Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

BACKGROUND: De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). METHODS AND FINDINGS: Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. CONCLUSIONS: Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.

Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

Update on cardiometabolic health effects of ω-3 fatty acids.

PURPOSE OF REVIEW: The fish fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may promote cardiometabolic health. This review summarizes the results of recent meta-analyses of prospective studies on cardiovascular diseases, diabetes type 2 and markers of atherosclerosis and thrombosis. RECENT FINDINGS: The results of recently published meta-analyses of prospective cohort studies showed that eating fish once a week was associated with a 16% lower risk of fatal coronary heart disease (CHD) and a 14% lower risk of stroke incidence, but was not related to heart failure. Fish consumption may be associated with a higher risk of diabetes in Western countries and a lower risk in Asian countries. Recent meta-analyses of randomized controlled trials showed that EPA-DHA supplementation reduced the risk of fatal CHD and sudden death by 10% of which the latter was not significant. Extra EPA-DHA did not reduce the risk of heart failure, stroke and cardiac arrhythmias. ω-3 fatty acid (FA) supplementation did reduce markers of ventricular fibrillation, inflammation and endothelial dysfunction and platelet aggregation. SUMMARY: There is strong evidence for a protective effect of ω-3 FA on fatal CHD and for some markers of atherosclerosis and thrombosis. Consistent results were not obtained for other vascular diseases and diabetes. ω-3 FA reduced markers of ventricular fibrillation but did not reduce the risk of atrial fibrillation.

Linoleic acid intake, plasma cholesterol and 10-year incidence of CHD in 20,000 middle-aged men and women in the Netherlands.

We studied the associations of a difference in linoleic acid or carbohydrate intake with plasma cholesterol levels and risk of CHD in a prospective cohort study in the Netherlands. Data on diet (FFQ) and plasma total and HDL-cholesterol were available at baseline (1993-7) of 20,069 men and women, aged 20-65 years, who were initially free of CVD. Incidence of CHD was assessed through linkage with mortality and morbidity registers. During an average of 10 years of follow-up, 280 CHD events occurred. The intake of linoleic acid ranged from 3·6 to 8·0 % of energy (en%), whereas carbohydrate intake ranged from 47·6 to 42·5 en% across quintiles of linoleic acid intake. Linoleic acid intake was inversely associated with total cholesterol and HDL-cholesterol in women but not in men. Linoleic acid intake was not associated with the ratio of total to HDL-cholesterol. No association was observed between linoleic acid intake and CHD incidence, with hazard ratios varying between 0·83 and 1·00 (all P>0·05) compared to the bottom quintile. We conclude that a 4-5 en% difference in linoleic acid or carbohydrate intake did not translate into either a different ratio of total to HDL-cholesterol or a different CHD incidence.

Health Effects of Increasing Protein Intake Above the Current Population Reference Intake in Older Adults: A Systematic Review of the Health Council of the Netherlands.

Whether older adults need more protein than younger adults is debated. The population reference intake for adults set by the European Food Safety Authority is 0.83 g/kg body weight (BW)/d based primarily on nitrogen balance studies, but the underlying data on health outcomes are outdated. An expert committee of the Health Council of the Netherlands conducted a systematic review (SR) of randomized controlled trials (RCTs) examining the effect of increased protein intake on health outcomes in older adults from the general population with an average habitual protein intake ≥0.8 g/(kg BW · d). Exposures were the following: 1) extra protein compared with no protein and 2) extra protein and physical exercise compared with physical exercise. Outcomes included lean body mass, muscle strength, physical performance, bone health, blood pressure, serum glucose and insulin, serum lipids, kidney function, and cognition. Data of >1300 subjects from 18 RCTs were used. Risk of bias was judged as high (n = 9) or "some concerns" (n = 9). In 7 of 18 RCTs, increased protein intake beneficially affected ≥1 of the tested outcome measures of lean body mass. For muscle strength, this applied to 3 of 8 RCTs in the context of physical exercise and in 1 of 7 RCTs without physical exercise. For the other outcomes, <30% (0-29%) of RCTs showed a statistically significant effect. The committee concluded that increased protein intake has a possible beneficial effect on lean body mass and, when combined with physical exercise, muscle strength; likely no effect on muscle strength when not combined with physical exercise, or on physical performance and bone health; an ambiguous effect on serum lipids; and that too few RCTs were available to allow for conclusions on the other outcomes. This SR provides insufficiently convincing data that increasing protein in older adults with a protein intake ≥0.8 g/(kg BW · d) elicits health benefits.

