in flicker light-induced retinal arteriolar dilation or heat-induced skin hyperemic response, however a higher serum phosphate was associated with a lower heat-induced skin hyperemic response among men (-149% [95% CI, -260 to -38] per 1 mg/dl higher serum phosphate) but not women ( interaction, 0.01).

Conclusions: Higher serum phosphate concentrations, even within the normal range, are associated with microvascular dysfunction in community-living individuals.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_20_CJN02610319.mp3.
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http://dx.doi.org/10.2215/CJN.02610319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832044PMC
November 2019

Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine.

Neurology 2019 04 3;92(16):e1899-e1911. Epub 2019 Apr 3.

From the Departments of Neurology (G.L.J.O., J.A.P., D.A.K., R.Z., I.d.B., M.D.F., G.M.T., A.M.J.M.v.d.M.), Human Genetics (A.D., L.S.V., P.A.C.'tH., A.M.J.M.v.d.M.), Molecular Epidemiology (M.B., P.E.S.), Radiology (D.A.K.), and Medical Statistics (J.J.G.), Leiden University Medical Centre; Department of Biological Psychology (L.L., R.P., D.I.B.), Vrije Universiteit Amsterdam; Amsterdam Public Health Institute (L.L.); Amsterdam Neuroscience and Amsterdam Public Health (M.B., C.S.T., Y.M., D.I.B., B.W.P.); Department of Psychiatry (M.B., C.S.T., Y.M., B.W.P.), VU University Medical Centre/GGZ inGeest, Amsterdam; Departments of Epidemiology (A.D., J.L., K.-x.W., N.A., M.A.I., C.M.v.D.) and Neurology (M.A.I.), Erasmus Medical Centre, Rotterdam; Departments of Genetics (J.F., L.F., C.W.) and Pediatrics (J.F.), University Medical Centre Groningen; Department of Internal Medicine (C.J.H.v.d.K., F.H.M.V., M.M.J.v.G., M.T.S., C.D.A.S.) and Heart and Vascular Center (M.T.S.), Maastricht University Medical Centre; CARIM School for Cardiovascular Diseases (C.J.H.v.d.K., M.M.J.v.G., I.C.W.A., M.T.S., P.C.D., C.D.A.S.), Department of Epidemiology (I.C.W.A.), MaCSBio Maastricht Centre for Systems Biology (I.C.W.A.), and Department of Epidemiology (P.C.D.), Maastricht University; Department of Radiology (M.A.I.), Erasmus MC University Medical Centre, Rotterdam; Leiden Academic Centre in Drug Research, Faculty Science (C.M.v.D.), Leiden University; and Centre for Molecular and Biomolecular Informatics (P.A.C.'tH.), Radboud University Medical Centre Nijmegen, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.

Objective: To identify a plasma metabolomic biomarker signature for migraine.

Methods: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses.

Results: Decreases in the level of apolipoprotein A1 (β -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β -0.10; 95% CI -0.15, -0.05; adjusted = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β -0.24; 95% CI -0.36, -0.12; adjusted = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status.

Conclusions: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.
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http://dx.doi.org/10.1212/WNL.0000000000007313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550500PMC
April 2019

The Maastricht FFQ: Development and validation of a comprehensive food frequency questionnaire for the Maastricht study.

Nutrition 2019 06 26;62:39-46. Epub 2018 Oct 26.

Department of Epidemiology, CAPHRI Care and Public Health Research Institute/CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands. Electronic address:

Objective: The aim of this study was to develop and validate a comprehensive food frequency questionnaire (FFQ) for The Maastricht Study, a population-based prospective cohort study in Maastricht, The Netherlands.

Methods: Item selection for the FFQ was based on explained variation and contribution to intake of energy and 24 nutrients. For validation, the FFQ was completed by 135 participants (25-70 y of age) of the Nutrition Questionnaires plus study. Per person, on average 2.8 (range 1-5) telephone-based 24-h dietary recalls (24HRs), two 24-h urinary samples, and one blood sample were available. Validity of 54 nutrients and 22 food groups was assessed by ranking agreement, correlation coefficients, attenuation factors, and ultimately deattenuated correlation coefficients (validity coefficients).

Results: Median correlation coefficients for energy and macronutrients, micronutrients, and food groups were 0.45, 0.36, and 0.38, respectively. Median deattenuated correlation coefficients were 0.53 for energy and macronutrients, 0.45 for micronutrients, and 0.64 for food groups, being >0.50 for 18 of 22 macronutrients, 16 of 30 micronutrients and >0.50 for 17 of 22 food groups. The FFQ underestimated protein and potassium intake compared with 24-h urinary nitrogen and potassium excretion by -18% and -2%, respectively. Correlation coefficients ranged from 0.50 and 0.55 for (fatty) fish intake and plasma eicosapentaenoic acid and docosahexaenoic acid, and from 0.26 to 0.42 between fruit and vegetable intake and plasma carotenoids.

