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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Associations of linoleic acid with markers of glucose metabolism and liver function in South African adults
    Pertiwi, Kamalita ; Küpers, Leanne K. ; Geleijnse, Johanna M. ; Zock, Peter L. ; Wanders, Anne J. ; Kruger, Herculina S. ; Zyl, Tertia Van; Kruger, Iolanthé M. ; Smuts, Cornelius M. - \ 2020
    Lipids in Health and Disease 19 (2020)1. - ISSN 1476-511X
    African - Alcohol intake - Gamma-glutamyl transferase - Glycemia - Linoleic acid - Liver enzymes - Polyunsaturated fatty acids

    Background: The relation between dietary and circulating linoleic acid (18:2 n-6, LA), glucose metabolism and liver function is not yet clear. Associations of dietary and circulating LA with glucose metabolism and liver function markers were investigated. Methods: Cross-sectional analyses in 633 black South Africans (aged > 30 years, 62% female, 51% urban) without type 2 diabetes at baseline of the Prospective Urban Rural Epidemiology study. A cultural-sensitive 145-item food-frequency questionnaire was used to collect dietary data, including LA (percentage of energy; en%). Blood samples were collected to measure circulating LA (% total fatty acids (FA); plasma phospholipids), plasma glucose, glycosylated hemoglobin (HbA1c), serum gamma-glutamyl transferase (GGT), alanine (ALT) and aspartate aminotransferase (AST). Associations per 1 standard deviation (SD) and in tertiles were analyzed using multivariable regression. Results: Mean (±SD) dietary and circulating LA was 6.8 (±3.1) en% and 16.0 (±3.5) % total FA, respectively. Dietary and circulating LA were not associated with plasma glucose or HbA1c (β per 1 SD: - 0.005 to 0.010, P > 0.20). Higher dietary LA was generally associated with lower serum liver enzymes levels. One SD higher circulating LA was associated with 22% lower serum GGT (β (95% confidence interval): - 0.25 (- 0.31, - 0.18), P < 0.001), but only ≤9% lower for ALT and AST. Circulating LA and serum GGT associations differed by alcohol use and locality. Conclusion: Dietary and circulating LA were inversely associated with markers of impaired liver function, but not with glucose metabolism. Alcohol use may play a role in the association between LA and liver function.

    Plasma and Dietary Linoleic Acid and 3-Year Risk of Type 2 Diabetes After Myocardial Infarction: A Prospective Analysis in the Alpha Omega Cohort
    Pertiwi, Kamalita ; Wanders, Anne J. ; Harbers, Marjolein C. ; Küpers, Leanne K. ; Soedamah-Muthu, Sabita S. ; Goede, Janette de; Zock, Peter L. ; Geleijnse, Johanna M. - \ 2020
    Diabetes Care 43 (2020)2. - ISSN 0149-5992 - p. 358 - 365.

    OBJECTIVE: To study plasma and dietary linoleic acid (LA) in relation to type 2 diabetes risk in post-myocardial infarction (MI) patients. RESEARCH DESIGN AND METHODS: We included 3,257 patients aged 60-80 years (80% male) with a median time since MI of 3.5 years from the Alpha Omega Cohort and who were initially free of type 2 diabetes. At baseline (2002-2006), plasma LA was measured in cholesteryl esters, and dietary LA was estimated with a 203-item food-frequency questionnaire. Incident type 2 diabetes was ascertained through self-reported physician diagnosis and medication use. Hazard ratios (with 95% CIs) were calculated by Cox regressions, in which dietary LA isocalorically replaced the sum of saturated (SFA) and trans fatty acids (TFA). RESULTS: Mean ± SD circulating and dietary LA was 50.1 ± 4.9% and 5.9 ± 2.1% energy, respectively. Plasma and dietary LA were weakly correlated (Spearman r = 0.13, P < 0.001). During a median follow-up of 41 months, 171 patients developed type 2 diabetes. Plasma LA was inversely associated with type 2 diabetes risk (quintile [Q]5 vs. Q1: 0.44 [0.26, 0.75]; per 5%: 0.73 [0.62, 0.86]). Substitution of dietary LA for SFA+TFA showed no association with type 2 diabetes risk (Q5 vs. Q1: 0.78 [0.36, 1.72]; per 5% energy: 1.18 [0.59, 2.35]). Adjustment for markers of de novo lipogenesis attenuated plasma LA associations. CONCLUSIONS: In our cohort of post-MI patients, plasma LA was inversely related to type 2 diabetes risk, whereas dietary LA was not related. Further research is needed to assess whether plasma LA indicates metabolic state rather than dietary LA in these patients.