Dietary and Circulating Long-Chain Omega-3 Polyunsaturated Fatty Acids and Mortality Risk After Myocardial Infarction: A Long-Term Follow-Up of the Alpha Omega Cohort.

Background Habitual intake of long-chain omega-3 fatty acids, especially eicosapentaenoic and docosahexaenoic acid (EPA+DHA) from fish, has been associated with a lower risk of fatal coronary heart disease (CHD) in population-based studies. Whether that is also the case for patients with CHD is not yet clear. We studied the associations of dietary and circulating EPA+DHA and alpha-linolenic acid, a plant-derived omega-3 fatty acids, with long-term mortality risk after myocardial infarction. Methods and Results We analyzed data from 4067 Dutch patients with prior myocardial infarction aged 60 to 80 years (79% men, 86% on statins) enrolled in the Alpha Omega Cohort from 2002 to 2006 (baseline) and followed through 2018. Baseline intake of fish and omega-3 fatty acids were assessed through a validated 203-item food frequency questionnaire and circulating omega-3 fatty acids were assessed in plasma cholesteryl esters. Hazard ratios (HRs) with 95% CIs were obtained from Cox regression analyses. During a median follow-up period of 12 years, 1877 deaths occurred, of which 515 were from CHD and 834 from cardiovascular diseases. Dietary intake of EPA+DHA was significantly inversely associated with only CHD mortality (HR, 0.69 [0.52-0.90] for >200 versus ≤50 mg/d; HR, 0.92 [0.86-0.98] per 100 mg/d). Similar results were obtained for fish consumption (HRCHD, 0.74 [0.53-1.03] for >40 versus ≤5 g/d; Ptrend: 0.031). Circulating EPA+DHA was inversely associated with CHD mortality (HR, 0.71 [0.53-0.94] for >2.52% versus ≤1.29%; 0.85 [0.77-0.95] per 1-SD) and also with cardiovascular diseases and all-cause mortality. Dietary and circulating alpha-linolenic acid were not significantly associated with mortality end points. Conclusions In a cohort of Dutch patients with prior myocardial infarction, higher dietary and circulating EPA+DHA and fish intake were consistently associated with a lower CHD mortality risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03192410.

Alcohol and Brain Development in Adolescents and Young Adults: A Systematic Review of the Literature and Advisory Report of the Health Council of the Netherlands.

Young people, whose brains are still developing, might entail a greater vulnerability to the effects of alcohol consumption on brain function and development. A committee of experts of the Health Council of the Netherlands evaluated the state of scientific knowledge regarding the question whether alcohol negatively influences brain development in young people. A systematic literature search for prospective studies was performed in PubMed and PsychINFO, for longitudinal studies of adolescents or young adults ranging between 12 and 24 y of age at baseline, investigating the relation between alcohol use and outcome measures of brain structure and activity, cognitive functioning, educational achievement, or alcohol use disorder (AUD), with measures at baseline and follow-up of the outcome of interest. Data were extracted from original articles and study quality was assessed using the Newcastle-Ottawa Scale. A total of 77 studies were included, 31 of which were of sufficient quality in relation to the study objectives. There were indications that the gray matter of the brain develops abnormally in young people who drink alcohol. In addition, the more often young people drink or the younger they start, the higher the risk of developing AUD later in life. The evidence on white matter volume or quality, brain activity, cognitive function, and educational achievement is still limited or unclear. The committee found indications that alcohol consumption can have a negative effect on brain development in adolescents and young adults and entails a risk of later AUD. The committee therefore considers it a wise choice for adolescents and young adults not to drink alcohol.

Effect of low doses of n-3 fatty acids on cardiovascular diseases in 4,837 post-myocardial infarction patients: design and baseline characteristics of the Alpha Omega Trial.

