Plasma Eicosapentaenoic Acid Levels Research Articles

Stearidonic acid improves eicosapentaenoic acid status: studies in humans and cultured hepatocytes

BackgroundAhiflower oil from the seeds of Buglossoides arvensis is rich in α-linolenic acid (ALA) and stearidonic acid (SDA). ALA and SDA are potential precursor fatty acids for the endogenous synthesis of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are n3-long chain polyunsaturated fatty acids (n3-LC-PUFAS), in humans. Since taurine, an amino sulfonic acid, is often associated with tissues rich in n3-LC-PUFAS (e.g., in fatty fish, human retina), taurine may play a role in EPA- and DHA-metabolism.ObjectiveTo examine the capacity of the plant-derived precursor fatty acids (ALA and SDA) and of the potential fatty acid metabolism modulator taurine to increase n3-LC-PUFAS and their respective oxylipins in human plasma and cultivated hepatocytes (HepG2 cells).MethodsIn a monocentric, randomized crossover study 29 healthy male volunteers received three sequential interventions, namely ahiflower oil (9 g/day), taurine (1.5 g/day) and ahiflower oil (9 g/day) + taurine (1.5 g/day) for 20 days. In addition, cultivated HepG2 cells were treated with isolated fatty acids ALA, SDA, EPA, DHA as well as taurine alone or together with SDA.ResultsOral ahiflower oil intake significantly improved plasma EPA levels (0.2 vs. 0.6% of total fatty acid methyl esters (FAMES)) in humans, whereas DHA levels were unaffected by treatments. EPA-levels in SDA-treated HepG2 cells were 65% higher (5.1 vs. 3.0% of total FAMES) than those in ALA-treated cells. Taurine did not affect fatty acid profiles in human plasma in vivo or in HepG2 cells in vitro. SDA-rich ahiflower oil and isolated SDA led to an increase in EPA-derived oxylipins in humans and in HepG2 cells, respectively.ConclusionThe consumption of ahiflower oil improves the circulating levels of EPA and EPA-derived oxylipins in humans. In cultivated hepatocytes, EPA and EPA-derived oxylipins are more effectively increased by SDA than ALA.

Abstract 126: Effect Of Icospaent Ethyl On In Vivo Atheroma Progression And Inflammatory Protease Activity

Background: Icosapent ethyl (IPE), a high purity ethyl ester of eicosapentaenoic acid (EPA), is FDA-approved to reduce cardiovascular events among patients with or at risk for cardiovascular disease with elevated triglyceride levels. However, in vivo mechanisms underlying these findings remain unclear. Here we investigated whether IPE reduces plaque progression and inflammation using intravascular molecular-structural imaging. Methods: Cholesterol-fed balloon-injured rabbits (N=16) bearing aortic atherosclerosis underwent intravascular ultrasound (IVUS) analysis of plaque burden and near-infrared fluorescence-optical coherence tomography (NIRF-OCT) molecular imaging of plaque inflammatory cathepsin protease activity (ProSense VM110 NIRF agent, 4 mg/kg/iv) at 6 weeks. Next, rabbits were randomized to control (N=8) or IPE (Vascepa, Amarin, NJ) treated group (N=8, 1 g/kg/day) milled in the diet. Four weeks later, imaging was repeated, animals were sacrificed, and histopathology analysis of dissected plaque was employed. Results: Quantitative IVUS analyses (40mm segment, 3200 slices/16 rabbits) revealed that IPE significantly suppressed atheroma progression (ΔPAV, 5.2% [2.36-12.98] vs. 9.1% [4.26-12.25] control, p=0.03). Inflammatory plaque cathepsin activity detected by NIRF-OCT was similar (ΔNIRF average plaque 17.6 [6.2- 51.5] vs. 30.5 [4.9- 55.5] nM control, p=0.19)). On fluorescence microscopy, however, plaques from IPE-treated animals exhibited reduced NIRF signal (1.16% [0.03-3.94] vs. 3.13% [0.04-12.92], p=0.005)) and fewer RAM11+ macrophages (23.5±15.6 vs. control 32.9±12.6 macrophages/section, 25 sections/group, p=0.04). In IPE-treated animals, plasma EPA levels were elevated (p<0.05), and EPA metabolite levels, particularly 5,6-diHETE, were also elevated in resected plaques (p<0.05). Conclusion: IPE reduces in vivo plaque progression and plaque cathepsin protease activity and plaque macrophages, providing novel experimental evidence supporting the anti-atherosclerosis effects of IPE.

