Plasma Docosahexaenoic Acid Concentrations Research Articles

APOE4 mice rely more on the plasma DHA than APOE3 mice, especially in glia morphology and cognitive performance.

AbstractBackgroundThe metabolism of docosahexaenoic acid (DHA), an omega‐3 fatty acid, is different in APOE4 carriers. Brain relies on the plasma DHA pool for its need but the plasma‐liver‐brain axis in relation to cognition remains obscure. We hypothesized that this relation is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice.MethodMale and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. Barnes maze and object recognition tests were performed in mice. Immunofluorescence was eprformed on parafin embeded brain slides with GFAP and IBA‐1 and multiplex cytokines were measured in hippocampus protein extracts.ResultIn the cortex, a genotype effect was found where APOE4 mice had higher concentration of DHA than APOE3 mice fed the control diet. APOE4 mice had 20‐30% lower plasma DHA and arachidonic acid (AA) concentrations, adipose tissue AA concentrations than APOE3 mice, independent of diet. In APOE4 mice, there was a significant correlation between plasma DHA and scores on the Barnes maze and with better recognition index. In addition, APOE4 mice fed the DHA diet had lower hippocampal concentrations of interleukin‐7, lipopolysaccharide‐induced CXC chemokine and monocyte chemoattractant protein 1, and higher concentration of interferon‐gamma compared to APOE4 mice fed the control diet. We also found that a diet rich in DHA enhances reactive astrogliosis and ramified microglia morphology in APOE4 mice.ConclusionAltogether, our data support that APOE4 mice rely more on the plasma DHA than APOE3 mice, especially in cognitive performance and astrocytes and microglia morphology. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele

The metabolism of docosahexaenoic acid (DHA), an omega-3 fatty acid, is different in carriers of APOE4, the main genetic risk factor for late-onset Alzheimer's disease. The brain relies on the plasma DHA pool for its need, but the plasma-liver-brain axis in relation to cognition remains obscure. We hypothesized that this relationship is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice. Male and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. There was a significant genotype × diet interaction for DHA concentration in the liver and adipose tissue. In the cortex, a genotype effect was found where APOE4 mice had a higher concentration of DHA than APOE3 mice fed the control diet. There was a significant genotype × diet interaction for the liver and hippocampal arachidonic acid (AA). APOE4 mice had 20–30% lower plasma DHA and AA concentrations than APOE3 mice, independent of diet. Plasma and liver DHA levels were significantly correlated in APOE3 and APOE4 mice. In APOE4 mice, there was a significant correlation between plasma, adipose tissues, cortex DHA and the Barnes maze and/or with a better recognition index. Moreover, higher AA levels in the liver and the hippocampus of APOE4 mice were correlated with lower cognitive performance. Our results suggest that there is a plasma-liver-brain axis of DHA that is modified in APOE4 mice. Moreover, our data support that APOE4 mice rely more on plasma DHA than APOE3 mice, especially in cognitive performance. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Docosahexaenoic Acid as the Bidirectional Biomarker of Dietary and Metabolic Risk Patterns in Chinese Children: A Comparison with Plasma and Erythrocyte.