    Associations of dairy and fiber intake with circulating odd-chain fatty acids in post-myocardial infarction patients
    Pertiwi, Kamalita ; Küpers, Leanne K. ; Wanders, Anne J. ; Goede, Janette De; Zock, Peter L. ; Geleijnse, Johanna M. - \ 2019
    Nutrition & Metabolism 16 (2019)1. - ISSN 1743-7075
    Biomarkers - Food frequency questionnaire - Margaric acid - Pentadecanoic acid - Plasma fatty acids

    Background: Circulating odd-chain fatty acids pentadecanoic (15:0) and heptadecanoic acid (17:0) are considered to reflect dairy intake. In cohort studies, higher circulating 15:0 and 17:0 were associated with lower type 2 diabetes risk. A recent randomized controlled trial in humans suggested that fiber intake also increased circulating 15:0 and 17:0, potentially resulting from fermentation by gut microbes. We examined the associations of dairy and fiber intake with circulating 15:0 and 17:0 in patients with a history of myocardial infarction (MI). Methods: We performed cross-sectional analyses in a subsample of 869 Dutch post-MI patients of the Alpha Omega Cohort who had data on dietary intake and circulating fatty acids. Dietary intakes (g/d) were assessed using a 203-item food frequency questionnaire. Circulating 15:0 and 17:0 (as % of total fatty acids) were measured in plasma phospholipids (PL) and cholesteryl esters (CE). Spearman correlations (r s ) were computed between intakes of total dairy, dairy fat, fiber, and circulating 15:0 and 17:0. Results: Patients were on average 69 years old, 78% was male and 21% had diabetes. Total dairy intake comprised predominantly milk and yogurt (69%). Dairy fat was mainly derived from cheese (47%) and milk (15%), and fiber was mainly from grains (43%). Circulating 15:0 in PL was significantly correlated with total dairy and dairy fat intake (both r s = 0.19, p < 0.001), but not with dietary fiber intake (r s = 0.05, p = 0.11). Circulating 17:0 in PL was correlated both with dairy intake (r s = 0.14 for total dairy and 0.11 for dairy fat, p < 0.001), and fiber intake (r s = 0.19, p < 0.001). Results in CE were roughly similar, except for a weaker correlation of CE 17:0 with fiber (r s = 0.11, p = 0.001). Circulating 15:0 was highest in those with high dairy intake irrespective of fiber intake, while circulating 17:0 was highest in those with high dairy and fiber intake. Conclusions: In our cohort of post-MI patients, circulating 15:0 was associated with dairy intake but not fiber intake, whereas circulating 17:0 was associated with both dairy and fiber intake. These data suggest that cardiometabolic health benefits previously attributed to 17:0 as a biomarker of dairy intake may partly be explained by fiber intake.

    Plant-derived polyunsaturated fatty acids and markers of glucose metabolism and insulin resistance : A meta-analysis of randomized controlled feeding trials
    Wanders, Anne J. ; Blom, Wendy A.M. ; Zock, Peter L. ; Geleijnse, Johanna M. ; Brouwer, Ingeborg A. ; Alssema, Marjan - \ 2019
    BMJ Open Diabetes Research and Care 7 (2019)1. - ISSN 2052-4897
    dietary fat - glucose metabolism - insulin resistance - Linoleic acid - meta-analysis

    The objective of this meta-analysis was to investigate the effects of plant-derived polyunsaturated fatty acids (PUFAs) on glucose metabolism and insulin resistance. Scopus and PubMed databases were searched until January 2018. Eligible studies were randomized controlled feeding trials that investigated the effects of a diet high in plant-derived PUFA as compared with saturated fatty acids (SFA) or carbohydrates and measured markers of glucose metabolism and insulin resistance as outcomes. Data from 13 relevant studies (19 comparisons of plant-derived PUFA with control) were retrieved. Plant-derived PUFA did not significantly affect fasting glucose (-0.01 mmol/L (95 % CI - 0.06 to 0.03 mmol/L)), but lowered fasting insulin by 2.6 pmol/L (-4.9 to -0.2 pmol/L) and homeostatic model assessment-insulin resistance (HOMA-IR) by 0.12 units (-0.23 to - 0.01 units). In dose-response analyses, a 5% increase in energy (En%) from PUFA significantly reduced insulin by 5.8 pmol/L (95% CI -10.2 to -1.3 pmol/L), but not glucose (change -0.07, 95% CI -0.17 to 0.04 mmol/L) and HOMA-IR (change - 0.24, 95% CI -0.56 to 0.07 units). In subgroup analyses, studies with higher PUFA dose (upper tertiles) reduced insulin (-6.7, -10.5 to -2.9 pmol/L) and HOMA-IR (-0.28, -0.45 to -0.12 units), but not glucose (-0.09, 95% CI -0.18 to 0.01 mmol/L), as compared with an isocaloric control. Subgroup analyses showed no differences in effects between SFA and carbohydrates as replacement nutrients (p interaction ≥0.05). Evidence from randomized controlled trials indicated that plant-derived PUFA as an isocaloric replacement for SFA or carbohydrates probably reduces fasting insulin and HOMA-IR in populations without diabetes.

    Circulating n-3 fatty acids and linoleic acid as indicators of dietary fatty acid intake in post-myocardial infarction patients
    Pertiwi, K. ; Kok, D.E. ; Wanders, A.J. ; Goede, J. de; Zock, P.L. ; Geleijnse, J.M. - \ 2019
    Nutrition, Metabolism & Cardiovascular Diseases 29 (2019)4. - ISSN 0939-4753 - p. 343 - 350.
    Biomarkers - Cardiac patients - Circulating fatty acids - Dietary fatty acids - Food frequency questionnaire - Linoleic acid - n-3 fatty acids - Plasma fatty acids