BACKGROUND: Weekly fish consumption has been related to a lower risk of fatal coronary heart disease (CHD) and incident stroke in populations with a low fish intake. This relation has mainly been attributed to n-3 fatty acids in fish, that is, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). It is at present unclear whether alpha-linolenic acid (ALA), a n-3 fatty acid from vegetable origin, could also be protective against cardiovascular diseases (CVDs). There is a need for food-based trials to establish the efficacy of low doses of n-3 fatty acids in CVD prevention. OBJECTIVES: The aim of the study was to evaluate the effect of an additional daily intake of 400 mg of EPA + DHA and 2 g of ALA on CVD morbidity and mortality in free-living subjects with a history of myocardial infarction. DESIGN: The multicenter Alpha Omega Trial is a randomized, double-blind, placebo-controlled trial with a 2 x 2 factorial design. Between May 2002 and December 2006, we enrolled a total of 4,837 men and women aged 60 through 80 who experienced a myocardial infarction within 10 years before entering the study. Subjects were randomized to 1 of 4 margarine spreads that were enriched with EPA + DHA and/or ALA, or placebo. Compliance was monitored via tub counts and assessment of n-3 fatty acids in plasma. Subjects were observed for 40 months for the occurrence of fatal and nonfatal CVD. RESULTS: The cohort was on average 69 years old at the start of the study and comprised 22% women. Subjects had their (last) myocardial infarction approximately 4 years before enrollment. Mean body mass index was 27.7 kg/m(2), and 17% smoked. Average serum total and high-density lipoprotein cholesterol were 4.7 and 1.3 mmol/L, respectively, and 85% used statins. Mean blood pressure was 142/80 mm Hg, and most subjects were on antihypertensive medication (88%). Diabetes mellitus was reported by 17% of the subjects, and 7% reported a history of stroke. The overall mortality rate during the trial period was 23 per 1,000 person-years, with approximately 40% due to CVD. CURRENT STATUS: Follow-up of the patients was completed in November 2009, and findings will be reported in the second part of 2010.

Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.

We assessed the dose-response relations within a low range of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and fish intake on fatal coronary heart disease (CHD) and nonfatal myocardial infarction (MI). In a Dutch population-based cohort study, EPA+DHA and fish intake were assessed at baseline among 21,342 participants aged 20-65 y with no history of MI or stroke. Hazard ratios were calculated with Cox proportional-hazard models. During 9-14 y of follow-up (mean 11.3 y), 647 participants (3%) died, of which 82 of CHD. Fatal CHD mainly comprised MI (64 cases). In total, 252 participants survived an MI. Median intakes in quartiles of EPA+DHA were 40, 84, 151, and 234 mg/d. Medians of fish consumption in quartiles were 1.1, 4.2, 10.7, and 17.3 g/d. Compared with the lowest quartile of EPA+DHA, participants in the top quartile had a 49% lower risk of fatal CHD (95% CI: 6-73%) and a 62% lower risk of fatal MI (95% CI: 23-81%). We observed inverse dose-response relations for EPA+DHA intake and fatal CHD (P-trend = 0.05) and fatal MI (P-trend = 0.01). Results were similar for fish consumption. Nonfatal MI was not associated with EPA+DHA or fish intake. In conclusion, in populations with a low fish consumption, EPA+DHA and fish may lower fatal CHD and MI risk in a dose-responsive manner. Low intakes of EPA+DHA or fish do not seem to protect against nonfatal MI.

Alpha-linolenic acid: is it essential to cardiovascular health?

There is a large body of scientific evidence that has been confirmed in randomized controlled trials indicating a cardioprotective effect for omega-3 fatty acids from fish. For alpha-linolenic acid (ALA), which is the omega-3 fatty acid from plants, the relation to cardiovascular health is less clear. We reviewed the recent literature on dietary ALA intake, ALA tissue concentrations, and cardiovascular health in humans. Short-term trials (6-12 weeks) in generally healthy participants mostly showed no or inconsistent effects of ALA intake (1.2-3.6 g/d) on blood lipids, low-density lipoprotein oxidation, lipoprotein(a), and apolipoproteins A-I and B. Studies of ALA in relation to inflammatory markers and glucose metabolism yielded conflicting results. With regard to clinical cardiovascular outcomes, there is observational evidence for a protective effect against nonfatal myocardial infarction. However, no protective associations were observed between ALA status and risk of heart failure, atrial fibrillation, and sudden death. Findings from long-term trials of ALA supplementation are awaited to answer the question whether food-based or higher doses of ALA could be important for cardiovascular health in cardiac patients and the general population.