Conclusion: Overall, the validity of the 253-item Maastricht FFQ was satisfactory. The comprehensiveness of this FFQ make it well suited for use in The Maastricht Study and similar populations.
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http://dx.doi.org/10.1016/j.nut.2018.10.015DOI Listing
June 2019

Impact of the definition of osteoarthritis and of the timing of its onset on the association between type 2 diabetes mellitus and osteoarthritis: Clinical Practice Research Datalink.

Diabetes Res Clin Pract 2019 Feb 24;148:240-248. Epub 2019 Jan 24.

Department of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands; Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, Maastricht, the Netherlands. Electronic address:

Aims: In a previous case-control study in a large primary care database, the Clinical Practice Research Datalink (CPRD), type 2 diabetes mellitus (T2DM) was associated with a decreased rate of total joint replacement (TJR). As this was in contrast to the hypothesis, selection bias due to the used definition of osteoarthritis (OA) or misclassification of the onset of OA were raised as possible explanations. We therefore aimed to explore the effect of the definition of OA, and hypothesized timing of its onset on the association between T2DM and OA.

Methods: All patients using a non-insulin anti-hyperglycaemic drug (NIAD) between 1989 and 2012 in the CPRD were included and matched to unexposed patients. Cox proportional hazard models were fitted estimating the risk of TJR or OA in T2DM patients compared to patients without T2DM. These analyses were repeated in sensitivity scenarios and joint-specific analyses. To assess whether misclassification of onset of OA may affect the association, analyses were repeated with addition of a latency period of up to 10 years after start of follow-up.

Results: The use of TJR as a proxy for OA (hazard ratio (HR) = 0.74; 95% Confidence Interval (CI) = 0.70-0.78) resulted in a HR that was approximately 0.2 lower than when OA diagnostic codes were used (HR = 0.93; 95% CI = 0.90-0.95). The joint-specific subgroup analyses, sensitivity scenarios, and latency analyses showed similar results.

Conclusion: When examining the association between T2DM and OA, the use of TJR as a proxy for OA resulted in a 20% lower estimate than the OA diagnosis.
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http://dx.doi.org/10.1016/j.diabres.2019.01.021DOI Listing
February 2019

[Risk stratification and role for additional diagnostic testing in patients with acute chest pain and normal high-sensitivity cardiac troponin levels].

Ned Tijdschr Geneeskd 2018 12 5;162. Epub 2018 Dec 5.

Maastricht UMC+, afd. Cardiologie.

Background: Normal high sensitivity cardiac troponin (hs-cTn) assays rule out acute myocardial infarction (AMI) with great accuracy, but additional non-invasive testing is frequently ordered. This observational study evaluates whether clinical characteristics can contribute to risk stratification and could guide referral for additional testing.

Methods: This observational study included 918 patients with acute chest pain and normal hs-cTnT values. Major adverse cardiac events (MACE) and non-invasive test results were assessed during one-year follow-up. Patients were classified as low and high risk based on clinical characteristics.

Results: In total, 6,4% of patients experienced MACE during follow-up and mainly comprised revascularisations (86%). Absence of both recent abnormal stress test and suspicious history identified 86% of patients. These patients were at very low risk for MACE (0,4% in 30-days). Despite this, the majority (287/345=83%) of additional tests were performed in low risk patients, with 8% abnormal test findings (positive predictive value for MACE was 17%). The diagnostic yield was significantly higher in the remaining higher risk patients, 40% abnormal test findings and a positive predictive value of 70% for MACE.

Conclusion: Clinical characteristics can be used to identify low risk patients with acute chest pain and normal hs-cTnT levels. Current strategies in the emergency department result in numerous additional tests, which are mostly ordered in patients at very low risk and have a low diagnostic yield.
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December 2018

Intakes of Vitamin B-12 from Dairy Food, Meat, and Fish and Shellfish Are Independently and Positively Associated with Vitamin B-12 Biomarker Status in Pregnant Dutch Women.

J Nutr 2019 01;149(1):131-138

Departments of Epidemiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.

Background: The effect of vitamin B-12 from different animal foods on vitamin B-12 biomarker status has not previously been evaluated in pregnant women.

Objective: We examined the association of vitamin B-12 intake from dairy, meat, fish (including shellfish), and eggs with circulating concentrations of vitamin B-12 biomarkers and with the presence of vitamin B-12 deficiency in 1266 pregnant women participating in the KOALA Birth Cohort Study.

