Does industry sponsorship undermine the integrity of nutrition research?
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Food Industry↗
Biomedical subjects
Martijn B Katan
Publications and source records attributed to Martijn B Katan.
Dietary n-3 fatty acids promote arrhythmias during acute regional myocardial ischemia in isolated pig hearts.
OBJECTIVE: Dietary supplementation with fish oil-derived n-3 fatty acids reduces mortality in patients with myocardial infarction, but may have adverse effects in angina patients. The underlying electrophysiologic mechanisms are poorly understood. We studied the arrhythmias and the electrophysiologic changes during regional ischemia in hearts from pigs fed a diet rich in fish oil. METHODS: Pigs received diets rich in fish oil, in sunflower oil, or a control diet for 8 weeks. Hearts were isolated and perfused. Ischemia was created by occluding the left anterior descending artery. Diastolic stimulation threshold, refractory period, conduction velocity, activation recovery intervals and the maximum downstroke velocity of 176 electrograms were measured in the ischemic zone. Spontaneous arrhythmias during 75 min of regional ischemia were counted. RESULTS: More episodes of spontaneous ischemia-induced sustained ventricular tachycardia and ventricular fibrillation occurred in the fish oil and sunflower oil group than in the control group. More inexcitable myocardium was present in the ischemic zone in the group fed fish oil or sunflower oil than in the control group after 20 min of ischemia. After 40 min of ischemia, more block occurred in the control group than in the other groups. The downstroke velocity of the electrograms in the ischemic border zone was lower in the fish oil group and sunflower oil group than in the control after 20 min. CONCLUSIONS: A diet rich in fish oil results in proarrhythmia compared to a control diet during regional ischemia in pigs. Myocardial excitability is reduced in the fish oil and sunflower oil group during the early phase of arrhythmogenesis. In the late phase of arrhythmogenesis, excitability is more reduced in the control group than in the fish oil and sunflower oil group.
Animals↗
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.
CONTEXT: Very-long-chain n-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish are thought to reduce risk of sudden death, possibly by reducing susceptibility to cardiac arrhythmia. OBJECTIVE: To study the effect of supplemental fish oil vs placebo on ventricular tachyarrhythmia or death. DESIGN, SETTING, AND PATIENTS: The Study on Omega-3 Fatty acids and ventricular Arrhythmia (SOFA) was a randomized, parallel, placebo-controlled, double-blind trial conducted at 26 cardiology clinics across Europe. A total of 546 patients with implantable cardioverter-defibrillators (ICDs) and prior documented malignant ventricular tachycardia (VT) or ventricular fibrillation (VF) were enrolled between October 2001 and August 2004. Patients were randomly assigned to receive 2 g/d of fish oil (n = 273) or placebo (n = 273) for a median period of 356 days (range, 14-379 days). MAIN OUTCOME MEASURE: Appropriate ICD intervention for VT or VF, or all-cause death. RESULTS: The primary end point occurred in 81 (30%) patients taking fish oil vs 90 (33%) patients taking placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.64-1.16; P = .33). In prespecified subgroup analyses, the HR was 0.91 (95% CI, 0.66-1.26) for fish oil vs placebo in the 411 patients who had experienced VT in the year before the study, and 0.76 (95% CI, 0.52-1.11) for 332 patients with prior myocardial infarctions. CONCLUSION: Our findings do not indicate evidence of a strong protective effect of intake of omega-3 PUFAs from fish oil against ventricular arrhythmia in patients with ICDs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00110838.
Aged↗
Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers.