Objective: The present study aims to measure docosahexaenoic acid (DHA) in both the plasma and erythrocyte of a child population and compares them with respect to their associations with dietary and metabolic risk patterns. Methods: A cross-sectional study was conducted, and a total of 435 children ages 5–7 years old were recruited. Diet information was collected using a food frequency questionnaire (FFQ). The physical indicators, blood pressure, and glycolipid metabolic indicators were determined. The plasma and erythrocyte DHA were analyzed using a gas chromatography mass spectrometer. Principal component analysis was used to identify dietary and metabolic risk patterns. Multivariate regression analyses were used to investigate the associations of DHA status with dietary and metabolic risk patterns. Results: A significant correlation between plasma and the erythrocyte DHA concentration was found (r = 0.232, p < 0.001). A diversified dietary pattern characterized that a high intake of diversified foods had a positive association with the plasma DHA level (β = 0.145, 95% CI: 0.045~0.244, p = 0.004). Children of obesity risk patterns with a high weight, pelvis breadth, BMI, upper arm circumference, and chest circumference had lower plasma DHA concentrations (OR = 0.873, 95% CI: 0.786~0.969, p = 0.011). Children with higher plasma and erythrocyte DHA concentrations were adhered to blood lipid risk patterns with high CHOL and LDL-C levels. The plasma DHA (OR = 1.271, 95% CI: 1.142~1.415, p < 0.001) had a stronger association with a blood lipid risk pattern than erythrocyte (OR = 1.043, 95% CI: 1.002~1.086, p = 0.040). Conclusions: The diversified dietary pattern had a higher plasma DHA concentration. Lower levels of plasma DHA were positively associated with obesity in children. DHA in plasma appears to be more strongly associated with blood lipid metabolism than erythrocyte. Plasma DHA may be a more sensitive bidirectional biomarker to evaluate the recently comprehensive diet intake and metabolic risk of children.

Effects of Fish Oil on Biomarkers of Axonal Injury and Inflammation in American Football Players: A Placebo-Controlled Randomized Controlled Trial.

There are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased (p < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (<0.001); placebo (p < 0.05)), with starting players (vs. non-starters) showing significant higher circulating concentrations at week 26 (p < 0.01). Fish oil (DHA+EPA) supplementation did not mitigate the adverse effects of RSHI, as measured by NfL levels; however, participants with the highest plasma DHA+EPA concentrations tended to have lower NfL levels. DHA+EPA supplementation had no effects on inflammatory cytokine levels at any of the timepoints tested. These findings emphasize the need for effective strategies to protect American football participants from the effects of RSHI.

59 Late gestation supplementation of long chain fatty acids increases foal docosahexaenoic acid concentrations at birth

Maternal supplementation of omega-3 fatty acids during gestation has a variety of benefits on the dam and resulting offspring in several species, including reduced latency to stand and suckle. The objective of the study is to test the hypothesis that foals born to mares supplemented with marine-derived algae during late gestation will have greater plasma DHA concentrations than foals born to either control mares or mares supplemented with flaxseed-derived ALA. The current study utilized 13 American Quarter Horse mares and their foals, assigned to one of 3 dietary treatments: a control basal diet (CON, n = 5), the basal diet plus 242.4 g of a supplement providing marine-derived omega-3 fatty acids (DigestaWell Ⓡ Omega; MAR, n = 5), or the basal diet with the addition of 190 g of a flaxseed supplement (Smartpak Simple Flax; FLAX, n = 3). Supplements were fed twice daily and were designed to deliver 40 g of omega-3 fatty acids. Mares began treatments 30 d before expected foaling dates and continued through d 5 post-parturition (PP). Plasma was collected from mares before supplementation, and on d 0, 5, and 30 PP. Milk samples were collected from mares at d 0 and 5 PP. Plasma samples were collected from foals at birth, and on d 5 and 30 PP. Fatty acid compositions of samples were determined using lipid extraction and gas chromatography. Data were analyzed using MIXED procedure of SAS, using repeated measures for milk and plasma. Simple effect differences were detected via Tukey test, and α = 0.05. The CON diet provided 29 g of α-linolenic acid (ALA), 0 g of eicosapentaenoic acid (EPA), and 4.5 g of docosahexaenoic acid (DHA), the MAR and FLAX diets provided 27 and 34 g of ALA, 0 and 0.03 g of EPA, and 17.4 and 4.5 g of DHA to mares, daily. Fatty acids are represented as g of fatty acid per 100 g of lipid. DHA (1.9 ± 0.2 g/100g) and EPA (0.3 ± 0.1 g/100g) contributed to a greater percent of plasma lipids in foals born to MAR supplemented mares compared with CON foals (DHA = 0.6 ± 0.2; EPA = 0 g/100g; P < 0.05). These fatty acids were not different between FLAX and CON foals ( P > 0.1) Samples obtained from foals at birth before nursing had the highest DHA levels (1.90 ± 0.18 g/100g), compared with all other samples, and DHA declined at d 5 (0.6 ± 0.2 g/100g) and 30 (0.1 ± 0.2 g/100g; P < 0.001) PP. No differences were observed in mare plasma or milk. Maternal supplementation of marine-derived omega-3 fatty acids in late gestation increased foal plasma DHA concentrations more so than that of foals from mares fed flax.