Abstract 12309: Effects of Sex and Age on Plasma Fatty Acids as Measured by Gas Chromatography/Mass Spectrometry in a Very Large Population Analysis

Background: Studies have documented the beneficial effects of omega-3 fatty acids, specifically, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as found in oily fish and/or fish oil capsules, on cardiovascular disease (CVD) risk reduction. JELIS using purified EPA 1800 mg/day and REDUCE-IT using EPA 4 g/day reported significant reductions in CVD endpoints in statin-treated subjects versus controls. Median plasma EPA levels increased from 97 to 166 μg/mL in the treatment group in JELIS and from 26 to 169 μg/mL in REDUCE-IT. Reductions in CVD endpoints were related to EPA levels. No benefit on CVD risk was observed in STRENGTH, when subjects were given 4 g/day of a carboxylic acid formulation containing both EPA and DHA. Objective: We aimed to ascertain interrelationships of sex and age with plasma fatty acids, especially omega-3 fatty acids, in a very large clinical population. Methods: Plasma fatty acids were measured by gas chromatography/mass spectrometry after lipid extraction in 1,169,621 fasting United States subjects (56.2% female; median age 58.2 yr). Results: Plasma fatty acid indices (median±IQR), expressed as percentage of total fatty acids, were 31.5±1.5% for saturated fatty acids (sum of 14:0, 16:0, and 18:0); 21.4±2.2%, monounsaturated fatty acids (sum of 16:1n7- cis and 18:1n9- cis ); 0.45±0.23%, trans fatty acids (sum of 16:1n7- trans and 18:1n9- trans ); 42.4±3.0%, omega-6 fatty acids (sum of 18:2n6, 20:3n6, and 20:4n6); and 2.55±0.80%, omega-3 fatty acids (sum of 20:5n3 and 22:6n3). EPA plasma levels were 22.0±9.6 μg/mL (median±IQR), significantly lower than levels ≥150 μg/mL required for significant CVD risk reduction in randomized trials. Females had significantly ( P <0.0001) lower indices of monounsaturated (-4.31%) and trans fatty acids (-9.30%) and significantly higher indices of omega-6 (+2.79%) and omega-3 fatty acids (+6.82%) than males. Older subjects (≥65 years of age) had a significantly ( P <0.001) higher median omega-3 fatty acid index (+29.68%) and higher plasma EPA levels (+57.05%) than younger subjects (<30 years of age). Conclusion: In one of the largest US population studies looking at fatty acids, we found sex and age specific differences. Plasma EPA levels were very low in all groups.

APOE Genotype Modifies the Plasma Oxylipin Response to Omega-3 Polyunsaturated Fatty Acid Supplementation in Healthy Individuals

The omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mediate inflammation in large part by affecting pro-inflammatory and anti-inflammatory/pro-resolving oxylipin concentrations. Common gene variants are thought to underlie the large inter-individual variation in oxylipin levels in response to n-3 PUFA supplementation, which in turn is likely to contribute to the overall heterogeneity in response to n-3 PUFA intervention. Given its known role in inflammation and as a modulator of the physiological response to EPA and DHA, here we explore, for the first time, the differential response of plasma hydroxy-, epoxy- and dihydroxy-arachidonic acid, EPA and DHA oxylipins according to apolipoprotein E (APOE) genotype using samples from a dose-response parallel design RCT. Healthy participants were given doses of EPA+DHA equivalent to intakes of 1, 2, and 4 portions of oily fish per week for 12 months. There was no difference in the plasma levels of EPA, DHA or ARA between the wildtype APOE3/E3 and APOE4 carrier groups after 3 or 12 months of n-3 PUFA supplementation. At 12 months, hydroxy EPAs (HEPEs) and hydroxy-DHAs (HDHAs) were higher in APOE4 carriers, with the difference most evident at the highest EPA+DHA intake. A significant APOE*n-3 PUFA dose effect was observed for the CYP-ω hydroxylase products 19-HEPE (p = 0.027) and 20-HEPE (p = 0.011). 8-HEPE, which, along with several other plasma oxylipins, is an activator of peroxisome proliferator activated receptors (PPARs), showed the highest fold change in APOE4 carriers (14-fold) compared to APOE3/E3 (4-fold) (p = 0.014). Low basal plasma EPA levels (EPA < 0.85% of total fatty acids) were associated with a greater change in 5-HEPE, 9-HEPE, 11-HEPE, and 20-HEPE compared to high basal EPA levels (EPA > 1.22% of total fatty acids). In conclusion, APOE genotype modulated the plasma oxylipin response to increased EPA+DHA intake, with APOE4 carriers presenting with the greatest increases following high dose n-3 PUFA supplementation for 12 months.

Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk

In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes. To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo. A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020). Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil. The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization. Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 μg/mL (interquartile range [IQR], 46-131 μg/mL) for EPA and 91 μg/mL (IQR, 71-114 μg/mL) for DHA with top tertile levels of 151 μg/mL (IQR, 132-181 μg/mL) and 118 μg/mL (IQR, 102-143 μg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results. Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk. ClinicalTrials.gov Identifier: NCT02104817.

High Plasma Docosahexaenoic Acid Associated to Better Prognoses of Patients with Acute Decompensated Heart Failure with Preserved Ejection Fraction.

The clinical relevance of polyunsaturated fatty acids (PUFAs) in heart failure remains unclear. The aim of this study was to investigate the association between PUFA levels and the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). This retrospective study included 140 hospitalized patients with acute decompensated HFpEF (median age 84.0 years, 42.9% men). The patients’ nutritional status was assessed, using the geriatric nutritional risk index (GNRI), and their plasma levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) were measured before discharge. The primary outcome was all-cause mortality. During a median follow-up of 23.3 months, the primary outcome occurred in 37 patients (26.4%). A Kaplan–Meier analysis showed that lower DHA and DGLA levels, but not EPA or AA levels, were significantly associated with an increase in all-cause death (log-rank; p < 0.001 and p = 0.040, respectively). A multivariate Cox regression analysis also revealed that DHA levels were significantly associated with the incidence of all-cause death (HR: 0.16, 95% CI: 0.06–0.44, p = 0.001), independent of the GNRI. Our results suggest that low plasma DHA levels may be a useful predictor of all-cause mortality and potential therapeutic target in patients with acute decompensated HFpEF.

Modifiable Lifestyle Factors Associated With Response to Treatment in Early Rheumatoid Arthritis.

ObjectiveWe aimed to evaluate the associations between response to algorithm‐directed treat‐to‐target conventional synthetic disease‐modifying antirheumatic drug therapy and potentially modifiable lifestyle factors, including dietary fish oil supplementation, body mass index (BMI), and smoking history in a rheumatoid arthritis (RA) inception cohort.MethodsPatients with RA with a duration of less than 12 months were reviewed every 3 to 6 weeks to adjust therapy according to disease response. All patients received advice to take fish oil supplements, and omega‐3 status was measured as plasma levels of eicosapentaenoic acid (EPA). Lifestyle factors and other variables potentially prognostic for 28‐joint Disease Activity Score (DAS28) remission and DAS28 low disease activity (LDA) at the 12‐month visit were included in multivariable logistic regression models.ResultsOf 300 participants, 57.7% reached DAS28 LDA, and 43.7% were in DAS28 remission at 1 year. Increase in plasma EPA was associated with an increase in the odds of being in LDA (adjusted odds ratio [OR] = 1.27; P < 0.0001) and remission (adjusted OR = 1.21; P < 0.001). There was some evidence that the effect of BMI on LDA might be modified by smoking history. An increase in BMI was associated with a decrease in the odds of being in LDA in current and former smokers but had no impact on LDA in patients who had never smoked. There were no meaningful associations between BMI or smoking history and remission.ConclusionOmega‐3 status, BMI, and smoking history are potential predictors of outcome in early RA. The possibility of an effect modification by smoking on the predictive value of BMI merits further investigation.

