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Assessment of national dietary guidelines in a number of European countries reveals that some are based on cohort studies, focusing on total seafood consumption, while others are based on the content of EPA and DHA, distinguishing between oily and other fish. The mean actual intake of fish in most countries is around or below the recommended intake, with differences in intake of fish being present between sex and age groups. Many people do not reach the national recommendation for total fish intake. Dietary recommendations for fish and EPA/DHA are based mainly on data collected more than 10 years ago. However, methods of farmed fish production have changed considerably since then. The actual content of EPA and DHA in farmed salmon has nearly halved as the traditional finite marine ingredients fish meal and fish oil in salmon diets have been replaced with sustainable alternatives of terrestrial origin. As farmed salmon is an important source of EPA and DHA in many Western countries, our intake of these fatty acids is likely to have decreased. In addition, levels of vitamin D and Se are also found to have declined in farmed fish in the past decade. Significant changes in the EPA and DHA, vitamin D and Se content of farmed fish means that average intakes of these nutrients in Western populations are probably lower than before. This may have consequences for the health-giving properties of fish as well as future dietary recommendations for fish intake.

Background: Higher intake of polyunsaturated fatty acids (PUFAs) and higher circulating PUFAs are associated with lower cardiovascular disease (CVD) risk. The positive influence of PUFAs might be via lowering arterial stiffness, resulting in a better CVD risk profile; however, studies investigating circulating PUFAs in relation to arterial stiffness in a general population are limited., Objective: We investigated the associations of plasma phospholipid n-3 (ω-3) and n-6 PUFAs and fish oil intake with arterial stiffness., Methods: We used data from a subgroup of the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) Study (n = 501, 75.0 ± 4.96 y, 46% men), a population-based study of community-dwelling older adults. Plasma phospholipid PUFAs were measured by GC at baseline, and fish oil intake was assessed at 3 time points: early life (ages 14-19 y), midlife (ages 40-50 y), and late life (ages 66-96 y, AGES-Reykjavik baseline) with the use of a validated food-frequency questionnaire. Arterial stiffness was determined as carotid-femoral pulse wave velocity (cf-PWV) with the use of an electrocardiogram after a mean follow-up of 5.2 ± 0.3 y. Regression coefficients (95% CIs), adjusted for demographics, follow-up time, risk factors, cholesterol, triglycerides, and serum vitamin D, were calculated by linear regression per SD increment in PUFAs., Results: Plasma total n-3 PUFAs, eicosapentaenoic acid, and docosahexaenoic acid were associated with lower cf-PWV [β (95% CI): -0.036 (-0.064, -0.008); -0.031 (-0.059, -0.003); -0.036 (-0.064, -0.009), respectively]. In contrast, plasma total n-6 PUFAs and linoleic acid were associated with higher cf-PWV [0.035 (0.009, 0.061) and 0.034 (0.008, 0.059)]. Regular fish oil consumption at early-, mid-, and late-life was not associated with cf-PWV., Conclusions: Our results show a positive association between plasma n-6 PUFAs and arterial stiffness, and suggest that higher concentrations of plasma long-chain n-3 PUFAs are associated with less arterial stiffness and therein may be one of the mechanisms underlying the association between plasma n-3 PUFAs and lower CVD risk., (© 2015 American Society for Nutrition.)