OBJECTIVES: We investigated whether lowering of fasting homocysteine concentrations, either with folic acid or with betaine supplementation, differentially affects vascular function, a surrogate marker for risk of cardiovascular disease, in healthy volunteers. As yet, it remains uncertain whether a high concentration of homocysteine itself or whether a low folate status--its main determinant--is involved in the pathogenesis of cardiovascular disease. To shed light on this issue, we performed this study. DESIGN: This was a randomized, placebo-controlled, double-blind, crossover study. SETTING: The study was performed at Wageningen University in Wageningen, the Netherlands. PARTICIPANTS: Participants were 39 apparently healthy men and women, aged 50-70 y. INTERVENTIONS: Participants ingested 0.8 mg/d of folic acid, 6 g/d of betaine, and placebo for 6 wk each, with 6-wk washout in between. OUTCOME MEASURES: At the end of each supplementation period, plasma homocysteine concentrations and flow-mediated dilation (FMD) of the brachial artery were measured in duplicate. RESULTS: Folic acid supplementation lowered fasting homocysteine by 20% (-2.0 micromol/l, 95% confidence interval [CI]: -2.3; -1.6), and betaine supplementation lowered fasting plasma homocysteine by 12% (-1.2 micromol/l; -1.6; -0.8) relative to placebo. Mean (+/- SD) FMD after placebo supplementation was 2.8 (+/- 1.8) FMD%. Supplementation with betaine or folic acid did not affect FMD relative to placebo; differences relative to placebo were -0.4 FMD% (95%CI, -1.2; 0.4) and -0.1 FMD% (-0.9; 0.7), respectively. CONCLUSIONS: Folic acid and betaine supplementation both did not improve vascular function in healthy volunteers, despite evident homocysteine lowering. This is in agreement with other studies in healthy participants, the majority of which also fail to find improved vascular function upon folic acid treatment. However, homocysteine or folate might of course affect cardiovascular disease risk through other mechanisms.
Journal Article↗
Acute effect of folic acid, betaine, and serine supplements on flow-mediated dilation after methionine loading: a randomized trial.
OBJECTIVES: We investigated whether reducing post-methionine homocysteine concentrations via various treatments other than folic acid affects vascular function, as measured through flow-mediated dilation (FMD) of the brachial artery. High fasting and post-methionine homocysteine concentrations are associated with cardiovascular disease risk, but homocysteine might be a surrogate marker for low folate status. DESIGN: This was a randomized, placebo-controlled, double-blind, crossover study. SETTING: The study took place at Wageningen University in Wageningen in the Netherlands. PARTICIPANTS: Participants were 39 apparently healthy men and women, aged 50-70 y. INTERVENTIONS: Participants ingested 10 mg of folic acid, 3 g of betaine, 5 g of serine, and placebo together with an oral methionine load. Each supplement was tested on two different days. OUTCOME MEASURES: On each of the eight treatment days, plasma homocysteine concentrations and FMD were measured before (t = 0 h, fasting) and 6 h (t = 6 h) after methionine loading. RESULTS: The mean (+/- SD) fasting homocysteine concentrations averaged over the eight test days were 9.6 +/- 2.1 micromol/l. Mean fasting FMD was 3.1 +/- 2.4 FMD%. A methionine load with placebo increased homocysteine concentrations by 17.2 +/- 9.3 micromol/l at 6 h after loading, similar to the increase following methionine loading with folic acid. A methionine load together with betaine and with serine increased homocysteine by 10.4 +/- 2.8 micromol/l (p < 0.001 relative to placebo) and by 12.1 +/- 8.2 micromol/l (p < 0.001 relative to placebo), respectively. Methionine loading with placebo did not affect FMD, and neither did methionine loading with folic acid, betaine, or serine; differences relative to placebo were +0.7 FMD% (95%CI, -0.6; 1.9), +0.2 FMD% (-1.0; 1.3), and +0.3 FMD% (-0.8; 1.4), respectively. CONCLUSIONS: Experimentally induced acute changes in homocysteine concentrations did not affect FMD in healthy volunteers. This implies that potential adverse effects of high homocysteine concentrations on the cardiovascular system are not mediated through vascular function. However, homocysteine or folate may affect cardiovascular disease risk through other mechanisms.
Journal Article↗
Regulation of trans fats: the gap, the Polder, and McDonald's French fries.
Lowering the intake of trans fatty acids (TFA) probably reduces the incidence of coronary heart disease. Estimates of the reduction vary from 4% based on changes in plasma LDL and HDL concentrations alone, to > 20% based on epidemiological associations when TFA intake is lowered by 2% of energy (5 g/day). Even the lowest estimate represents enough cases to justify measures to reduce TFA intake. In The Netherlands, a major reduction in TFA content of retail foods has been achieved in the 1990s through efforts of industry; government intervention has been minimal. Societal pressure is now helping to reduce the TFA content of fast foods. McDonald's French fries in The Netherlands now have less than 4% trans and 24% saturates, as opposed to 21% trans and 21% saturates in the USA. This illustrates the feasibility of reducing TFA in fast foods without increasing saturates. As a result of these developments, dairy and meat have become the major remaining source of TFA in Europe. The question whether these ruminant TFA have the same effect on coronary heart disease risk as industrial TFA has not been settled.