Translating plasma eicosapentaenoic acid concentrations into erythrocyte percentages of eicosapentaenoic acid plus docosahexaenoic acid during treatment with icosapent ethyl

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) study demonstrated that 4g/d of eicosapentaenoic acid (EPA) ethyl esters (icosapent ethyl [IPE]) reduced risk for major cardiovascular events by 25% in statin-treated patients with residual hypertriglyceridemia. How this treatment affected red blood cell (RBC) EPA and docosahexaenoic acid (DHA) levels (ie, the Omega-3 Index [O3I]) was not reported, but effects on plasma EPA concentrations were reported. The aim of the study was to estimate baseline and final O3I levels in REDUCE-IT. First, deidentified data from our laboratory on RBC and plasma EPA and DHA from 2311 patients with similar lipid profiles as those in REDUCE-IT were used to generate a regression equation, which was then used to estimate the O3I from plasma FA concentrations. Second, previously published data on the effects of IPE on RBC FA concentrations were also converted to the O3I. Both approaches (from calculations and prior publications) suggested that baseline and follow-up O3I levels were about 5% and 7%, respectively. In addition, plasma EPA levels (but not the O3I) were noted to be influenced by triglyceride levels. For patients using 4 g of IPE, an estimated O3I value of about 7% reflects a cardioprotective state. Plasma EPA concentrations may be ill-suited as treatment targets because they are confounded by triglyceride levels.

Correlation of Various Foods Intakes and Plasma Levels of Omega Fatty Acids in Healthy Japanese Old Men

Background: Trans fatty acids are considered to impair health and some ω fatty acids are protective against atherosclerosis and diabetes mellitus. Trans fatty acids are said to be formed by the partial hydrogenation of vegetable oils. Some amounts are produced in digestive organs of ruminants and present in dairy products or meat. It is important how much these intaken fatty acids influence their plasma levels. Methods: Plasma levels of fatty acids including transforms of healthy old men are measured by gas chromatography and correlations between various foods intakes and plasma levels of trans fatty acids, and ω fatty acids are examined. Results: Intake of fish resulted in increase in plasma levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) but intake of meat such as beef, cow and chicken meat did not increase plasma levels of arachidonic acid (AA). Intakes of oils increased plasma levels of dihomo-g-linolenic acid significantly and AA to some extent. Conclusion: Plasma levels of EPA and DHA increased upon intakes of fish in Japanese old men. Oil intake but not meat intake increased DGLA significantly. These results may explain low incidence of cardiovascular diseases in Japanese people compared with American people whose plasma levels of DHA and EPA are lower.

Plasma polyunsaturated fatty acid profile is associated with vascular endothelial function in patients with type 2 diabetes.

Decreased plasma n-3 polyunsaturated fatty acid levels or the n-3/n-6 polyunsaturated fatty acid ratios are associated with a risk of cardiovascular events. In this cross-sectional study, we measured plasma levels of eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and investigated the association between the plasma polyunsaturated fatty acid profile and vascular endothelial function in 396 patients with type 2 diabetes. Endothelium-dependent, flow-mediated dilatation of the brachial artery was measured using ultrasonography. Multiple regression analyses, including age, sex, body mass index, and other cardiovascular risk factors, revealed that plasma eicosapentaenoic acid levels ( β = 0.140, p = 0.008) and the eicosapentaenoic acid/arachidonic acid ratio ( β = 0.127, p = 0.019), but not plasma docosahexaenoic acid levels ( β = 0.067, p = 0.220) or the docosahexaenoic acid/arachidonic acid ratio ( β = 0.034, p = 0.559), were independently and positively associated with flow-mediated dilatation. In conclusion, plasma eicosapentaenoic acid levels and the eicosapentaenoic acid/arachidonic acid ratio are independently associated with endothelial function in patients with type 2 diabetes. This study indicates a positive association between eicosapentaenoic acid, rather than docosahexaenoic acid, and endothelial function in type 2 diabetes.