Comparison of pharmacokinetics of omega-3 fatty acid supplements in monoacylglycerol or ethyl ester in humans: a randomized controlled trial

BackgroundA diet low in omega-3 fatty acids (n-3 FA) results in low plasma concentrations of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the two main long chain n-3 FA. n-3 FA supplements on the market are esterified in triglycerides (TG) or ethyl ester (EE); the latter is absorbed less than other esterification forms. The objective of this study was to test and compare the pharmacokinetics of n-3 FA esterified in monoacylglycerides (MAG), a predigested form, with the EE form.MethodsThis study was a randomized, double-blind, crossover, controlled, clinical trial. Ten men and ten women between 18 and 60 years old were recruited. Participants received a single oral dose of 3 g of n-3 FA esterified in EE or MAG. Eleven blood samples were collected over 24 h post-dose. Plasma total lipids were extracted, methylated, and analyzed using gas chromatography.ResultsAfter receiving the MAG form, plasma EPA and DHA peaked at a concentration 3 and 2.5 times higher, respectively, than with the EE form. When provided in MAG form, n-3 FA plasma concentration during the absorption phase was on average 3–5 times higher than in EE form. When n-3 FAs were provided esterified in MAG, their concentration 24 h post-dose was higher than in EE. Males had a lower n-3 FA plasma concentration than females when n-3 FAs were provided in EE but there was no sexe difference when provided in MAG.ConclusionsPlasma concentration of DHA and EPA was higher when provided in MAG than EE form.

Single-Dose SDA-Rich Echium Oil Increases Plasma EPA, DPAn3, and DHA Concentrations.

The omega-3 (n3) polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with health benefits. The primary dietary source of EPA and DHA is seafood. Alpha-linoleic acid (ALA) has not been shown to be a good source for EPA and DHA; however, stearidonic acid (SDA)—which is naturally contained in echium oil (EO)—may be a more promising alternative. This study was aimed at investigating the short-term n3 PUFA metabolism after the ingestion of a single dose of EO. Healthy young male subjects (n = 12) ingested a single dose of 26 g of EO after overnight fasting. Plasma fatty acid concentrations and relative amounts were determined at baseline and 2, 4, 6, 8, 24, 48, and 72 h after the ingestion of EO. During the whole examination period, the participants received standardized nutrition. Plasma ALA and SDA concentrations increased rapidly after the single dose of EO. Additionally, EPA and DPAn3 concentrations both increased significantly by 47% after 72 h compared to baseline; DHA concentrations also significantly increased by 21% after 72 h. To conclude, EO increases plasma ALA, SDA, EPA, DPAn3, and DHA concentrations and may be an alternative source for these n3 PUFAs.

A randomized trial comparing omega-3 fatty acid plasma levels after ingestion of emulsified and non-emulsified cod liver oil formulations