    Background and aims: Population-based studies often use plasma fatty acids (FAs) as objective indicators of FA intake, especially for n-3 FA and linoleic acid (LA). The relation between dietary and circulating FA in cardiometabolic patients is largely unknown. We examined whether dietary n-3 FA and LA were reflected in plasma lipid pools in post-myocardial infarction (MI) patients. Methods and results: Patients in Alpha Omega Cohort filled out a 203-item food-frequency questionnaire from which eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and LA intake were calculated. Circulating individual FA (% total FA) were assessed in cholesteryl esters (CE; n = 4066), phospholipids (PL; n = 838), and additionally in total plasma for DHA and LA (n = 739). Spearman correlation coefficients (rs) were calculated for dietary vs. circulating FA. Circulating FA were also compared across dietary FA quintiles, overall and in subgroups by sex, obesity, diabetes, statin use, and high alcohol intake. Patients were on average 69 years old and 79% was male. Moderate correlations between dietary and circulating levels were observed for EPA (rs ∼0.4 in CE and PL) and DHA (rs ∼0.5 in CE and PL, ∼0.4 in total plasma), but not for ALA (rs ∼0.0). Weak correlations were observed for LA (rs 0.1 to 0.2). Plasma LA was significantly lower in statin users and in patients with a high alcohol intake. Conclusions: In post-MI patients, dietary EPA and DHA were well reflected in circulating levels. This was not the case for LA, which may partly be influenced by alcohol use and statins.

    Circulating Polyunsaturated Fatty Acids as Biomarkers for Dietary Intake across Subgroups : The CODAM and Hoorn Studies
    Wanders, Anne J. ; Alssema, Marjan ; Hoon, Sabine E.M. De; Feskens, Edith J.M. ; Woudenbergh, G.J. van; Kallen, Carla J. van der; Zock, Peter L. ; Refsum, Helga ; Drevon, Christian A. ; Elshorbagy, Amany ; Schalkwijk, Casper G. ; Stehouwer, Coen D.A. ; Dekker, Jacqueline M. ; Greevenbroek, Marleen M.J. van - \ 2018
    Annals of Nutrition & Metabolism 72 (2018)2. - ISSN 0250-6807 - p. 117 - 125.
    Biomarker - Circulating fatty acids - Dietary fat - Polyunsaturated fat
    Aims: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Methods: Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (µg/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. Results: Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA β = 0.28, ALA β = 0.13, EPA β = 0.34, and DHA β = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influenced associations for LA; gender influenced LA, EPA, and DHA; alcohol intake influenced LA and DHA; and glucose tolerance status influenced ALA (p values interaction <0.05). Coefficients for circulating FA as concentrations were LA β = 0.19, ALA β = 0.10, EPA β = 0.31, and DHA β = 0.41. Conclusions: This study suggests that characteristics such as BMI, alcohol intake, and expressing circulating FA as proportions or concentrations, influence associations between dietary and circulating FA.
    Dietary fatty acid intake after myocardial infarction : A theoretical substitution analysis of the Alpha Omega Cohort
    Molenberg, Famke ; Goede, Janette de; Wanders, A.J. ; Zock, Peter L. ; Kromhout, Daan ; Geleijnse, Johanna M. - \ 2017
    American Journal of Clinical Nutrition 106 (2017)3. - ISSN 0002-9165 - p. 895 - 901.
    Cardiac patients - Cardiovascular disease - Coronary heart disease - Dietary fatty acids - Prospective cohort study - Substitution analysis

    Background: Replacement of saturated fatty acids (SFAs) with unsaturated fatty acids (UFAs), especially polyunsaturated fatty acids (PUFAs), has been associated with a lower risk of ischemic heart disease (IHD). Whether this replacement is beneficial for drug-treated patients with cardiac disease is not yet clear. Objective: In a prospective study of Dutch patients with cardiac disease (Alpha Omega Cohort), we examined the risk of cardiovascular disease (CVD) and IHD mortality when the sum of SFAs and trans fatty acids (TFAs) was theoretically replaced by total UFAs, PUFAs, or cis monounsaturated fatty acids (MUFAs). Design: We included 4146 state-of-the-art drug-treated patients aged 60-80 y with a history of myocardial infarction (79% male patients) and reliable dietary data at baseline (2002-2006). Cause-specific mortality was monitored until 1 January 2013. HRs for CVD mortality and IHD mortality for theoretical, isocaloric replacement of dietary fatty acids (FAs) in quintiles (1-5) and continuously (per 5% of energy) were obtained from Cox regression models, adjusting for demographic factors, medication use, and lifestyle and dietary factors. Results: Patients consumed, on average, 17.5% of energy of total UFAs, 13.0% of energy of SFAs, and <1% of energy of TFAs. During 7 y of follow-up, 372 CVD deaths and 249 IHD deaths occurred. Substitution modeling yielded significantly lower risks of CVD mortality when replacing SFAs plus TFAs with total UFAs [HR in quintile 5 compared with quintile 1: 0.45 (95% CI: 0.28, 0.72)] or PUFAs [HR: 0.66 (95% CI: 0.44, 0.98)], whereas HRs in cis MUFA quintiles were nonsignificant. HRs were similar for IHD mortality. In continuous analyses, replacement of SFAs plus TFAs with total UFAs, PUFAs, or cis MUFAs (per 5% of energy) was associated with significantly lower risks of CVD mortality (HRs between 0.68 and 0.75) and IHD mortality (HRs between 0.55 and 0.70). Conclusion: Shifting the FA composition of the diet toward a higher proportion of UFAs may lower CVD mortality risk in drug-treated patients with cardiac disease.

