Ingeborg A. Brouwer

Effect of Animal and Industrial Trans Fatty Acids on HDL and LDL Cholesterol Levels in Humans – A Quantitative Review

Background Trans fatty acids are produced either by industrial hydrogenation or by biohydrogenation in the rumens of cows and sheep. Industrial trans fatty acids lower HDL cholesterol, raise LDL cholesterol, and increase the risk of coronary heart disease. The effects of conjugated linoleic acid and trans fatty acids from ruminant animals are less clear. We reviewed the literature, estimated the effects trans fatty acids from ruminant sources and of conjugated trans linoleic acid (CLA) on blood lipoproteins, and compared these with industrial trans fatty acids. Methodology/Principal Findings We searched Medline and scanned reference lists for intervention trials that reported effects of industrial trans fatty acids, ruminant trans fatty acids or conjugated linoleic acid on LDL and HDL cholesterol in humans. The 39 studies that met our criteria provided results of 29 treatments with industrial trans fatty acids, 6 with ruminant trans fatty acids and 17 with CLA. Control treatments differed between studies; to enable comparison between studies we recalculated for each study what the effect of trans fatty acids on lipoprotein would be if they isocalorically replaced cis mono unsaturated fatty acids. In linear regression analysis the plasma LDL to HDL cholesterol ratio increased by 0.055 (95%CI 0.044–0.066) for each % of dietary energy from industrial trans fatty acids replacing cis monounsaturated fatty acids The increase in the LDL to HDL ratio for each % of energy was 0.038 (95%CI 0.012–0.065) for ruminant trans fatty acids, and 0.043 (95% CI 0.012–0.074) for conjugated linoleic acid (p = 0.99 for difference between CLA and industrial trans fatty acids; p = 0.37 for ruminant versus industrial trans fatty acids). Conclusions/Significance Published data suggest that all fatty acids with a double bond in the trans configuration raise the ratio of plasma LDL to HDL cholesterol.

Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators

AIMS To determine the effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish on the incidence of recurrent ventricular arrhythmia in implantable cardioverter defibrillator (ICD) patients by combining results from published trials. METHODS AND RESULTS We searched in the Medline, EMBASE, and Cochrane databases and performed a meta-analysis on all three available trials on fish oil and ventricular arrhythmia. Furthermore, we pooled individual data of two of these randomized, double-blind, placebo-controlled trials (Raitt et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884-2891 and Brouwer et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 2006;295:2613-2619). The main outcome was time to first confirmed ventricular fibrillation (VF) or ventricular tachycardia (VT) combined with death for the meta-analysis, and time to first spontaneous confirmed VF or VT for the pooled analysis. The meta-analysis (n = 1148) showed no convincing protective effect of fish oil (RR 0.90; 95% CI 0.67-1.22). The hazard ratio for the subgroup of patients with coronary artery disease at baseline (0.79; 0.60-1.06) tended towards a protective effect. The pooled analysis (n = 722) showed that time to appropriate ICD intervention was similar for fish oil and placebo treatment (log-rank P = 0.79). CONCLUSION These findings do not support a protective effect of omega-3 PUFAs from fish oil on cardiac arrhythmia in all patients with an ICD. Current data neither prove nor disprove a beneficial or a detrimental effect for subgroups of patients with specific underlying pathologies.

Long‐chain n‐3 polyunsaturated fatty acids: new insights into mechanisms relating to inflammation and coronary heart disease

Evidence from observational studies, prospective cohort studies and randomized clinical intervention studies indicate that moderate doses of long‐chain n‐3 polyunsaturated fatty acids (LC n‐3 PUFA) significantly decrease risk of fatal coronary heart disease (CHD). Higher doses and longer duration of intervention may also protect from non‐fatal CHD events. The exact mechanisms through which LC n‐3 PUFA has an effect on CHD are not well established but may include a decrease in fasting and postprandial triacylglycerol levels, a decrease in arrhythmias, modulation of platelet aggregation and decreased synthesis of pro‐inflammatory agents. The mechanistic relation between LC n‐3 PUFA and inflammation has attracted great interest, and in vitro studies have revealed that these fatty acids decrease endothelial activation, affect eicosanoid metabolism (including epoxygenation pathways) and induce inflammatory resolution. However, the effects of LC n‐3 PUFA on established biomarkers of inflammation and endothelial activation in vivo are not strong. Consequently we need new and more sensitive and systemic biomarkers to reveal the effects of LC n‐3 PUFA on localized inflammatory processes.