Objectives: Emulsified formulations of omega-3 fatty acids may increase plasma concentrations of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) compared with non-emulsified formulations. The current study evaluated plasma concentrations of DHA + EPA as well as DHA and EPA individually following administration of emulsified vs non-emulsified cod liver oil formulations.Methods: In this randomized, 2-period, crossover study (ClinicalTrials.gov NCT02428699), 47 healthy adults received single doses of an emulsified cod liver oil formulation and a non-emulsified cod liver oil formulation, each containing 10% cod liver oil plus 10% cod oil and closely matched DHA and EPA content. Blood samples were collected for 24 h after dosing to analyze DHA and EPA plasma concentrations using a validated methodology. DHA + EPA, DHA, and EPA pharmacokinetics were compared using an analysis of covariance model. The incremental area under the plasma concentration curve at 24 h (iAUC0–24 h) for DHA + EPA was the primary endpoint.Results: DHA + EPA, DHA, and EPA plasma concentrations reached higher levels in plasma following administration of the emulsified vs non-emulsified formulation. The emulsified cod liver oil formulation produced iAUC0–24 h values for DHA + EPA, DHA, and EPA that were 1.66, 1.78, and 1.64 times higher, respectively, than the non-emulsified formulation; iAUC0–10 h values were 1.84, 1.96, and 1.79 times higher, respectively (all p < 0.01). Maximum concentrations of DHA + EPA, DHA, and EPA in plasma were significantly higher for the emulsified than the non-emulsified formulation (p < 0.001).Conclusions: DHA + EPA, DHA, and EPA plasma concentrations were significantly higher for the emulsified cod liver oil supplement vs the reference non-emulsified cod liver oil supplement.Trial registration: ClinicalTrials.gov identifier: NCT02428699.

Investigation into the plasma concentration of ω3 polyunsaturated fatty acids in Japanese attention-deficit hyperactivity disorder patients.

Several studies report that patients with attention-deficit hyperactivity disorder (ADHD) have a low plasma concentration of polyunsaturated fatty acids (PUFAs). Since fish intake varies among countries and is high in Japan, those results may not apply to Japanese patients with ADHD. However, there is currently not enough evidence to support this. We compared the plasma PUFAs levels of patients with ADHD with the standard reference levels for healthy subjects, and examined the relationship between those PUFAs levels and the subject's psychological evaluation. The subjects were 24 patients (age < 20years) previously diagnosed with ADHD (according to the DSM-IV-TR criteria) at the psychiatric department of the Nagasaki University Hospital, between November 2010 and November 2015. The plasma concentrations of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) were measured using gas chromatography. Data pertaining to global assessment of functioning (GAF), clinical global impressions, ADHD Rating Scale-IV, and the drug used for treatment (atomoxetine or methylphenidate) were obtained from the medical records. The plasma concentrations of DHA, EPA, and EPA/AA were significantly lower than the normal reference range, indicating that ADHD patients present an imbalance in PUFAs levels. This trend is similar to ADHD patients in other countries and replacement therapy in Japanese ADHD patients may be useful.

Dietary fish oil differentially ameliorates high-fructose diet-induced hepatic steatosis and hyperlipidemia in mice depending on time of feeding

Chrononutrition is the science of nutrition based on chronobiology. Numerous epidemiological studies have shown that fish oil (FO) reduces the risk of cardiovascular events through various actions such as lowering triglycerides. The present study aimed to determine the time of day when the hypertriglyceridemia-decreasing ability of FO is optimal in mice. A high-fructose diet (HFrD) that induces hyperlipidemia in mice was replaced with the same diet containing 4% FO (HFrD-4% FO) at different times of the day for 2 weeks as described below. Mice were fed with HFrD alone (CTRL) or with HFrD containing 4% FO for 12 h around the time of activity onset [breakfast (BF)-FO] or offset [dinner (DN)-FO]. Plasma and liver concentrations of triglycerides and total cholesterol were reduced in BF-FO but not in DN-FO mice compared with CTRL mice. The temporal expression of genes associated with fatty acid synthesis such as Fasn, Acaca, Scd1 and Acly in the liver was significantly suppressed in both BF-FO and DN-FO mice. Expression levels of Scd1 in epididymal adipose tissue were significantly suppressed only in the BF-FO mice. Plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid were far more increased in BF-FO than in DN-FO mice. Significantly more of these n-3 polyunsaturated fatty acids (PUFAs) were excreted in the feces of DN-FO than of BF-FO mice. These findings suggest that dietary FO exerts more hypolipidemic activity at the time of breakfast than dinner because the intestinal absorption of n-3 PUFAs is more effective at that time.