    Fatty acid intake and its dietary sources in relation with markers of type 2 diabetes risk : The NEO study
    Wanders, A.J. ; Alssema, M. ; Koning, E.J.P. de; Cessie, S. Le; Vries, J.H. de; Zock, P.L. ; Rosendaal, F.R. ; Heijer, M. den; Mutsert, R. de - \ 2017
    European Journal of Clinical Nutrition 71 (2017)2. - ISSN 0954-3007 - p. 245 - 251.

    Objective: The aim of this study was to examine the relations between intakes of total, saturated, mono-unsaturated, poly-unsaturated and trans fatty acids (SFA, MUFA, PUFA and TFA), and their dietary sources (dairy, meat and plant) with markers of type 2 diabetes risk. Subjects/Methods: This was a cross-sectional analysis of baseline data of 5675 non-diabetic, middle-aged participants of the Netherlands Epidemiology of Obesity (NEO) study. Associations between habitual dietary intake and fasting and postprandial blood glucose and insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), HOMA of β-cell function (HOMA-B) and Disposition Index were assessed through multivariable linear regression models with adjustments for demographic, lifestyle and dietary factors. Results: Mean (s.d.) intakes in percent of energy (En%) were 34.4 (5.8) for total fatty acids, 12.4 (2.9) for SFA, 12.2 (2.4) for MUFA, 6.9 (1.9) for PUFA and 0.6 (0.2) for TFA. As compared with carbohydrates, only SFA was weakly inversely associated with fasting insulin, HOMA-IR and HOMA-B. When stratified by dietary source, all fatty acids from meat were positively associated with fasting insulin-total fatty acidsmeat (per 5 En%: 10.0%; 95% confidence interval: 4.0, 16.3), SFAmeat (per 1 En%: 3.7%; 0.4, 7.2), MUFAmeat (per 1 En%: 5.0%; 2.0, 8.1), PUFAmeat (per 1 En%: 17.3%; 6.0, 29.7) and TFAmeat (per 0.1 En%: 10.5%; 3.2, 18.3). Similarly, all fatty acids from meat were positively associated with HOMA-IR and HOMA-B and inversely with Disposition Index. Conclusions: Our study suggests that the relations between fatty acid intakes and markers of type 2 diabetes risk may depend on the dietary sources of the fatty acids. More epidemiological studies on diet and cardiometabolic disease are needed, addressing possible interactions between nutrients and their dietary sources.

    Impact of volunteer-related and methodology-related factors on the reproducibility of brachial artery flow-mediated vasodilation : Analysis of 672 individual repeated measurements
    Mil, Anke C.C.M. van; Greyling, Arno ; Zock, Peter L. ; Geleijnse, Marianne ; Hopman, Maria T. ; Mensink, Ronald P. ; Reesink, Koen D. ; Green, Daniel J. ; Ghiadoni, Lorenzo ; Thijssen, Dick H. - \ 2016
    Journal of Hypertension 34 (2016)9. - ISSN 0263-6352 - p. 1738 - 1745.
    Doppler - endothelial function - flow-mediated dilation - reproducibility - ultrasonography

    Objectives: Brachial artery flow-mediated dilation (FMD) is a popular technique to examine endothelial function in humans. Identifying volunteer and methodological factors related to variation in FMD is important to improve measurement accuracy and applicability. Methods: Volunteer-related and methodology-related parameters were collected in 672 volunteers from eight affiliated centres worldwide who underwent repeated measures of FMD. All centres adopted contemporary expert-consensus guidelines for FMD assessment. After calculating the coefficient of variation (%) of the FMD for each individual, we constructed quartiles (n = 168 per quartile). Based on two regression models (volunteer-related factors and methodology-related factors), statistically significant components of these two models were added to a final regression model (calculated as β-coefficient and R 2). This allowed us to identify factors that independently contributed to the variation in FMD%. Results: Median coefficient of variation was 17.5%, with healthy volunteers demonstrating a coefficient of variation 9.3%. Regression models revealed age (β = 0.248, P <0.001), hypertension (β = 0.104, P <0.001), dyslipidemia (β = 0.331, P <0.001), time between measurements (β = 0.318, P <0.001), lab experience (β = -0.133, P <0.001) and baseline FMD% (β = 0.082, P <0.05) as contributors to the coefficient of variation. After including all significant factors in the final model, we found that time between measurements, hypertension, baseline FMD% and lab experience with FMD independently predicted brachial artery variability (total R2 = 0.202). Conclusion: Although FMD% showed good reproducibility, larger variation was observed in conditions with longer time between measurements, hypertension, less experience and lower baseline FMD%. Accounting for these factors may improve FMD% variability.

    Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized double-blind, placebo-controlled, crossover trial
    Dower, J.I. ; Geleijnse, J.M. ; Gijsbers, L. ; Zock, P.L. ; Kromhout, D. ; Hollman, P.C.H. - \ 2015
    American Journal of Clinical Nutrition 101 (2015)5. - ISSN 0002-9165 - p. 914 - 921.
    homeostasis model assessment - reduces blood-pressure - flavanol-rich cocoa - insulin-resistance - dark chocolate - cardiovascular-disease - hypertensive subjects - endothelial function - plasma epicatechin - catechin contents
    BACKGROUND: Prospective cohort studies showed inverse associations between the intake of flavonoid-rich foods (cocoa and tea) and cardiovascular disease (CVD). Intervention studies showed protective effects on intermediate markers of CVD. This may be due to the protective effects of the flavonoids epicatechin (in cocoa and tea) and quercetin (in tea). OBJECTIVE: We investigated the effects of supplementation of pure epicatechin and quercetin on vascular function and cardiometabolic health. DESIGN: Thirty-seven apparently healthy men and women aged 40-80 y with a systolic blood pressure (BP) between 125 and 160 mm Hg at screening were enrolled in a randomized, double-blind, placebo-controlled, crossover trial. CVD risk factors were measured before and after 4 wk of daily flavonoid supplementation. Participants received (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 wk in random order. The primary outcome was the change in flow-mediated dilation from pre- to postintervention. Secondary outcomes included other markers of CVD risk and vascular function. RESULTS: Epicatechin supplementation did not change flow-mediated dilation significantly (1.1% absolute; 95% CI: -0.1%, 2.3%; P = 0.07). Epicatechin supplementation improved fasting plasma insulin (¿ insulin: -1.46 mU/L; 95% CI: -2.74, -0.18 mU/L; P = 0.03) and insulin resistance (¿ homeostasis model assessment of insulin resistance: -0.38; 95% CI: -0.74, -0.01; P = 0.04) and had no effect on fasting plasma glucose. Epicatechin did not change BP (office BP and 24-h ambulatory BP), arterial stiffness, nitric oxide, endothelin 1, or blood lipid profile. Quercetin-3-glucoside supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors. CONCLUSIONS: Our results suggest that epicatechin may in part contribute to the cardioprotective effects of cocoa and tea by improving insulin resistance. It is unlikely that quercetin plays an important role in the cardioprotective effects of tea. This study was registered at as NCT01691404.
    Phytosterols and blood lipid risk factors for cardiovascular disease
    Ras, R.T. - \ 2014
    Wageningen University. Promotor(en): Frans Kok, co-promotor(en): Marianne Geleijnse; P.L. Zock. - Wageningen : Wageningen University - ISBN 9789462571006 - 234
    hart- en vaatziekten - hart- en vaatstoornissen - phytosterolen - sterolen - bloedvetten - risicofactoren - cholesterol - cardiovascular diseases - cardiovascular disorders - phytosterols - sterols - blood lipids - risk factors - cholesterol

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Lifestyle improvements including dietary changes are important for CVD prevention. This thesis aimed to advance insights in the role of phytosterols, lipid-like compounds present in foods or plant origin, in the management of blood lipid risk factors for CVD. Phytosterols include plant sterols and their saturated form, plant stanols. These compounds resemble cholesterol in both structure and function, but cannot be produced by the human body. The intake of phytosterols occurs through plant-based foods and/or enriched foods like margarine.

    Elevated blood low-density lipoprotein cholesterol (LDL-C) is a major risk factor for CVD, especially for coronary heart disease (CHD) resulting from atherosclerosis. We studied the dose-response relationship between dietary phytosterols and blood LDL-C in two meta-analyses (Chapters 2 and 3). A meta-analysis of 81 randomized controlled trials (Chapter 2) demonstrated a non-linear, continuous dose-response relationship for the LDL-C-lowering effect of phytosterols. Based on this dose-response curve, it may be predicted that phytosterols at a dose of 2 g/d lower LDL-C by 0.35 mmol/L or 9%. The dose-response curve reached a plateau at phytosterol doses of ~3 g/d, above which there is limited additional LDL-C-lowering effect. In another meta-analysis of 124 randomized controlled trials (Chapter 3), we showed that plant sterols and plant stanols up to ~3 g/d are equally effective in lowering LDL-C by a maximum of 12%. No conclusions could be drawn for phytosterol doses exceeding 4 g/d because of the limited number of studies.

    Elevated blood triglycerides (TGs) may also be involved in the onset of CVD, although its role is less established than for LDL-C. The effect of plant sterols on blood TG concentrations was assessed in a meta-analysis of individual subject data from 12 randomized controlled trials (Chapter 4). We showed that plant sterols, at a dose of ~2 g/d, modestly reduce TG concentrations by on average 0.12 mmol/L or 6%. The TG-lowering effect of plant sterols was larger in subjects with higher initial TG concentrations. Our double-blind, placebo-controlled, randomized trial with 332 subjects (Chapter 5) showed more pronounced TG-lowering effects of 9-16% when plant sterols (2.5 g/d) were combined with low doses of omega-3 fish fatty acids (0.9 to 1.8 g/d).

    Dietary phytosterols are, after initial absorption by intestinal cells, actively excreted back into the intestinal lumen. Nevertheless, small amounts reach the circulation. We assessed the effect of plant sterol intake on blood plant sterol concentrations in a meta-analysis of 41 randomized controlled trials (Chapter 6). The intake of plant sterols, at a dose of ~1.6 g/d, increased blood sitosterol concentrations by on average 2 μmol/L (31%) and campesterol concentrations by 5 μmol/L (37%). At the same time, total cholesterol and LDL-C concentrations were reduced by on average 0.36 mmol/L (6%) and 0.33 mmol/L (9%), respectively. After supplemental intake, plant sterol concentrations remained below 1% of total sterols circulating in the blood.