Acute administration of fish oil inhibits triggered activity in isolated myocytes from rabbits and patients with heart failure

Background— Fish oil reduces sudden death in patients with prior myocardial infarction. Sudden death in heart failure may be due to triggered activity based on disturbed calcium handling. We hypothesized that superfusion with &ohgr;3-polyunsaturated fatty acids (&ohgr;3-PUFAs) from fish inhibits triggered activity in heart failure. Methods and Results— Ventricular myocytes were isolated from explanted hearts of rabbits with volume- and pressure-overload–induced heart failure and of patients with end-stage heart failure. Membrane potentials (patch-clamp technique) and intracellular calcium (indo-1 fluorescence) were recorded after 5 minutes of superfusion with Tyrode’s solution (control), &ohgr;-9 monounsaturated fatty acid oleic acid (20 &mgr;mol/L), or &ohgr;3-PUFAs (docosahexaenoic acid or eicosapentaenoic acid 20 &mgr;mol/L). &ohgr;3-PUFAs shortened the action potential at low stimulation frequencies and caused an ≈25% decrease in diastolic and systolic calcium (all P<0.05). Subsequently, noradrenalin and rapid pacing were used to evoke triggered activity, delayed afterdepolarizations, and calcium aftertransients. &ohgr;3-PUFAs abolished triggered activity and reduced the number of delayed afterdepolarizations and calcium aftertransients compared with control and oleic acid. &ohgr;3-PUFAs reduced action potential shortening and intracellular calcium elevation in response to noradrenalin. Results from human myocytes were in accordance with the findings obtained in rabbit myocytes. Conclusion— Superfusion with &ohgr;3-PUFAs from fish inhibits triggered arrhythmias in myocytes from rabbits and patients with heart failure by lowering intracellular calcium and reducing the response to noradrenalin.

Parathyroid hormone and cardiovascular disease events: A systematic review and meta-analysis of prospective studies.

BACKGROUND Parathyroid hormone (PTH) excess might play a role in cardiovascular health. We therefore conducted a systematic review and meta-analysis to evaluate the association between PTH and cardiovascular disease (CVD) events, and intermediate outcomes. METHODS We conducted a systematic and comprehensive database search using MEDLINE and Embase between 1947 and October 2012. We included English-language prospective studies that reported risk estimates for PTH and CVD events, and intermediate outcomes. The characteristics of study populations, exposure, and outcomes of total CVD events, fatal and non-fatal CVD events were reported, and a quality assessment was conducted. Results were extracted for the highest versus lowest PTH concentrations, and meta-analyses were carried out using random effects models. RESULTS The systematic literature search yielded 5770 articles, and 15 studies were included. Study duration ranged between 2 and 14 years. All studies were performed primarily in whites with a mean age between 55 and 75 years. The meta-analyses included 12 studies, of which 10 investigated total CVD events; 7, fatal CVD events; and 3, non-fatal CVD events. PTH excess indicated an increased risk for total CVD events: pooled HR (95% CI), 1.45 (1.24-1.71). The results for fatal CVD events and non-fatal CVD events were: HR 1.50 (1.18-1.91) and HR 1.48 (1.14-1.92). Heterogeneity was moderately present; however, sensitivity analyses for follow-up duration, prior CVD, or PTH as dichotomous values showed similar results. CONCLUSIONS The meta-analysis indicates that higher PTH concentrations are associated with increased risk of CVD events.

No effect of fish oil supplementation on serum inflammatory markers and their interrelationships: a randomized controlled trial in healthy, middle-aged individuals.

Background:A high intake of n-3 polyunsaturated fatty acids (PUFAs), mainly present in fish, may be associated with decreased inflammation. Previous intervention studies on fish PUFA and inflammatory markers in healthy individuals did not analyze a broad spectrum of inflammatory cytokines, chemokines and cell adhesion molecules, or their interrelationships. Therefore, we determined the effects of fish oil supplementation on 19 serum inflammatory markers and their interrelationships in healthy, middle-aged individuals.Methods:Individuals (n=77) aged 50–70 years completed a randomized, double-blind placebo-controlled intervention study. Participants received 3.5 g/day fish oil (1.5 g/day total n-3 PUFA) (n=39) or placebo (high oleic sunflower oil) (n=38) for 12 weeks. Serum concentrations of 19 inflammatory markers were determined using a multiplex immunoassay before and after intervention. Changes in concentrations were analyzed using analysis of covariance and differences in patterns in inflammatory markers between the fish oil and placebo group were analyzed by principal component analysis.Results:Fish oil supplementation did not significantly affect serum concentrations of cytokines, chemokines or cell adhesion molecules as compared with placebo. However, there was a trend for all inflammatory markers to increase after fish oil supplementation. PCA did not result in markedly distinctive patterns of inflammatory markers for the fish oil and placebo group.Conclusion:In conclusion, this 12-week randomized, double-blind placebo-controlled intervention trial did not show that 1.5 g/day n-3 PUFA significantly affected the serum inflammatory response in healthy individuals, nor did patterns of inflammatory markers. Thus, a healthy middle-aged population may not benefit from fish oil as an anti-inflammatory agent.