Methods: Blood samples were collected in weeks 34-36 of pregnancy, and vitamin B-12 intake from foods and supplements was estimated with a semiquantitative food-frequency questionnaire (FFQ). Total vitamin B-12, holotranscobalamin (holoTC), and methylmalonic acid (MMA) were determined in plasma. Vitamin B-12 deficiency was defined as holoTC <35 pmol/L and MMA >0.45 μmol/L. Associations were evaluated with linear and logistic regression analyses, adjusting for potential confounders.

Results: Significant dose-response relations were observed between vitamin B-12 intake from dairy, meat, and fish and plasma vitamin B-12, holoTC, and MMA [P-trend for (shell)fish with MMA = 0.002; P-trend for dairy, meat, and fish with all other markers < 0.001]. The OR (95% CI) of vitamin B-12 deficiency in the third compared with the first tertile of dairy-derived vitamin B-12 was 0.13 (0.04, 0.49), and the ORs for vitamin B-12 from meat and fish were 0.33 (0.11, 0.97) and 0.25 (0.08, 0.82), respectively. Egg-derived vitamin B-12 was only associated with holoTC. Additional analyses showed that self-defined vegetarians and FFQ-defined lacto-ovo-vegetarians had lower median total dietary vitamin B-12 intake and considerably worse vitamin B-12 biomarker status than omnivores and pescatarians.

Conclusions: In pregnant Dutch women, higher intakes of vitamin B-12 from dairy, meat, and fish were positively associated with vitamin B-12 status, suggesting that dairy, meat, and fish are good sources of bioactive vitamin B-12 in pregnancy. Nevertheless, for (lacto-)vegetarians, vitamin B-12 supplementation is recommended.
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http://dx.doi.org/10.1093/jn/nxy233DOI Listing
January 2019

Prediabetes Is Associated With Structural Brain Abnormalities: The Maastricht Study.

Diabetes Care 2018 12 16;41(12):2535-2543. Epub 2018 Oct 16.

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

Objective: Structural brain abnormalities are key risk factors for brain diseases, such as dementia, stroke, and depression, in type 2 diabetes. It is unknown whether structural brain abnormalities already occur in prediabetes. Therefore, we investigated whether both prediabetes and type 2 diabetes are associated with lacunar infarcts (LIs), white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and brain atrophy.

Research Design And Methods: We used data from 2,228 participants (1,373 with normal glucose metabolism [NGM], 347 with prediabetes, and 508 with type 2 diabetes (oversampled); mean age 59.2 ± 8.2 years; 48.3% women) of the Maastricht Study, a population-based cohort study. Diabetes status was determined with an oral glucose tolerance test. Brain imaging was performed with 3 Tesla MRI. Results were analyzed with multivariable logistic and linear regression analyses.

Results: Prediabetes and type 2 diabetes were associated with the presence of LIs (odds ratio 1.61 [95% CI 0.98-2.63] and 1.67 [1.04-2.68], respectively; = 0.027), larger WMH (β 0.07 log10-transformed mL [log-mL] [95% CI 0.00-0.15] and 0.21 log-mL [0.14-0.28], respectively; <0.001), and smaller white matter volumes (β -4.0 mL [-7.3 to -0.6] and -7.2 mL [-10.4 to -4.0], respectively; <0.001) compared with NGM. Prediabetes was not associated with gray matter volumes or the presence of CMBs.

Conclusions: Prediabetes is associated with structural brain abnormalities, with further deterioration in type 2 diabetes. These results indicate that, in middle-aged populations, structural brain abnormalities already occur in prediabetes, which may suggest that the treatment of early dysglycemia may contribute to the prevention of brain diseases.
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http://dx.doi.org/10.2337/dc18-1132DOI Listing
December 2018

Gut Microbiota and Body Weight in School-Aged Children: The KOALA Birth Cohort Study.

Obesity (Silver Spring) 2018 11 8;26(11):1767-1776. Epub 2018 Oct 8.

Department of Epidemiology, CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, the Netherlands.

Objective: This study aimed to examine the intestinal microbiota composition of school-aged children in association with (over)weight.

Methods: The fecal microbiota composition of 295 children was analyzed using the Human Intestinal Tract Chip. Anthropometric outcomes (overweight [BMI  ≥  85th percentile], age- and sex-standardized BMI and weight z scores) were measured at 6 to 7 years of age, and elastic net was used to select genus-like bacterial groups related to all anthropometric outcomes. Subsequently, multiple linear and logistic regression models were used to model associations between selected bacterial groups and anthropometric measures while controlling for confounders.