    Whether phytosterols, due to their LDL-C-lowering properties, affect the risk of CVD events is at present unknown. The relation between phytosterol intake from natural sources (e.g. vegetables, cereals, nuts) and CVD risk in the population was examined in a large prospective cohort of 35,597 Dutch men and women with 12 years of follow-up (Chapter 7). The intake of phytosterols from natural sources (~300 mg/d) was not related to risk of CVD (total of 3,047 events) with a relative risk ranging from 0.90 to 0.99 across quintiles of phytosterol intake. Also, no association with incident CHD and myocardial infarction were found. In a cross-sectional analysis using baseline data of this cohort, phytosterol intake was associated with lower blood LDL-C in men (-0.18 mmol/L per 50 mg/d; 95% CI: -0.29; -0.08) but not in women (-0.03 mmol/L; 95% CI: -0.08; 0.03).

    Most randomized trials with enriched foods have tested phytosterol doses between 1.5 and 2.4 g/d. In practice, however, users of such foods consume much lower amounts (~1 g/d), which is about 3 times higher than obtained from a regular Western diet. Individuals who consume diets with emphasis on plant-based foods (e.g. vegetarians) may reach phytosterol intakes between 0.5 and 1 g/d. Health authorities recommend various types of diets for CVD prevention, almost all rich in plant-based foods and, consequently, relatively rich in phytosterols.

    In conclusion, a high intake of phytosterols with enriched foods was shown to lower LDL-C in a dose-dependent manner. Furthermore, a high intake of plant sterols with enriched foods modestly lowered TG concentrations and increased plasma plant sterol concentrations. A low intake of naturally occurring phytosterols in the general population did not show a clear association with CVD risk. Based on these findings, the intake of phytosterols may be considered in the management of hypercholesterolemia. Whether a high intake of phytosterols can play a role in CVD prevention in the population at large remains to be established.

    Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis
    Ras, R.T. ; Streppel, M.T. ; Draijer, R. ; Zock, P.L. - \ 2013
    International Journal of Cardiology 168 (2013)1. - ISSN 0167-5273 - p. 344 - 351.
    coronary-artery-disease - chronic heart-failure - endothelial dysfunction - brachial-artery - prognostic role - chest-pain - postmenopausal women - mortality risk - events - vasodilation
    Background Flow-mediated dilation (FMD) is an accepted technique to quantify endothelial function and has shown to have prognostic value for future cardiovascular disease (CVD). The predictive strength of FMD in CVD patients compared to populations not diagnosed for CVD warrants further investigation. We systematically reviewed prospective studies that investigated the association between brachial FMD and future cardiovascular events, with particular focus on the role of underlying health status. Methods To obtain eligible studies, several literature databases were systematically searched through March 2011. Pooled overall risk estimates were calculated separately for continuous risk estimates for CVD (per 1% higher FMD) and for categorical risk estimates for CVD (having high vs. low FMD), based on random-effects models. Results A total of 23 studies including 14,753 subjects were eligible for inclusion in the meta-analysis. For studies reporting continuous risk estimates, the pooled overall CVD risk was 0.92 (95%CI: 0.88; 0.95) per 1% higher FMD. The observed association seemed stronger (P-value <0.01) in diseased populations than in asymptomatic populations (0.87 (95%CI: 0.83; 0.92) and 0.96 (95%CI: 0.92; 1.00) per 1% higher FMD, respectively). For studies reporting categorical risk estimates, the pooled overall CVD risk for high vs. low FMD was similar in both types of populations, on average 0.49 (95%CI: 0.39; 0.62). Conclusions Our findings show that brachial FMD is inversely associated with future CVD events, with some indications for a stronger relation in diseased populations. Endothelial dysfunction may be considered relevant for classifying subjects in terms of CVD risk.
    The effect of plant sterols on serum triglyceride concentrations is dependent on baseline concentrations: a pooled analysis of 12 randomised controlled trials
    Demonty, I. ; Ras, R.T. ; Knaap, H.C.M. van der; Meijer, L. ; Zock, P.L. ; Geleijnse, J.M. ; Trautwein, E.A. - \ 2013
    European Journal of Nutrition 52 (2013)1. - ISSN 1436-6207 - p. 153 - 160.
    ldl-cholesterol concentrations - mildly hypercholesterolemic subjects - density-lipoprotein cholesterol - enriched spread - cardiovascular-disease - phytosterol intake - clinical-trials - plasma-lipids - fat spreads - diet
    Purpose - Plant sterols (PS) are well known for their low-density lipoprotein cholesterol-lowering effect. Until recently, they were believed to have little or no impact on blood triglycerides (TG). However, studies taken individually were possibly lacking statistical power to detect modest TG decreases. This study was performed to quantify the TG-lowering effect of PS by pooling individual subject data from 12 randomised controlled trials that investigated the effects of PS on blood lipids. Methods - The main outcome variable was the control-adjusted PS effect on relative (%) and absolute (mmol/L) changes in TG. The relative and absolute changes in high-density lipoprotein cholesterol (HDL-C) were also assessed. Differences in changes of serum lipid concentrations between PS and control treatments were estimated by an ANCOVA using a random effect model which included PS intake (active or control), study and predefined subject characteristics. Results - The twelve randomised controlled trials included in total 935 hypercholesterolaemic subjects not preselected based on their baseline TG concentrations. In most studies, the PS dose ranged between 1.6 and 2.5 g/day. PS intake significantly lowered serum TG by 6.0% (95% CI: -10.7, -1.2) or 0.12 mmol/L (95% CI: -0.20, -0.04). No significant interaction was observed between PS intake and baseline TG concentrations on relative changes, but, on absolute changes, interaction was significant with larger TG decreases observed with higher TG concentrations at baseline. No effects were observed on HDL-C concentrations. Conclusions - These results show that PS exert a modest TG-lowering effect which is dependent on baseline concentrations.
    Flow-mediated dilation is inversely associated with cardiovascular disease risk: a meta -analysis of prospective studies
    Ras, R.T. ; Streppel, M.T. ; Zock, P.L. ; Draijer, R. - \ 2012
    Circulation 125 (2012). - ISSN 0009-7322 - p. AP006 - AP006.
    Background - Flow-mediated dilation (FMD) is an accepted technique to quantify endothelial (dys)function. The predictive value of FMD for future cardiovascular disease (CVD) risk has been investigated in several prospective studies. The purpose of the present study was to systematically review these studies and to quantify the relationship between FMD and CVD risk. It was hypothesized that the risk of experiencing a cardiovascular event later in life would be smaller when having a higher FMD value at baseline. Methods - Potentially relevant prospective studies were searched in several databases and by hand searching, through March 2011. Studies were selected based on predefined selection criteria. The statistical analysis was performed separately for continuous (per 1% increase in FMD) and categorical (when having a high vs. low FMD) risk estimates for CVD. The pooled overall risk estimate was calculated based on a random-effects model while weighting each study by the inverse of its variance. Potential sources of heterogeneity were investigated as well as presence of publication bias. Results - In total, 23 studies including 14,753 subjects were eligible for inclusion in the present meta-analysis. Subjects were followed for an average duration of 42.9 months (range: 12.1-94.6 months). The average age was 60.1 years (range: 46.0-78.6 years). In 8 out of 23 studies, asymptomatic subjects were included whereas in 15 studies, subjects were diagnosed as having various forms of diseases. In studies reporting continuous risk estimates, the pooled overall risk estimate for CVD expressed per 1 % increase in FMD was 0.90 (95%CI: 0.86, 0.94). One study, that was the only study including exclusively renal patients, reported results that significantly differed from this estimate. Excluding this study from the analysis did not materially affect the pooled overall risk estimate (RR = 0.92 (95%CI: 0.88; 0.95). Based on studies with categorical risk estimates, the pooled overall risk estimate for CVD when having a high FMD vs. a low FMD was 0.49 (95%CI: 0.38, 0.63). Covariate analysis revealed that health status significantly affected the association between FMD and CVD risk with a stronger association in diseased populations. Presence of publication bias could not be excluded. Conclusions - Our findings show that baseline FMD is inversely associated with CVD risk, particularly in diseased populations. Further studies should address the impact of underlying health status on the relationship between FMD and CVD.
    Flow-mediated dilation is inversely associated with cardiovascular disease risk: a meta-analysis of prospective studies
    Draijer, R. ; Streppel, M.T. ; Zock, P.L. - \ 2012
    Journal of Hypertension 30 (2012)eS1. - ISSN 0263-6352 - p. e64 - e64.
    Levels and trends in cardiovascular risk factors and drug treatment in 4837 eldery Dutch myocardial infarction patients between 2002 and 2006
    Soedamah-Muthu, S.S. ; Geleijnse, J.M. ; Giltay, E.J. ; Goede, J. de; Oude Griep, L.M. ; Waterham, E. ; Teitsma-Jansen, A.M. ; Mulder, B.J.M. ; Boer, M.J. de; Deckers, J.W. ; Zock, P.L. ; Kromhout, D. - \ 2012
    Netherlands Heart Journal 20 (2012)3. - ISSN 1568-5888 - p. 102 - 109.
    coronary-heart-disease - life-style - prevention - mortality - guidelines - trial
    Background It is important to gain insight into opportunities for secondary prevention of cardiovascular disease. Our aim was to investigate levels and trends in cardiovascular risk factors and drug treatment in Dutch post-myocardial infarction (MI) patients between 2002 and 2006 and to make comparisons with the EUROASPIRE surveys (1999–2007). Methods We analysed data from 4837 post-MI patients (aged 69 years, 78% men) from 32 Dutch hospitals, using baseline cross-sectional data from the Alpha Omega Trial. Results Between 2002 and 2006, significant declines were found in the prevalence of smoking (23% to 16%, p¿
    Plant sterols do exert a modest serum triglyceride lowering effect: a meta analysis of individual subject data
    Demonty, I. ; Meijer, L. ; Knaap, H.C.M. van der; Ras, R.T. ; Zock, P.L. ; Geleijnse, J.M. ; Trautwein, E.A. - \ 2011
    Atherosclerosis Supplements 12 (2011)1. - ISSN 1567-5688 - p. 137 - 137.
    N-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes
    Kromhout, D. ; Geleijnse, J.M. ; Goede, J. de; Oude Griep, L.M. ; Mulder, B.J.M. ; Boer, M.J. de; Deckers, J.W. ; Boersma, E. ; Zock, P.L. ; Giltay, E.J. - \ 2011
    Diabetes Care 34 (2011)12. - ISSN 0149-5992 - p. 2515 - 2520.
    coronary-heart-disease - base-line characteristics - placebo-controlled trial - cardiovascular-disease - dietary-supplements - sudden-death - fish intake - risk - omega-3-fatty-acids - mortality
    OBJECTIVE We carried out a secondary analysis in high-risk patients with a previous myocardial infarction (MI) and diabetes in the Alpha Omega Trial. We tested the hypothesis that in these patients an increased intake of the n-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and a-linolenic acid (ALA) will reduce the incidence of ventricular arrhythmias and fatal MI. RESEARCH DESIGN AND METHODS A subgroup of 1,014 post-MI patients with diabetes aged 60–80 years was randomly allocated to receive one of four trial margarines, three with an additional amount of n-3 fatty acids and one placebo for 40 months. The end points were ventricular arrhythmia–related events and fatal MI. The data were analyzed according to the intention-to-treat principle, using multivariable Cox proportional hazards models. RESULTS The patients consumed on average 18.6 g of margarine per day, which resulted in an additional intake of 223 mg EPA plus 149 mg DHA and/or 1.9 g ALA in the active treatment groups. During follow-up, 29 patients developed a ventricular arrhythmia–related events and 27 had a fatal MI. Compared with placebo patients, the EPA-DHA plus ALA group experienced less ventricular arrhythmia–related events (hazard ratio 0.16; 95% CI 0.04–0.69). These n-3 fatty acids also reduced the combined end-point ventricular arrhythmia–related events and fatal MI (0.28; 0.11–0.71). CONCLUSIONS Our results suggest that low-dose supplementation of n-3 fatty acids exerts a protective effect against ventricular arrhythmia–related events in post-MI patients with diabetes
    Suboptimal Potassium Intake and Potential Impact on Population Blood Pressure
    Mierlo, L.A.J. van; Greyling, A. ; Zock, P.L. ; Kok, F.J. ; Geleijnse, J.M. - \ 2010
    Archives of Internal Medicine 170 (2010)16. - ISSN 0003-9926 - p. 1501 - 1503.
    Nutritional interventions and blood pressure : role of specific micronutrients and other food components
    Mierlo, L.A.J. van - \ 2010
    Wageningen University. Promotor(en): Frans Kok, co-promotor(en): Marianne Geleijnse; P.L. Zock. - [S.l.] : S.n. - ISBN 9789085856900 - 187
    bloeddruk - dieet - ziektepreventie - maatregel op voedingsgebied - sporenelementen - hypertensie - mineralen - blood pressure - diet - disease prevention - nutritional intervention - trace elements - hypertension - minerals
    Elevated blood pressure is an important risk factor for cardiovascular diseases (CVD). Modest reductions in blood pressure at the population level, as can be achieved by dietary and lifestyle changes, have a large impact on the burden of CVD. Blood pressure is regulated by several physiological mechanisms, including vascular endothelial function.