Background: Polyunsaturated fatty acids (PUFAs) may play a role in fracture, but studies have been largely confined to estimates of dietary intake., Objective: We aimed to examine associations between fatty acids measured in late life and fish-oil consumption in early life, midlife, and late life with osteoporotic fracture risk., Design: Osteoporotic fractures were determined from medical records over 5-9 y of follow-up in men and women aged 66-96 y. Data were analyzed from 1438 participants including 898 participants who were randomly selected from the Age, Gene/Environment Susceptibility Study, which is an observational study, and 540 participants with incident fracture. Plasma phospholipid fatty acids were assessed by using gas chromatography. Fish-oil consumption was assessed by using validated questionnaires as never (referent), less than daily, or daily. HRs and 95% CIs adjusted for age, education, height, weight, diabetes, physical activity, and medications were estimated by using Cox regression., Results: In men, the highest tertile of PUFAs, n-3 (ω-3), and eicosapentaenoic acid were associated with decreased fracture risk [HRs (95% CIs): 0.60 (95% CI: 0.41, 0.89), 0.66 (0.45, 0.95), and 0.59 (0.41, 0.86), respectively]. In women, PUFAs tended to be inversely associated with fracture risk (P-trend = 0.06), but tertiles 2 and 3 were not independently associated with risk. Tertile 2 of n-6 and arachidonic acid was associated with fracture risk in women [HRs (95% CIs): 1.43 (1.10, 1.85) and 1.42 (1.09, 1.85), respectively]. Daily fish-oil consumption in late life was associated with lower fracture risk in men (HR: 0.64; 95% CI: 0.45, 0.91). Daily fish-oil consumption in midlife was associated with lower fracture risk in women (HR: 0.75; 95% CI: 0.58, 0.98)., Conclusions: Greater PUFA concentrations may be associated with lower osteoporotic fracture risk in older adults, particularly in men. Critical time periods for n-3 fatty acid consumption may differ by sex., (© 2015 American Society for Nutrition.)

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.

Background: Omega-3 polyunsaturated fatty acids (omega3-PUFAs) from fish oil (FO) reduce heart rate in humans. The mechanism underlying this cardioprotective effect of FO is unknown., Objective: We studied the effects of an FO diet on heart rate, pacemaker activity, and pacemaker current (I(f)) in sinoatrial node (SAN) cells., Methods: Rabbits were fed a diet enriched with 2.5% (w/w) FO or 2.5% high oleic sunflower oil (SO) as control for 3 weeks. Heart rate was measured in Langendorff-perfused hearts. Pacemaker activity and I(f) were recorded using the perforated patch-clamp technique in isolated SAN cells., Results: In SAN cells, the FO diet reduced I(f) density by approximately 30%, without changes in its voltage dependence, reversal potential, (de)activation kinetics, and sensitivity to beta-stimulation. Dietary FO significantly prolonged the cycle length in both isolated perfused hearts (337 +/- 8 [mean +/- SEM, n = 8] vs. 301 +/- 9 ms [n = 8]) and single cells (363 +/- 20 [n = 19] vs. 276 +/- 8 ms [n = 22]). In single cells, dietary FO significantly decreased the diastolic depolarization rate by 33% and prolonged the action potential by 27%, whereas other action potential parameters were unaltered. I(f) blockade experiments substantiated that the reduced diastolic depolarization rate in the FO group was partially caused by the I(f) density reduction., Conclusion: An FO diet prolongs the sinus cycle length because of, at least in part, a reduction in I(f) density. Our results explain FO-induced heart rate reduction and suggest FO as an alternative or adjunct to I(f)-lowering drugs.

Very long-chain n-3 PUFA from fish are suggested to play a role in the development of the brain. Fish oil feeding results in higher proportions of n-3 PUFA in the brains of newborn piglets. However, the effect of fish oil on the fatty acid composition of specific cerebral brain lobes in juvenile pigs is largely uninvestigated. This study examined the effect of a fish oil diet on the fatty acid composition of the frontal, parietal, temporal and occipital brain lobes in juvenile pigs (7 weeks old). Pigs were randomly allocated to a semipurified pig diet containing either 4% (w/w) fish oil (n 19) or 4% (w/w) high-oleic acid sunflower oil (HOSF diet, n 18) for a period of 8 weeks. The fish oil diet resulted in significantly higher proportions (%) of DHA in the frontal (10.6 (SD1.2)), parietal (10.2 (SD1.5)) and occipital brain lobes (9.9 (SD 1.3)), but not in the temporal lobe (7.7 (SD1.6)), compared with pigs fed the HOSF diet (frontal lobe, 7.5 (SD1.0); parietal lobe, 8.1 (SD 1.3); occipital lobe, 7.3 (SD1.2), temporal lobe, 6.6 (SD1.2). Moreover, the proportion of DHA was significantly lower in the temporal lobe compared with the frontal, parietal and occipital brain lobes in pigs fed a fish oil diet. In conclusion, the brains of juvenile pigs appear to be responsive to dietary fish oil, although the temporal brain lobe is less responsive compared with the other three brain lobes. The functional consequences of these differences are a challenging focus for future investigation.