Results: Prevotella melaninogenica, Prevotella oralis, Dialister, and uncultured Clostridiales II (UCII) accounted for 26.1% of the variation in microbiota composition. Several bacterial groups were inversely associated with the anthropometric outcomes: Sutterella wadsworthensis, Marvinbryantia formatexigens, Prevotella melanogenica, P oralis, Burkholderia, uncultured Clostridiales II, and Akkermansia, while Streptococcus bovis was positively associated with overweight. Microbial diversity and richness, and Bacteroidetes to Firmicutes ratio, were not significantly associated with any of the outcomes.

Conclusions: In the largest population-based study on childhood gut microbiota and body weight so far, both new and previously identified bacterial groups were found to be associated with overweight. Further research should elucidate their role in energy metabolism.
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http://dx.doi.org/10.1002/oby.22320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646907PMC
November 2018

Consumption of dairy products in relation to the presence of clinical knee osteoarthritis: The Maastricht Study.

Eur J Nutr 2019 Oct 21;58(7):2693-2704. Epub 2018 Sep 21.

Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.

Purpose: Observational studies showed inverse associations between milk consumption and knee osteoarthritis (knee OA). There is lack of information on the role of specific dairy product categories. We explored the association between dairy consumption and the presence of knee osteoarthritis in 3010 individuals aged 40-75 years participating in The Maastricht Study.

Methods: The presence of knee OA was defined according to a slightly modified version of the American College of Rheumatology (ACR) clinical classification criteria. Data on dairy consumption were appraised by a 253-item FFQ covering 47 dairy products with categorization on fat content, fermentation or dairy type. Multivariable logistic regression analyses were performed to estimate odd ratios (ORs) and 95% confidence intervals (95%CI), while correcting for relevant factors.

Results: 427 (14%) participants were classified as having knee OA. Significant inverse associations were observed between the presence of knee OA and intake of full-fat dairy and Dutch, primarily semi-hard, cheese, with OR for the highest compared to the lowest tertile of intake of 0.68 (95%CI 0.50-0.92) for full-fat dairy, and 0.75 (95%CI 0.56-0.99) for Dutch cheese. No significant associations were found for other dairy product categories.

Conclusion: In this Dutch population, higher intake of full-fat dairy and Dutch cheese, but not milk, was cross-sectionally associated with the lower presence of knee OA. Prospective studies need to assess the relationship between dairy consumption, and in particular semi-hard cheeses, with incident knee OA.
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http://dx.doi.org/10.1007/s00394-018-1818-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768906PMC
October 2019

Efficacy of Nutritional Intervention in Elderly After Hip Fracture: A Multicenter Randomized Controlled Trial.

J Gerontol A Biol Sci Med Sci 2018 09;73(10):1429-1437

Department of Epidemiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.

Background: Malnutrition after hip fracture is associated with increased rehabilitation time, complications, and mortality. We assessed the effect of intensive 3 month nutritional intervention in elderly after hip fracture on length of stay (LOS).

Methods: Open-label, randomized controlled trial. Exclusion criteria: age < 55 years, bone disease, life expectancy < 1 year, bedridden, using oral nutritional supplements (ONS) before hospitalization, and cognitive impairment. Intervention: weekly dietetic consultation, energy-protein-enriched diet, and ONS (400 mL per day) for 3 months. Control: usual nutritional care. Primary outcome: total LOS in hospital and rehabilitation clinic, including readmissions over 6 months (Cox regression adjusted for confounders); hazard ratio (HR) < 1.0 reflects longer LOS in the intervention group. Secondary outcomes: nutritional and functional status, cognition, quality of life, postoperative complications (6 months); subsequent fractures and all-cause mortality (1 and 5 years). Effect modification by baseline nutritional status was also tested.

Results: One hundred fifty-two patients were randomized (73 intervention, 79 control). Median total LOS was 34.0 days (range 4-185 days) in the intervention group versus control 35.5 days (3-183 days; plogrank = .80; adjusted hazard ratio (adjHR): 0.98; 95% CI: 0.68-1.41). Hospital LOS: 12.0 days (4-56 days) versus 11.0 days (3-115 days; p = .19; adjHR: 0.75; 95% CI: 0.53-1.06) and LOS in rehabilitation clinics: 19.5 days (0-174 days) versus 18.5 days (0-168 days; p = .82; adjHR: 1.04; 95% CI: 0.73-1.48). The intervention improved nutritional intake/status at 3, but not at 6 months, and did not affect any other outcome. No difference in intervention effect between malnourished and well-nourished patients was found.

Conclusions: Intensive nutritional intervention after hip fracture improved nutritional intake and status, but not LOS or clinical outcomes. Paradigms underlying nutritional intervention in elderly after hip fracture may have to be reconsidered.
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http://dx.doi.org/10.1093/gerona/gly030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132112PMC
September 2018