Importance of pancreatic exocrine dysfunction in patients with type 2 diabetes: A randomized crossover study

BackgroundLevels of faecal elastase-1 (FE-1), a marker of exocrine pancreatic function, are lower in patients with type 2 diabetes than without diabetes. We aimed to investigate the association between FE-1 and nutritional status, gastrointestinal symptoms, and lipid absorption. MethodsThis randomized, open-label, crossover study included 315 patients with type 2 diabetes aged 18–70 years treated with oral antidiabetics, with HbA1c 6.5–9.0% and BMI 18–40 kg/m2. Assessments included levels of FE-1 and blood biomarkers of nutrition, and Bristol Stool Scale and Gastrointestinal Symptom Rating Scale (GSRS) scores. Plasma exposure of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) after oral administration of free omega-3 carboxylic acids or ethyl esters with breakfast was investigated in patients with low, intermediate, and normal FE-1 levels. ResultsThe prevalence of low and intermediate FE-1 levels was 5.2% and 4.9%, respectively. Bristol Stool Scale scores and mean values of GSRS Diarrhoea and Indigestion domain symptoms were similar across groups, but patients with low FE-1 were heavier and reported lower stool frequency. FE-1 levels correlated positively with plasma levels of amylase, lipase, 25-hydroxy vitamin D, and albumin. Mean EPA + DHA exposure was similarly higher after intake of free vs. esterified omega-3 fatty acids in all FE-1 groups. ConclusionsThe prevalence of low FE-1 (<100 μg/g) as a measure of pancreatic exocrine insufficiency was infrequent in type 2 diabetes. Except for low plasma concentrations of EPA and 25-hydroxy vitamin D, type 2 diabetes patients with low FE-1 had no other signs of malabsorption or gastrointestinal disorders. Plasma levels of EPA and DHA after the intake of esterified versus free EPA and DHA did not correlate with FE-1 levels. Trial registrationClinicalTrials.gov NCT02370537.

The Large Effect Size of Urinary Total Antioxidant Capacity in Behavioral Symptoms of Young Autistic Individuals: Comparion with Omega-3 Fatty Acid and Superoxide Dismutase in Plasma

Objective: The imbalance between increased oxidative stress and reduced antioxidant defense has been implicated in the pathophysiology of autism spectrum disorders (ASD). Which of these has a greater impact on ASD behavioral symptoms is still unclear. We measured urinary levels of the oxidative stress biomarker hexanoyl-lysine (HEL), the total antioxidant capacity (TAC) and the DNA methylation biomarker 8-hydroxy-2′-deoxyguanosine (8- OHdG) and their relation to the plasma levels of the oxidative stress biomarker superoxide dismutase (SOD) and of the anti-inflammatory fatty acid eicosapentaenoic acid (EPA). Methods: We studied the relationships between these biomarkers and behavioral symptoms in 19 individuals with ASD (mean age 10.9 ± 5.3 years) and 11 healthy controls (mean age 14.3 ± 6.3 years). Behavioral symptoms were evaluated using the Aberrant Behavior Checklist (ABC). Results: Ages were not significant difference between two groups. The ASD group showed significantly reduced levels of urinary TAC and significantly increased levels of urinary HEL compared to the control group. Urinary 8- OHdG levels or plasma SOD and EPA levels were not significantly different between the two groups. The ABC subscale and total scores were significantly higher in the ASD group had significantly higher ABC subscale and total scores than he control group. Stepwise regression analysis and the standardized regression coefficient indicated that urinary TAC levels provided greater impact for distinguishing the two groups. There was significant correlation between the urinary TAC levels and plasma EPA levels and the ABC irritability scores. Conclusion: Urinary TAP levels may be important in the imbalance between the urinary levels of HEL and TAC, and altered plasma SOD levels may contribute to this imbalance.

Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiation in Vitro.

To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF-driven Th17 cell differentiation. Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25- T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry. Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (-0.51, p = 0.007 and -0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequencies in vitro. Physiological concentrations of EPA, but not LA, prevented this. EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

Plasma levels of marine n-3 fatty acids and cardiovascular risk markers in renal transplant recipients