Docosahexaenoic acid prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice

At a population level, dietary consumption of fish rich in docosahexaenoic acid (DHA) is associated with prevention of cognitive decline but this association is not clear in carriers of the apolipoprotein E epsilon 4 allele (E4). Plasma and liver DHA concentrations show significant alterations in E4 carriers, in part corrected by DHA supplementation. However, whether DHA sufficiency in E4 carriers has consequences on cognition is unknown. Mice expressing human E4 or apolipoprotein E epsilon 3 allele (E3) were fed either a control diet or a diet containing DHA for 8 months and cognitive performance was tested using the object recognition test and the Barnes maze test. In E4 mice fed the control diet, impaired memory was detected and arachidonic acid concentrations were elevated in the hippocampus compared to E3 mice fed the control diet. DHA consumption prevented memory decline and restored arachidonic acid concentrations in the hippocampus of E4 mice. Our results suggest that long-term high-dose DHA intake may prevent cognitive decline in E4 carriers.

Maternal Plasma DHA Levels Increase Prior to 29 Days Post-LH Surge in Women Undergoing Frozen Embryo Transfer: A Prospective, Observational Study of Human Pregnancy.

Docosahexaenoic acid (DHA) is an important fatty acid required for neurological development but its importance during early fetal neurological organogenesis is unknown. This study aimed to assess plasma fatty acid changes in early pregnancy in women undergoing natural cycle-frozen embryo transfer as a means of achieving accurately timed periconceptual sampling. Women undergoing frozen embryo transfer were recruited and serial fasting blood samples were taken pre-luteinizing hormone (LH) surge, and at 18, 29, and 45 d post-LH surge and fatty acids were analyzed using gas chromatography. This study took place at the Assisted Conception Unit, Glasgow Royal Infirmary, Scotland. Plasma fatty acid concentrations and influence of twin pregnancies on DHA plasma concentration were measured. In pregnant women, there was a rapid, early increase in the maternal rate of change of plasma DHA concentration observed by 29 d post-LH surge (mean ± SD, from 0.1 ± 1.3 to 1.6 ± 2.9 nmol DHA per mL plasma per day). This early pressure to increase plasma DHA concentration was further emphasized in twin pregnancies where the increase in DHA concentration over 45 d was 2-fold higher than in singleton pregnancies (mean ± SD increase, 74 ± 39 nmol/mL vs 36 ± 40 nmol/mL). An index of delta-6 desaturase activity increased 30% and positively correlated with the rate of change of DHA concentration between 18 and 29 d post-LH surge (R2 adjusted = 41%; P = .0002). DHA was the only fatty acid with a continual accelerated increase in plasma concentration and a positive incremental area under the curve (mean ± SD, 632 ± 911 nmol/mL × d) during the first 45 d of gestation. An increase in maternal plasma DHA concentration is initiated in human pregnancy prior to neural tube closure which occurs at 28 d gestation.

Ethnicity, sex, FADS genetic variation, and hormonal contraceptive use influence delta-5- and delta-6-desaturase indices and plasma docosahexaenoic acid concentration in young Canadian adults: a cross-sectional study.