Coronary Disease↗
n-3 Fatty acids, cardiac arrhythmia and fatal coronary heart disease.
n-3 Polyunsaturated fatty acids (n-3 PUFA) are suggested to prevent cardiac death via inhibition of cardiac arrhythmia. In this review we discuss the results of human studies on intake of n-3 PUFAs and heart disease and, more specifically, on cardiac arrhythmia. Observational studies indicate that intake of fish is associated with a lower incidence of fatal coronary heart disease in several populations. These studies are fairly consistent, but people that have a high intake of fatty fish might have a healthier lifestyle in general, and such confounding is difficult to remove completely with statistical adjustments and corrections. Evidence from trials is less clear. In two open label trials in patients with a previous myocardial infarction intake of fish or fish oil prevented fatal coronary heart disease. In contrast, a trial in patients with angina suggested a higher risk of sudden cardiac death in patients taking fish oil. Furthermore, results of trials in patients with an implantable cardioverter defibrillator (ICD) that investigated effects of fish oil on arrhythmia in patients already suffering from ventricular tachycardia are not consistent. Also, studies on relationships between intake of n-3 PUFA from fish and less life-threatening forms of arrhythmia, such as atrial fibrillation and premature ventricular complexes (PVCs) are equivocal. Thus, after 35 years of research the question whether fish prevents heart disease remains unanswered, and an anti-arrhythmic effect of fish oil remains unproven although the idea is still viable and is being actively tested in further trials.
Animals↗
Trans fatty acids and cardiovascular disease.
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Cardiovascular Diseases↗
Low HDL cholesterol levels.
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Cholesterol, HDL↗
The response of lipoproteins to dietary fat and cholesterol in lean and obese persons.
Individuals differ in the response of their blood lipoproteins to cholesterol-lowering diets. One characteristic clearly associated with susceptibility to diet is leanness; many studies show that total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations respond more strongly to dietary fat and cholesterol in lean subjects than in obese subjects. This is unlikely to be due to differences in dietary compliance. A metabolic explanation is that obese people have a higher rate of total body cholesterol synthesis. The low-density lipoprotein receptors in their liver cells are partly suppressed by this large stream of endogenous cholesterol coming in from their enterohepatic circulation, and the amount added by dietary cholesterol relative to the endogenous pool would be less than in lean people. Whatever the mechanism, diets low in saturated fat and cholesterol are less effective in the obese. The most effective way for obese people to normalize their blood lipids is to lose weight, which is, unfortunately, hard to do in our society.
Journal Article↗
Alternatives to low-fat diets.
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Diet, Carbohydrate-Restricted↗
Conversion of alpha-linolenic acid in humans is influenced by the absolute amounts of alpha-linolenic acid and linoleic acid in the diet and not by their ratio.
BACKGROUND: Human in vivo data on dietary determinants of alpha-linolenic acid (ALA; 18:3n-3) metabolism are scarce. OBJECTIVE: We examined whether intakes of ALA or linoleic acid (LA; 18:2n-6) or their ratio influences ALA metabolism. DESIGN: During 4 wk, 29 subjects received a control diet (7% of energy from LA, 0.4% of energy from ALA, ALA-to-LA ratio = 1:19). For the next 6 wk, a control diet, a low-LA diet (3% of energy from LA, 0.4% of energy from ALA, ratio = 1:7), or a high-ALA diet (7% of energy from LA, 1.1% of energy from ALA, ratio = 1:7) was consumed. Ten days before the end of each dietary period, [U-13C]ALA was administered orally for 9 d. ALA oxidation was determined from breath. Conversion was estimated by using compartmental modeling of [13C]- and [12C]n-3 fatty acid concentrations in fasting plasma phospholipids. RESULTS: Compared with the control group, ALA incorporation into phospholipids increased by 3.6% in the low-LA group (P = 0.012) and decreased by 8.0% in the high-ALA group (P < 0.001). In absolute amounts, it increased by 34.3 mg (P = 0.020) in the low-LA group but hardly changed in the high-ALA group. Nearly all ALA from the plasma phospholipid pool was converted into eicosapentaenoic acid. Conversion of eicosapentaenoic acid into docosapentaenoic acid and docosahexaenoic acid hardly changed in the 3 groups and was <0.1% of dietary ALA. In absolute amounts, it was unchanged in the low-LA group, but increased from 0.7 to 1.9 mg (P = 0.001) in the high-ALA group. ALA oxidation was unchanged by the dietary interventions. CONCLUSION: The amounts of ALA and LA in the diet, but not their ratio, determine ALA conversion.