Association of n-3 long-chain PUFA and fish intake with depressive symptoms and low dispositional optimism in older subjects with a history of myocardial infarction.

Individuals with CHD are at increased risk of poor mental well-being. Dietary intake of EPA and DHA, the main n-3 fatty acids from fish, may be beneficial to mental well-being. We examined the association of EPA+DHA and fish intake with mental well-being in 644 participants, aged 60-80 years, with a history of myocardial infarction. Habitual food intake was assessed with a 203-item FFQ. Depressive symptoms were assessed with the self-report geriatric depression scale, and dispositional optimism was assessed with the revised life orientation test (LOT-R) and a four-item questionnaire (4Q). In Cox-regression models modified for cross-sectional analyses, we adjusted for sex, age, energy intake, BMI, family history of depression, education, marital status, smoking, physical activity and intake of saturated fat, alcohol and fibre. Compared with the lower tertile, subjects in the higher tertile of EPA+DHA intake had a lower prevalence of depressive symptoms, but this association was not statistically significant (prevalence ratio (PR) 0.78; 95 % CI 0.50, 1.22, P-trend 0.27). The higher tertile of EPA+DHA intake was positively associated with dispositional optimism measured with the 4Q (PR 0.69; 95 % CI 0.46, 1.03, P-trend 0.05), but not according to the LOT-R. Fish intake was not related to either depressive symptoms or dispositional optimism. In conclusion, intake of EPA+DHA was positively associated with dispositional optimism assessed with the 4Q, but not with optimism assessed with the LOT-R or with depressive symptoms.

Plasma and Dietary Linoleic Acid and 3-Year Risk of Type 2 Diabetes After Myocardial Infarction: A Prospective Analysis in the Alpha Omega Cohort.

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.

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.

Biomarkers of food intake for nuts and vegetable oils: an extensive literature search.

Nuts and vegetable oils are important sources of fat and of a wide variety of micronutrients and phytochemicals. Following their intake, several of their constituents, as well as their derived metabolites, are found in blood circulation and in urine. As a consequence, these could be used to assess the compliance to a dietary intervention or to determine habitual intake of nuts and vegetable oils. However, before these metabolites can be widely used as biomarkers of food intake (BFIs), several characteristics have to be considered, including specificity, dose response, time response, stability, and analytical performance. We have, therefore, conducted an extensive literature search to evaluate current knowledge about potential BFIs of nuts and vegetable oils. Once identified, the strengths and weaknesses of the most promising candidate BFIs have been summarized. Results from selected studies have provided a variety of compounds mainly derived from the fatty fraction of these foods, but also other components and derived metabolites related to their nutritional composition. In particular, α-linolenic acid, urolithins, and 5-hydroxyindole-3-acetic acid seem to be the most plausible candidate BFIs for walnuts, whereas for almonds they could be α-tocopherol and some catechin-derived metabolites. Similarly, several studies have reported a strong association between selenium levels and consumption of Brazil nuts. Intake of vegetable oils has been mainly assessed through the measurement of specific fatty acids in different blood fractions, such as oleic acid for olive oil, α-linolenic acid for flaxseed (linseed) and rapeseed (canola) oils, and linoleic acid for sunflower oil. Additionally, hydroxytyrosol and its metabolites were the most promising distinctive BFIs for (extra) virgin olive oil. However, most of these components lack sufficient specificity to serve as BFIs. Therefore, additional studies are necessary to discover new candidate BFIs, as well as to further evaluate the specificity, sensitivity, dose-response relationships, and reproducibility of these candidate biomarkers and to eventually validate them in other populations. For the discovery of new candidate BFIs, an untargeted metabolomics approach may be the most effective strategy, whereas for increasing the specificity of the evaluation of food consumption, this could be a combination of different metabolites.

Dairy Consumption and Cardiometabolic Diseases: Systematic Review and Updated Meta-Analyses of Prospective Cohort Studies.

PURPOSE OF REVIEW: Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. RECENT FINDINGS: We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3-4% lower risk of diabetes. Yogurt was non-linearly inversely associated with diabetes (RR = 0.86, 95% CI: 0.83-0.90 at 80 g/d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases.