BackgroundThere is great interest in the relationship between polyunsaturated fatty acids and health. Yet, the combinatory effect of factors such as sex, ethnicity, genetic polymorphisms and hormonal contraceptives (HC) on the concentrations of these fatty acids is unknown. Therefore, we sought to determine the effects of FADS polymorphisms, and HC use in females, on aggregate desaturase indices (ADI), and plasma docosahexaenoic acid (DHA) concentrations in Caucasian and East Asian males and females.MethodsFasting plasma samples were collected from subjects (Caucasian males: 113 and females: 298; East Asian males: 98 and females: 277) from the Toronto Nutrigenomics and Health Study. Fatty acid concentrations were measured by gas chromatography. ADI were estimated by dividing concentrations of arachidonic acid by linoleic acid (n-6 ADI) and eicosapentaenoic acid (EPA) by α-linolenic acid (n-3 ADI). [DHA/EPA] desaturase index was used to determine effects of FADS2 polymorphisms and HC use on EPA conversion to DHA.ResultsIn Caucasians, associations between n-6 ADI and multiple SNP (FADS1 rs174547, FADS2 rs174576, and rs174611 in males; FADS1 rs174547, FADS2 rs174570, rs174576, rs174679, rs174611, rs174593, rs174626, rs2072114, rs2845573, and rs2851682 in females) withstood multiple testing. In East Asian females, 5 SNP-n-6 ADI associations (FADS2 rs174602, rs174626, rs2072114, rs2845573, and rs2851682) withstood multiple testing. One FADS2 SNP was associated with altered [DHA/EPA] desaturase index in Caucasian females only (rs174576, p < 0.0001). HC use had a significant effect on DHA concentrations in Caucasian females only (P < 0.0001).ConclusionsWe demonstrate ethnic- and sex-specific effects of FADS polymorphisms on desaturase indices, and ethnic-specific effect of HC use on plasma DHA concentrations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-015-0010-9) contains supplementary material, which is available to authorized users.

Docosahexaenoic acid supplementation in lactating women increases breast milk and plasma docosahexaenoic acid concentrations and alters infant omega 6:3 fatty acid ratio

This study investigated the effects of docosahexaenoic acid (DHA) supplementation on the fatty acid composition of breast milk and plasma concentrations in lactating women and their infants. Eighty-nine lactating women 4–6 weeks post-partum received placebo, 200mg or 400mg DHA for 6 weeks with usual diets. Breast milk fatty acids and maternal plasma fatty acids were measured at the beginning and end of the study and infant plasma at the end of the study. Breast milk and maternal plasma DHA were significantly greater with 200mg and 400mg DHA compared with placebo (50% and 123% breast milk p<0.05; 71% and 101% plasma, p<0.0001), respectively. Infant plasma omega 6:3 and arachidonic acid (AA):DHA were significantly greater in the placebo group compared to both supplement groups (67% and 106%; 71% and 116%, respectively, p<0.05). DHA supplementation impacts infant fatty acids important for brain development and breast milk fatty acid composition.

Associations of dietary intake and plasma concentrations of eicosapentaenoic and docosahexaenoic acid with prenatal depressive symptoms in Japan.

The association between depression and omega-3 polyunsaturated fatty acids, including eicosapentaenoic and docosahexaenoic acid, continues to gain focus. In this study, we examined whether dietary intakes and plasma concentrations of eicosapentaenoic and docosahexaenoic acid were associated with depressive symptoms during pregnancy. Healthy Japanese women with singleton pregnancies were recruited at a university hospital in Tokyo between 2010 and 2012. The depressive-symptom group included participants with Edinburgh Postnatal Depression Scale scores greater than eight. Of the 329 participants, 19 (5.8%) had depressive symptoms. Lower plasma docosahexaenoic acid concentration was significantly associated with prenatal depressive symptoms. Women with depressive symptoms had a higher rate of pregnancy-associated nausea than those with non-depressive symptoms (52.6% vs 28.7%, respectively). Although we adjusted for the presence of pregnancy-associated nausea, dietary fatty acid intake was not associated with depressive symptoms in the multiple logistic regression analyses. Further large studies would be required to examine any preventive effect of dietary fatty acid intake on depressive symptoms among pregnant women.

