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OBJECTIVE: Low baroreflex sensitivity (BRS) has been hypothesized to underlie high blood pressure (BP) and greater BP variability on the longer term, but evidence is scarce. In addition, these associations may differ by sex and (pre)diabetes. Therefore, we investigated whether cardiovagal BRS is associated with short- to mid-term mean BP and BP variability, and differs according to sex and (pre)diabetes.METHODS: Cross-sectional data from the population-based Maastricht study (age 60 ± 8 years, 52% men), where office (n = 2846), 24-h (n = 2404) and 7-day BP measurements (n = 2006) were performed. Spontaneous BRS was assessed by cross-correlating systolic BP and instantaneous heart rate. We used linear regression with adjustments for age, sex, BP or BP variability, and cardiovascular risk factors.RESULTS: With regard to BP, 1-SD (standard deviation) lower BRS (-5.75 ms/mmHg) was associated with higher office, 24-h and 7-day systolic BP (2.22 mmHg [95% confidence interval [CI]: 1.59; 2.80], 0.95 mmHg [0.54; 1.36], and 1.48 mmHg [0.99; 1.97], respectively) and diastolic BP (1.31 mmHg [0.97; 1.66], 0.57 mmHg [0.30; 0.84], and 0.86 mmHg [0.54; 1.17], respectively). Per 1-SD lower BRS, these associations were stronger in women (0.5-1.5 mmHg higher compared to men), and weaker in those with type 2 diabetes (1-1.5 mmHg lower compared to normal glucose metabolism). With regard to BP variability, BRS was not consistently associated with lower BP variability.CONCLUSIONS: Lower cardiovagal BRS is associated with higher mean BP from the short- to mid-term range, and not consistently with BP variability. The associations with mean BP are stronger in women and weaker in those with type 2 diabetes.

OBJECTIVE: Epidemiological evidence regarding the relationship between fructose intake and intrahepatic lipid (IHL) content is inconclusive. We, therefore, assessed the relationship between different sources of fructose and IHL at the population level.RESEARCH DESIGN AND METHODS: We used cross-sectional data from The Maastricht Study, with a population-based cohort (n = 3,981; mean ± SD age: 60 ± 9 years; 50% women). We assessed the relationship between fructose intake (assessed with a food-frequency questionnaire)-total and derived from fruit, fruit juice, and sugar-sweetened beverages (SSB)-and IHL (quantified with 3T Dixon MRI) with adjustment for age, sex, type 2 diabetes, education, smoking status, physical activity, and intakes of total energy, alcohol, saturated fat, protein, vitamin E, and dietary fiber.RESULTS: Energy-adjusted total fructose intake and energy-adjusted fructose from fruit were not associated with IHL in the fully adjusted models (P = 0.647 and P = 0.767). In contrast, energy-adjusted intake of fructose from fruit juice and SSB was associated with higher IHL in the fully adjusted models (P = 0.019 and P = 0.009). Individuals in the highest tertile of energy-adjusted intake of fructose from fruit juice and SSB had a 1.04-fold (95% CI 0.99; 1.11) and 1.09-fold (95% CI 1.03; 1.16) higher IHL, respectively, in comparison with the lowest tertile in the fully adjusted models. Finally, the association for fructose from fruit juice was stronger in individuals with type 2 diabetes (P for interaction = 0.071).CONCLUSIONS: Fructose from fruit juice and SSB is independently associated with higher IHL. These cross-sectional findings contribute to current knowledge in support of measures to reduce the intake of fructose-containing beverages as a means to prevent nonalcoholic fatty liver disease at the population level.

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 (n = 10,663 diabetes, n = 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

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*10-3 /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.

Background Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. Methods This study includes baseline data from 634 adults with overweight or obesity (BMI >= 27 kg/m(2)) (= 27 kg/m(2); 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. Results Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p <0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p <0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. Conclusions In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.

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.

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 [QR] 24-h UNaE and UKE were 3.7 (2.8-4.71 g/24 h and 3.0 12.4-3.61 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 r