Epidemiologic observational research shows that higher intake of fish fatty acids is associated with a lower risk of fatal heart disease and sudden death, but this effect is not observed with non-fatal heart disease. Currently available trials with clinical endpoints provide no convincing evidence that supplementation with fish oil prevents cardiovascular disease. The theory that fish fatty acids can prevent cardiac arrhythmias is not supported by the trials performed in patients with life-threatening cardiac arrhythmias. For the specific group of patients who have previously experienced a ventricular tachycardia and who have not been prescribed an anti-arrhythmia medication for this, there are indications that the intake of fish oil might even lead to a slightly increased risk ofsevere cardiac arrhythmias. However, other subgroups of patients, such as patients with a recent myocardial infarction may benefit from taking fish oil to prevent cardiac arrhythmias. The advice of the Health Council of the Netherlands to eat fish twice per week, of which fatty fish once per week, or to take 450 mg of the combination eicosapentaenic acid (EPA) and docosahexaenic acid (DHA) per day remains justifiable until the results from current studies become available. However, patients with a ventricular arrhythmia who do not receive specific anti-arrhythmic medication should be careful about taking fish oil capsules.

Long chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) lower risk of coronary heart disease (CHD), but mechanisms are not well understood. We used proteomics to identify human serum proteins that are altered by n-3 LCPUFA. Such proteins could identify pathways whereby they affect CHD. Eighty-one healthy volunteers entered a double blind randomised trial to receive 3.5 g of fish oil or 3.5 g of high oleic sunflower oil daily. Serum was collected before and after 6 wk of intervention. Serum was analysed by proteomics using 2-DE. Proteins that were differentially regulated were identified by MS. We also analysed serum apolipoprotein A1 (apo A1), high-density lipoprotein (HDL) particle size and haptoglobin. Serum levels of apo A1, apo L1, zinc-alpha-2-glycoprotein, haptoglobin precursor, alpha-1-antitrypsin precursor, antithrombin III-like protein, serum amyloid P component and haemopexin were significantly downregulated (all p<0.05) by fish oil compared with high oleic sunflower oil supplementation. Fish oil supplementation caused a significant shift towards the larger, more cholesterol-rich HDL(2) particle. The alterations in serum proteins and HDL size imply that fish oil activates anti-inflammatory and lipid modulating mechanisms believed to impede the early onset of CHD. These proteins are potential diagnostic biomarkers to assess the mechanisms whereby fish oil protects against CHD in humans.

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 omega3-polyunsaturated fatty acids (omega3-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), omega-9 monounsaturated fatty acid oleic acid (20 micromol/L), or omega3-PUFAs (docosahexaenoic acid or eicosapentaenoic acid 20 micromol/L). omega3-PUFAs shortened the action potential at low stimulation frequencies and caused an approximately 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. omega3-PUFAs abolished triggered activity and reduced the number of delayed afterdepolarizations and calcium aftertransients compared with control and oleic acid. Omega3-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., Conclusions: Superfusion with omega3-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.

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.

n-3 Fatty acids may protect against heart disease mortality by preventing fatal arrhythmias. Underlying effects on cardiac electrophysiology may be demonstrable in the standard electrocardiogram (ECG) and provide insight into the mechanism. Therefore, we investigated the effect of dietary n-3 fatty acids on heart-rate-corrected QT interval, T-loop width, spatial QRS-T angle and spatial U-wave amplitude in patients with frequent premature ventricular complexes. Seventy-four patients received either capsules providing 1.5 g n-3 fatty acids daily or placebo for approximately 14 weeks. ECG were recorded before and after intervention. None of the ECG characteristics was significantly affected by treatment. The present results do not provide additional support for the hypothesis that n-3 fatty acids prevent cardiac arrhythmia through generic electrophysiologic effects on heart cell membranes. However, we cannot exclude effects of n-3 fatty acids on clinical relevant endpoints that are not easily detected by prior changes in the ECG.