A Highly Bioavailable Omega-3 Free Fatty Acid Formulation Improves the Cardiovascular Risk Profile in High-Risk, Statin-Treated Patients With Residual Hypertriglyceridemia (the ESPRIT Trial)

BackgroundA novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia. ObjectiveThis study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non–HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease. MethodsIn this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events. ResultsIn the 627 subjects in the intention to treat sample, non–HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (–3.9% and –6.9%, respectively) compared with OO (–0.9%) (both, P < 0.05), as were TG levels (–14.6% and –20.6%, respectively, vs –5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d. ConclusionsOM3-FFA was well tolerated and lowered non–HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d. ClinicalTrials.gov identifier: NCT01408303.

Fish‐Oil Fat Emulsion Supplementation Reduces the Risk of Retinopathy in Very Low Birth Weight Infants

Preliminary studies suggest that fish-oil lipid emulsion given parenterally to very preterm infants reduces the severity of retinopathy (ROP) and cholestasis. Infants weighing <1250 g at birth were randomly allocated to 2 groups: an experimental group of 60 infants that received an intravenous (IV) soybean, olive oil, and fish oil emulsion, and a control group of 70 infants that was given a parenteral soybean and olive oil emulsion. Plasma and erythrocyte concentrations of docosahexaenoic acid (DHA) were determined using a high-performance liquid chromatography-mass spectrometry analysis. Nine infants in the fish oil group required laser therapy for ROP compared with 22 infants in the standard intralipid group (risk ratio [RR], 0.48; 95% confidence interval [CI], 0.24-0.96). Three infants in the fish oil group developed cholestasis compared with 20 infants in the standard intralipid group (RR, 0.18; 95% CI, 0.055-0.56). The mean plasma DHA concentrations in treated infants were 2.9-fold higher in the fish oil group than in control infants on the 7th and 14th days of life. The mean DHA content in erythrocytes of treated infants was 4.5-fold and 2.7-fold higher compared with controls at 7 and 14 days of age. Premature infants receiving an IV fat emulsion containing fish oil had less ROP requiring laser treatment and less cholestasis than those receiving a standard lipid emulsion. These infants also had higher plasma and erythrocyte DHA levels at 7 and 14 days, suggesting potential long-term neurodevelopmental benefits.

A randomized placebo-controlled study on high-dose oral algal docosahexaenoic acid supplementation in children with cystic fibrosis

Low plasma concentrations of docosahexaenoic acid (DHA) are reported in unsupplemented cystic fibrosis (CF) patients. Forty-one CF patients aged from 6 to 12 years were randomized to receive high-dose DHA (100mg/kg/day in the first month and 1g per day thereafter through a 12-month supplementation) or placebo (germ oil). Primary outcome was percentage change in plasma AA:DHA ratio. Secondary outcomes were changes in the number of pulmonary exacerbations compared to previous year, lung function, BMI, skinfold thicknesses, and body composition assessed by DXA and in serum concentrations of C-reactive protein, cytokines and vitamin (α-tocopherol and retinol). Compared to the control group plasma AA:DHA ratio decreased in the intervention group after 6 months (median percentage changes: −73% in the intervention group vs. −10% in the control group, P=0.001). No differences were detected between groups for secondary outcomes. Despite a decrease of the AA/DHA ratio, DHA supplementation for one year did not induce any significant biochemical and clinical improvement in CF patients.

Abstract 18549: Effects of AMR101, a Pure Eicosapentaenoic Omega-3 Fatty Acid, on the Fatty Acid Profile in Plasma and Red Blood Cells in Statin-Treated Patients With Persistent High Triglycerides (Results from the ANCHOR Study)