The etiology of late-life depression (LLD) is still poorly understood. Microvascular dysfunction (MVD) has been suggested to play a role in the etiology of LLD, but direct evidence of this association is scarce. The aim of this study was to investigate whether direct and indirect markers of early microvascular dysfunction are associated with prevalent and incident LLD in the population-based Maastricht Study cohort. We measured microvascular dysfunction at baseline by use of flicker light-induced retinal vessel dilation response (Dynamic Vessel Analyzer), heat-induced skin hyperemic response (laser- Doppler flowmetry), and plasma markers of endothelial dysfunction (endothelial 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]). Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) at baseline and annually over 4 years of follow-up (n=3029; mean age 59.6±8.2 years, 49.5% were women, n=132 and n=251 with prevalent and incident depressive symptoms [PHQ-9≥10]). We used logistic, negative binominal and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle factors. Retinal venular dilatation and plasma markers of endothelial dysfunction were associated with the more prevalent depressive symptoms after full adjustment (PHQ-9 score, RR, 1.05 [1.00–1.11] and RR 1.06 [1.01–1.11], respectively). Retinal venular dilatation was also associated with prevalent depressive symptoms (PHQ-9≥10; odds ratio, 1.42 [1.09–1.84]), after full adjustment. Retinal arteriolar dilatation and plasma markers of endothelial dysfunction were associated with incident depressive symptoms (PHQ-9≥10; HR, 1.23 [1.04–1.46] and HR, 1.19 [1.05–1.35]), after full adjustment. These findings support the concept that microvascular dysfunction in the retina, and plasma markers of endothelial dysfunction is involved in the

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.

Background: Glucose variability (GV) measured by continuous glucose monitoring (CGM) has become an accepted marker of glycemic control. Nevertheless, several methodological aspects of GV assessment require further study. We, therefore, investigated the minimum number of days needed to reliably measure GV, assessed GV reference values, and studied the correlation of GV with established glycemic indices (i.e., HbA(1c), seven-point oral glucose tolerance test [OGTT]-derived indices). Methods: We used cross-sectional data from The Maastricht Study, an observational population-based cohort enriched with type 2 diabetes. Participants with more than 48 h of CGM (iPro2; Medtronic) were included for analysis (n = 851; age: 60 +/- 9years; 49% women; 23% type 2 diabetes). We used mean sensor glucose (MSG), standard deviation (SD), and coefficient of variation (CV) as CGM-derived indices (the latter two for GV quantification). We calculated reliability using the Spearman-Brown prophecy formula, established reference values by calculating 2.5th-97.5th percentiles, and studied correlations using Spearman's rho. Results: Sufficient reliability (R > 0.80) was achieved with two (MSG and SD), or three monitoring days (CV). The reference ranges, assessed in individuals with normal glucose metabolism (n = 470), were 90.5-120.6 mg/dL (MSG), 7.9-24.8 mg/dL (SD), and 7.74%-22.45% (CV). For MSG, the strongest correlation was found with fasting plasma glucose (rho = 0.65 [0.61; 0.69]); for SD, with the 1-h OGTT value (rho = 0.61 [0.56; 0.65]); and for CV, with both the incremental glucose peak (IGP) during the OGTT (rho = 0.50 [0.45; 0.55]) and the 1-h OGTT value (rho = 0.50 [0.45; 0.55]). Conclusions: The reliability findings and reference values are relevant for studies that aim to investigate CGM-measured GV. One-hour OGTT and IGP values can be used as GV indices when CGM is unavailable.

The etiology of late-life depression (LLD) is still poorly understood. Microvascular dysfunction (MVD) has been suggested to play a role in the etiology of LLD, but direct evidence of this association is scarce. The aim of this study was to investigate whether direct and indirect markers of early microvascular dysfunction are associated with prevalent and incident LLD in the population-based Maastricht Study cohort. We measured microvascular dysfunction at baseline by use of flicker light-induced retinal vessel dilation response (Dynamic Vessel Analyzer), heat-induced skin hyperemic response (laser- Doppler flowmetry), and plasma markers of endothelial dysfunction (endothelial 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]). Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) at baseline and annually over 4 years of follow-up (n=3029; mean age 59.6±8.2 years, 49.5% were women, n=132 and n=251 with prevalent and incident depressive symptoms [PHQ-9≥10]). We used logistic, negative binominal and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle factors. Retinal venular dilatation and plasma markers of endothelial dysfunction were associated with the more prevalent depressive symptoms after full adjustment (PHQ-9 score, RR, 1.05 [1.00-1.11] and RR 1.06 [1.01-1.11], respectively). Retinal venular dilatation was also associated with prevalent depressive symptoms (PHQ-9≥10; odds ratio, 1.42 [1.09-1.84]), after full adjustment. Retinal arteriolar dilatation and plasma markers of endothelial dysfunction were associated with incident depressive symptoms (PHQ-9≥10; HR, 1.23 [1.04-1.46] and HR, 1.19 [1.05-1.35]), after full adjustment. These findings support the concept that microvascular dysfunction in the retina, and plasma markers of endothelial dysfunction is involved in