Breath Tests↗
A dual-isotope-labeling method of studying the bioavailability of hexaglutamyl folic acid relative to that of monoglutamyl folic acid in humans by using multiple orally administered low doses.
BACKGROUND: The bioavailability of dietary folate may be hampered by the need of the glutamate moieties to be deconjugated before absorption. Previous studies comparing the bioavailabilities of polyglutamyl and monoglutamyl folic acid had inconsistent results. OBJECTIVE: The objective was to estimate the bioavailability of polyglutamyl relative to that of monoglutamyl folic acid by using a sensitive stable-isotope approach that allowed for the administration of multiple low doses in humans. DESIGN: Twenty subjects aged 20-50 y ingested 2 capsules daily for 28 d; each capsule contained approximately 50 nmol [(13)C(6)]hexaglutamyl and approximately 50 nmol [(13)C(11)]monoglutamyl folic acid. Amounts of the isotopically labeled compounds in the capsules were verified by various methods. The degrees of isotopic enrichment of plasma 5-methyltetrahydrofolate with (13)C(6) and (13)C(11) were measured by using liquid chromatography tandem mass spectrometry, and the ratio of (13)C(6) to (13)C(11) ((13)C(6):(13)C(11)) in plasma on day 28 was used as a measure of their relative bioavailability. RESULTS: The (13)C(11):(13)C(6) in plasma 5-methyltetrahydrofolate reached equilibrium on day 4 and was 0.66 (95% CI: 0.58, 0.74) on day 28. The (13)C(11):(13)C(6) content in the capsules varied between 1.18 and 1.96. After correction for this ratio, the estimated bioavailability of hexaglutamyl relative to that of monoglutamyl folic acid was >/=78%. CONCLUSION: Multiple dosing of low amounts of labeled folic acid is a sensitive, accurate, and efficient method of measuring the relative bioavailability of folic acid compounds, provided that the administered doses can be reliably assessed.
Administration, Oral↗
Effects of n-3 fatty acids on arrhythmic events and mortality in the SOFA implantable cardioverter defibrillator trial.
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Cardiovascular Diseases↗
Dietary fructooligosaccharides affect intestinal barrier function in healthy men.
In contrast to most expectations, we showed previously that dietary fructooligosaccharides (FOS) stimulate intestinal colonization and translocation of invasive Salmonella enteritidis in rats. Even before infection, FOS increased the cytotoxicity of fecal water, mucin excretion, and intestinal permeability. In the present study, we tested whether FOS has these effects in humans. A double-blind, placebo-controlled, crossover study of 2 x 2 wk, with a washout period of 2 wk, was performed with 34 healthy men. Each day, subjects consumed lemonade containing either 20 g FOS or placebo and the intestinal permeability marker chromium EDTA (CrEDTA). On the last 2 d of each supplement period, subjects scored their gastrointestinal complaints on a visual analog scale and collected feces and urine for 24 h. Fecal lactic acid was measured using a colorimetric enzymatic kit. The cytotoxicity of fecal water was determined with an in vitro bioassay, fecal mucins were quantified fluorimetrically, and intestinal permeability was determined by measuring urinary CrEDTA excretion. In agreement with our animal studies, FOS fermentation increased fecal wet weight, bifidobacteria, lactobacilli, and lactic acid. Consumption of FOS increased flatulence and intestinal bloating. In addition, FOS consumption doubled fecal mucin excretion, indicating mucosal irritation. However, FOS did not affect the cytotoxicity of fecal water and intestinal permeability. The FOS-induced increase in mucin excretion in our human study suggests mucosal irritation in humans, but the overall effects are more moderate than those in rats.
Adult↗
The elimination of trans fats from spreads: how science helped to turn an industry around.
Mensink and Katan showed in 1990 that trans fats reduce high- and increase low-density lipoprotein cholesterol. Unilever aided this study because the company considered knowledge on trans fats incomplete in spite of their long history of safe use. The decision in 1994 to remove trans fats from Unilever's retail spreads was triggered by media events, but it was built on a solid understanding of the nutritional and technological aspects of trans fats. Over the next 14 years, manufacturers worldwide followed suit. This experience illustrates that food companies need to know about the health effects of their products and how to apply that knowledge.
Dietary Fats, Unsaturated↗
Effect of fish oil on heart rate in humans: a meta-analysis of randomized controlled trials.