AMR101 is an omega-3 fatty acid (FA) investigational new drug containing ≥96% pure icosapent ethyl, the ethyl ester of eicosapentaenoic acid (EPA). This subanalysis of the ANCHOR study evaluated the effects of AMR101 on the FA profiles and relationships between AMR101 and triglyceride (TG) lowering in plasma and RBCs. ANCHOR was a phase 3, double-blind, 12-week clinical study in high-risk statin-treated patients with residually high TG levels (≥200 and &lt;500 mg/dL) despite LDL cholesterol control (≥40 and &lt;100 mg/dL). Patients (N=702) on stable diet were randomized to AMR101 4 g/d, 2 g/d, or placebo. Twenty eight FAs were measured in plasma and RBCs for 153 patients using a gas chromatography/flame ionization detection method. Mean baseline plasma EPA levels were 20, 27, and 24 μg/g for AMR101 4 g/d, 2 g/d, and placebo, respectively; Mean placebo-adjusted EPA levels increased by 650% (P&lt;0.0001) and 268% (P&lt;0.0001) with AMR101 4 g/d and 2 g/d by week 12. Mean baseline plasma EPA expressed as percentage of total FAs (mol%) was 0.4, 0.5, and 0.5% for AMR101 4 g/d, 2 g/d, and placebo, respectively. Mean plasma EPA (mol%) at Week 12 was 3.6, 1.9, and 0.5% for AMR101 4 g/d, 2 g/d, and placebo, respectively. Levels of the EPA metabolite omega-3 docosapentaenoic acid also increased with both doses of AMR101 (P&lt;0.0001). The arachidonic acid (AA)/EPA plasma ratio has been suggested to be useful as a biomarker for arteriosclerotic disease. Mean placebo-adjusted AA/EPA plasma ratio decreased from baseline by 90% (P&lt;0.0001) and 75% (P&lt;0.0001) with AMR101 4 g/d and 2 g/d. Total omega-3 FAs increased and total omega-6 FAs decreased with both doses of AMR101 (P&lt;0.0001). Similar results were observed in RBCs. Increased doses of AMR101 resulted in increased EPA levels and corresponded with reductions in TG. The TG-lowering effect of AMR101 was due to the increase in EPA, as there were no statistically significant changes in plasma docosahexaenoic acid concentrations. Overall, AMR101 significantly increased EPA in plasma and RBCs in a linear, dose-dependent fashion consistent with its TG-lowering effect and caused other shifts in FA concentration and RBC membrane content that may have clinical benefit.

P2‐436: Dose‐dependent effects of dietary folate, vitamin B‐12 and vitamin B‐6 on plasma lipid profile in rats

Folate, vitamins B-12 and B-6 are essential nutritional components in one-carbon metabolism in different ways and typically increase methylation capacity. This could support methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by PE- N -methyltransferase (PEMT) in the liver. It has been suggested that PC synthesis by PEMT influence circulating levels of polyunsaturated fatty acids, like docosahexaenoic acid (DHA) (Watkins et al., J Nutr 2003; Pynn et al., J Lipid Res 2011). The aim of the present experiment was to investigate whether dietary enrichment with the three B-vitamins could affect plasma lipid composition and particularly plasma DHA levels in rats. After feeding rats one of four diets with increasing levels of folate, vitamins B-12 and B-6 (0%, 100%, 400%, or 1600% of the recommended daily intake) for 4 weeks, plasma fatty acid composition was analyzed using GC and the polar lipid profile was analyzed at the Kansas Lipidomics Research Center using triple quadrupole MS. In addition, plasma homocysteine concentration was measured as an indicator of methylation capacity. The results of the GC analysis indicate that dietary folate, vitamins B-12 and B-6 dose-dependently increased plasma DHA concentration. Plasma DHA and homocysteine showed a significant negative correlation. Data analysis of the polar lipid profile is ongoing. The first results demonstrate the interdependence between folate, vitamins B-12 and B-6 intake and plasma DHA. In this way, intake of supplemental B-vitamins may increase the availability of DHA for processes like neuronal membrane phospholipid synthesis. The increase in plasma DHA may be explained by the effects of B-vitamins on methylation capacity and subsequent enhancement of PC synthesis by the PEMT pathway. Details on this mechanism, implications for Alzheimer's disease, and pending additional results of the MS analysis will be presented.