Dietary fatty acid intake after myocardial infarction: a theoretical substitution analysis of the Alpha Omega Cohort.

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. This study was registered at clinicaltrials.gov as NCT03192410.

Kidney dysfunction, systemic inflammation and mental well-being in elderly post-myocardial infarction patients.

BACKGROUND: The aim was to investigate whether mild kidney dysfunction and low-grade inflammation in post-myocardial infarction patients are independently associated with markers of mental well-being (i.e. depressive and apathy symptoms, and dispositional optimism). METHODS: In post-myocardial infarction patients, kidney function was assessed by estimated glomerular filtration rate (eGFR) calculated from the combined CKD-EPI formula based on serum levels of both creatinine and cystatine C. Systemic inflammation was assessed using high sensitivity C-reactive protein (hs-CRP) levels. The 15-item Geriatric Depression Scale (GDS-15), the 3-item apathy subscale and the 4-item optimism questionnaire (4Q) were used to measure mental well-being and were analyzed using linear multivariable regression analysis. RESULTS: Of the 2355 patients, mean age was 72.3 (range 63-84) years and 80.1% were men. After multivariable adjustment, a poorer kidney function was associated with more depressive symptoms (ß = -0.084, p < 0.001), more apathy symptoms (ß = -0.101, p < 0.001), and less dispositional optimism (ß = 0.072, p = 0.002). Moreover, higher levels of hs-CRP were associated with more depressive symptoms (ß = 0.051, p = 0.013), more apathy symptoms (ß = 0.083, p < 0.001) and less dispositional optimism (ß = -0.047 p = 0.024). Apathy showed the strongest independent relation with both low eGFR and high hs-CRP. CONCLUSIONS: In post-myocardial infarction patients, impaired kidney function and systemic inflammation showed a stronger association with apathy than with depressive symptoms and dispositional optimism.

Kidney function and specific mortality in 60-80 years old post-myocardial infarction patients: A 10-year follow-up study.

Chronic kidney disease (CKD) is highly prevalent among older post-myocardial infarction (MI) patients. It is not known whether CKD is an independent risk factor for mortality in older post-MI patients with optimal cardiovascular drug-treatment. Therefore, we studied the relation between kidney function and all-cause and specific mortality among older post-MI patients, without severe heart failure, who are treated with state-of-the-art pharmacotherapy. From 2002-2006, 4,561 Dutch post-MI patients were enrolled and followed until death or January 2012. We estimated Glomerular Filtration Rate (eGFR) with cystatin C (cysC) and creatinine (cr) using the CKD-EPI equations and analyzed the relation with any and major causes of death using Cox models and restricted cubic splines. Mean (SD) for age was 69 years (5.6), 79% were men, 17% smoked, 21% had diabetes, 90% used antihypertensive drugs, 98% used antithrombotic drugs and 85% used statins. Patients were divided into four categories of baseline eGFRcysC: ≥90 (33%; reference), 60-89 (47%), 30-59 (18%), and <30 (2%) ml/min/1.73m2. Median follow-up was 6.4 years. During follow-up, 873 (19%) patients died: 370 (42%) from cardiovascular causes, 309 (35%) from cancer, and 194 (22%) from other causes. After adjustment for age, sex and classic cardiovascular risk factor, hazard ratios (95%-confidence intervals) for any death according to the four eGFRcysC categories were: 1 (reference), 1.4 (1.1-1.7), 2.9 (2.3-3.6) and 4.4 (3.0-6.4). The hazard ratios of all-cause and cause-specific mortality increased linearly below kidney functions of 80 ml/min/1.73 m2. Weaker results were obtained for eGFRcr. To conclude, we found in optimal cardiovascular drug-treated post-MI patients an inverse graded relation between kidney function and mortality for both cardiovascular as well as non-cardiovascular causes. Risk of mortality increased linearly below kidney function of about 80 ml/min/1.73 m2.

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies.

BACKGROUND: The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes. METHODS: We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis. FINDINGS: Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m2, who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I2=53·9%, pheterogeneity=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I2=63·0%, pheterogeneity<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all pheterogeneity≥0·13). INTERPRETATION: Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful. FUNDING: Funders are shown in the appendix.