Bioavailability and bioefficacy of folate and folic acid in man

Folic acid is important because supplementation around the time of conception has been proven to lower the risk of having offspring with a neural-tube defect. Furthermore, both dietary folate and folic acid decrease plasma total homocysteine concentrations. Elevated plasma homocysteine concentrations are considered to be an independent risk factor for cardiovascular disease. The aim of the present review is to give an overview of factors influencing bioavailability and bioefficacy (the proportion of ingested nutrient converted to its active form) of food folate and folic acid, and to discuss the functional bioefficacy of folate and folic acid in decreasing plasma homocysteine concentrations. We use the mnemonic SLAMENGHI to group factors influencing bioavailability and bioefficacy: Species of folate; Linkage at molecular level; Amount of folate and folic acid consumed; Matrix; Effect modifiers; Nutrient status; Genetic factors; Host-related factors; mathematical Interactions between the various factors. Bioefficacy of folate from some foods is 50 % that of folic acid. This factor is most probably explained by the matrix factors, encapsulation and binding. However, often such effects cannot be distinguished from factors such as species, chain length of folate in food, effect modifiers and the amount of folate consumed in a meal. Folic acid provided as a supplement is well absorbed. However, the homocysteine-lowering capacity of doses of folic acid >500 mug is limited. It is unclear whether unmetabolised folic acid poses health risks. This factor is of importance, because food fortification is now implemented in many countries and folic acid supplements are freely available. In particular circumstances host-related factors, such as gastrointestinal illness and pH of the jejunum, can influence bioavailability. Genetic factors also deserve attention for future research, because polymorphisms may influence folate bioavailability.

Maternal Triglyceride Levels during Early Pregnancy are Associated with Birth Weight and Postnatal Growth

OBJECTIVE To investigate whether randomly sampled maternal total cholesterol (TC) and triglycerides (TG) levels during early pregnancy are associated with birth weight (BW) and postnatal growth. STUDY DESIGN Data were derived from the prospective Amsterdam Born Children and their Development cohort study. Randomly sampled TC and TG levels were determined in early gestation (median, 13; IQR, 12-14 weeks). Outcome measures were BW SDS and weight-for-gestational age; postnatal outcome measures were SDS in weight, length, and body mass index during the first year of life (total n = 2502). RESULTS The highest TG level was associated with a higher BW SDS (differences 0.20 ± 0.06 between highest and middle quintile; P = .002) and with a higher prevalence (13%) of an infant large for gestational age compared with middle quintile (9%; P = .04). Infants from mothers in the lowest TG quintile had lower SDS in weight, length, and body mass index until age 3 months, and displayed accelerated postnatal growth patterns. Maternal TC was not associated with BW or postnatal growth. CONCLUSION High maternal TG levels in the first term of pregnancy were associated with higher BWs and subsequently a higher occurrence of infants large for gestational age, whereas low TG levels were associated with accelerated postnatal growth.

Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Background Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. Methods In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. Findings We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

Association of 25-hydroxyvitamin D and parathyroid hormone with incident hypertension: MESA (Multi-Ethnic Study of Atherosclerosis).

OBJECTIVES This study investigated whether lower 25-hydroxyvitamin D and higher parathyroid hormone concentrations are associated with incident hypertension. BACKGROUND Disturbances in vitamin D metabolism are plausibly related to hypertension. METHODS MESA (Multi-Ethnic Study of Atherosclerosis) is a community-based, prospective cohort with baseline measurements obtained between 2000 and 2002. We studied 3,002 men and women free of prevalent cardiovascular disease and hypertension, age 45 to 84 years at baseline. Serum 25-hydroxyvitamin D and intact parathyroid hormone were measured from previously frozen baseline samples using liquid chromatography-mass spectroscopy and a 2-site immunoassay, respectively. We used a complementary log-log model with interval censoring to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for 25-hydroxyvitamin D and parathyroid hormone concentrations with incident hypertension through 2010. RESULTS During a median follow-up of 9.0 years, 41% of the cohort (n = 1,229) developed hypertension. Mean serum 25-hydroxyvitamin D was 26.3 ± 11.2 ng/ml and mean parathyroid hormone was 41.2 ± 17.3 pg/ml. Compared with 25-hydroxyvitamin D ≥30 ng/ml, 25-hydroxyvitamin D <20 ng/ml was associated with a greater hypertension risk (HR: 1.28 [95% CI: 1.09 to 1.50]), although the association was attenuated and not statistically significant after adjusting for potential confounders (HR: 1.13 [95% CI: 0.96 to 1.33]). Compared with parathyroid hormone <33 pg/ml, parathyroid hormone ≥65 pg/ml was associated with a significantly greater risk of hypertension (HR: 1.27 [95% CI: 1.01 to 1.59]) after adjusting for potential confounders. CONCLUSIONS Lower 25-hydroxyvitamin D concentrations were not associated with a greater risk of incident hypertension. Higher serum parathyroid hormone concentrations showed a significant, but statistically marginal, relationship to the development of hypertension. These findings will require further confirmation. (Multi-Ethnic Study of Atherosclerosis; NCT00005487).