    This thesis
    The studies described in this thesis examined the potential effects of various micronutrients and other food components on blood pressure and endothelial function. The first aim was to assess the importance of selected minerals on population blood pressure levels and the second was to investigate the vascular effects of food components other than minerals that have recently attracted attention in the field of nutrition and blood pressure.
    A review of 21 national surveys showed that current dietary potassium intakes are suboptimal (1.7-3.7 gram per day). We estimated that increasing intakes to the recommended level of 4.7 gram per day can reduce population systolic blood pressure by 2-3 mmHg in Western countries, this effect being similar to that which can be achieved by reducing current sodium intakes to recommended levels. Our meta-analysis of 40 randomized controlled intervention studies showed that increasing calcium intake by ~1200 mg per day significantly lowers systolic blood pressure by 2 mmHg and diastolic blood pressure by 1 mmHg. This effect tended to be stronger in populations with lower intakes (<800 mg per day). In an 8-week placebo controlled parallel study in 124 subjects with elevated blood pressure, we found no significant blood pressure lowering effects of skimmed milk enriched in potassium (1500 or 750 mg per daily serving) combined with calcium, magnesium, selenium, vitamin C and vitamin E. However, this study was not designed to detect reductions in systolic blood pressure of 2-3 mmHg, which are still relevant at the population level.
    In two 4-week placebo controlled cross-over studies, in 162 subjects with untreated elevated blood pressure, we could not demonstrate an antihypertensive effect of a yogurt drink with lactotripeptides obtained by enzymatic hydrolysis (study 1: 10.2 mg per day; study 2: 4.6 mg per day plus 350 mg added potassium). In another 2-week placebo controlled cross-over study in 35 healthy males we found no consistent effect on endothelial function and blood pressure of ~800 mg polyphenols per day from either a wine-grape mix or grape seeds. Finally, a meta-analysis of 14 randomized controlled intervention studies showed that folic acid at a high dose (≥5000 g per day), which can not be attained with a regular diet, significantly improved flow-mediated dilation by 8%.

    Adequate potassium and calcium intakes can play an important role in the prevention of hypertension at the population level. Lactotripeptides have no relevant effect on blood pressure in Caucasian populations. The potential of grape polyphenols and folic acid to improve endothelial function is limited.
    Multiple actions are needed to lower blood pressure at the population level and reduce the burden of CVD. To improve intakes of potassium and calcium, public health measures should re-emphasize the intake of fruits, vegetables, and low-fat dairy products. Further optimization of mineral intakes, in particular reduction of sodium intake, requires collaborative actions of government and food industry.

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