BACKGROUND: The effect of fish oil on heart rate (HR), a major risk factor for sudden death, is not well established. We calculated this effect in a meta-analysis of randomized, double-blind, placebo-controlled trials in humans. METHODS AND RESULTS: Randomized trials of fish oil that evaluated HR were identified through MEDLINE (1966 through January 2005), hand-searching of references, and contact with investigators for unpublished results. Two investigators independently extracted trial data. A pooled estimate was calculated from random-effects meta-analysis. Predefined stratified meta-analyses and meta-regression were used to explore potential heterogeneity. Of 197 identified articles, 30 met inclusion criteria. Evidence for publication bias was not present. In the overall pooled estimate, fish oil decreased HR by 1.6 bpm (95% CI, 0.6 to 2.5; P=0.002) compared with placebo. Between-trial heterogeneity was evident (Q test, P<0.001). Fish oil reduced HR by 2.5 bpm (P<0.001) in trials with baseline HR > or =69 bpm (median) but had little effect (0.04-bpm reduction; P=0.56) in trials with baseline HR <69 bpm (P for interaction=0.03). Fish oil reduced HR by 2.5 bpm (P<0.001) in trials with duration > or =12 weeks but had less effect (0.7-bpm reduction; P=0.27) in trials with duration <12 weeks (P for interaction=0.07). HR reduction with fish oil intake did not significantly vary by fish oil dose (range, 0.81 to 15 g/d), type of HR measure, population age, population health, parallel versus crossover design, type of control oil, or study quality by Delphi criteria (P for interaction >0.25 for each). CONCLUSIONS: In randomized controlled trials in humans, fish oil reduces HR, particularly in those with higher baseline HR or longer treatment duration. These findings provide firm evidence that fish oil consumption directly or indirectly affects cardiac electrophysiology in humans. Potential mechanisms such as effects on the sinus node, ventricular efficiency, or autonomic function deserve further investigation.
Adult↗
Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans.
BACKGROUND: Betaine (trimethylglycine) lowers plasma homocysteine, a possible risk factor for cardiovascular disease. However, studies in renal patients and in obese individuals who are on a weight-loss diet suggest that betaine supplementation raises blood cholesterol; data in healthy individuals are lacking. Such an effect on cholesterol would counteract any favourable effect on homocysteine. We therefore investigated the effect of betaine, of its precursor choline in the form of phosphatidylcholine, and of the classical homocysteine-lowering vitamin folic acid on blood lipid concentrations in healthy humans. METHODS AND FINDINGS: We measured blood lipids in four placebo-controlled, randomised intervention studies that examined the effect of betaine (three studies, n = 151), folic acid (two studies, n = 75), and phosphatidylcholine (one study, n = 26) on plasma homocysteine concentrations. We combined blood lipid data from the individual studies and calculated a weighted mean change in blood lipid concentrations relative to placebo. Betaine supplementation (6 g/d) for 6 wk increased blood LDL cholesterol concentrations by 0.36 mmol/l (95% confidence interval: 0.25-0.46), and triacylglycerol concentrations by 0.14 mmol/l (0.04-0.23) relative to placebo. The ratio of total to HDL cholesterol increased by 0.23 (0.14-0.32). Concentrations of HDL cholesterol were not affected. Doses of betaine lower than 6 g/d also raised LDL cholesterol, but these changes were not statistically significant. Further, the effect of betaine on LDL cholesterol was already evident after 2 wk of intervention. Phosphatidylcholine supplementation (providing approximately 2.6 g/d of choline) for 2 wk increased triacylglycerol concentrations by 0.14 mmol/l (0.06-0.21), but did not affect cholesterol concentrations. Folic acid supplementation (0.8 mg/d) had no effect on lipid concentrations. CONCLUSIONS: Betaine supplementation increased blood LDL cholesterol and triacylglycerol concentrations in healthy humans, which agrees with the limited previous data. The adverse effects on blood lipids may undo the potential benefits for cardiovascular health of betaine supplementation through homocysteine lowering. In our study phosphatidylcholine supplementation slightly increased triacylglycerol concentrations in healthy humans. Previous studies of phosphatidylcholine and blood lipids showed no clear effect. Thus the effect of phosphatidylcholine supplementation on blood lipids remains inconclusive, but is probably not large. Folic acid supplementation does not seem to affect blood lipids and therefore remains the preferred treatment for lowering of blood homocysteine concentrations.
Adult↗