Cardiovascular (CV) disease is the leading cause of death after renal transplantation. Marine n-3 polyunsaturated fatty acids (PUFAs) exert potential cardio-protective metabolic effects and might reduce CV morbidity and mortality in renal transplant recipients (RTRs). In this cross-sectional study of 1990 Norwegian RTRs, transplanted between 1999 and 2011, associations between plasma phospholipid marine n-3 PUFA levels and various CV risk markers at 10 weeks after transplant were evaluated. Higher plasma marine n-3 PUFA levels were associated with lower resting heart rate (rHR), lower fasting plasma glucose (fPG) levels, lower plasma triglyceride levels and higher plasma high-density lipoprotein (HDL) cholesterol levels. Plasma levels of eicosapentaenoic acid, but not docosahexaenoic acid, showed a positive association with plasma HDL cholesterol levels. Plasma marine n-3 PUFA levels were not associated with plasma low-density lipoprotein cholesterol levels, pulse wave velocity or systolic and diastolic blood pressure. A negative association between plasma marine n-3 PUFA levels and CV mortality was weakened by additional adjustment for plasma triglyceride levels and rHR. The ratio of n-6 to n-3 PUFAs showed similar associations with CV risk markers as absolute plasma marine n-3 PUFA levels. This is the first study in RTRs showing that marine n-3 PUFAs are negatively associated with rHR and fPG in addition to beneficial effects on plasma HDL cholesterol and triglyceride levels. Especially, effects on autonomic nervous function and triglyceride metabolism might contribute to explain the lower CV mortality risk with higher plasma marine n-3 PUFA levels previously shown in this cohort.

Plasma linoleic acid partially mediates the association of bipolar disorder on self-reported mental health scales

We have shown that bipolar individuals have reduced quality diets, including lower intake of polyunsaturated fatty acids (PUFA). We have also reported reduced plasma levels of the n-6 PUFA, linoleic acid (LA), and the n-3 PUFA, eicosapentaenoic acid (EPA) in bipolar subjects. In the current analysis we hypothesized that LA and EPA plasma levels would mediate lower self-reported mental health and life functioning scores in bipolar subjects. In a cross-sectional study, we collected a 7-day diet record in bipolar (n = 56) and control subjects (n = 46) followed by a fasted blood draw. We used structured equation modeling path analysis to test for mediating effects of dietary intake and plasma levels of LA and EPA on self-reported mental health questionnaire scores, including the Life Functioning Questionnaire (LFQ), the Patient Health Questionnaire (PHQ9), and the Short Form Health Survey (SF12), extracting the mental health component summary score (SF12-MH). We adjusted for age, gender, psychiatric medication use, body mass index (BMI), and total caloric intake as covariates with bipolar disorder as the primary predictor. We found a significant path association from bipolar disorder to lower plasma LA levels (p = 0.03) and significant paths from plasma LA to PHQ9 (p = 0.05), LFQ (p = 0.01) and SF12-MH (p = 0.05) scores, such that lower plasma LA predicted worse outcomes. We found no significant paths from plasma EPA levels to any of the outcome measures. These findings suggest that plasma LA levels partially mediate the effect of bipolar disorder on self-reported measures of mental health and life functioning.

Mental health: New horizons in nutrition research and dietetic practice

Mental health: New horizons in nutrition research and dietetic practice

Protective effect of eicosapentaenoic acid on insulin resistance in hyperlipidemic patients and on the postoperative course of cardiac surgery patients: the possible involvement of adiponectin.

Accumulated studies have shown that ω-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have protective roles against inflammatory responses such as hyperlipidemia, diabetes mellitus (DM) and cardiovascular diseases. Here we examined the effects of administering EPA to hyperlipidemic patients and other patients undergoing cardiac surgery to determine whether this treatment would increase plasma EPA levels and to clarify the association between EPA treatment and adiponectin production in hyperlipidemic patients. We also assessed the effect of preoperative EPA administration on postoperative adverse events such as postoperative atrial fibrillation (POAF) and postoperative infection in the cardiac surgery patients. The EPA administration significantly increased the serum EPA concentrations in both patient populations (p＜0.001). In the hyperlipidemic patients, the EPA administration significantly increased plasma adiponectin levels (p＜0.05), accompanied by a decrease in insulin resistance designated by the HOMA-IR (homeostasis model assessment of insulin resistance) score (p＜0.05) and Hs-CRP (high sensitivity C-reactive protein) value (p＜0.05). In the cardiac surgery patients, no significant effect of EPA on cardiac adverse events such as POAF was observed. However, our results clearly demonstrated that both the neutrophil-to-lymphocyte ratio and the 2nd-line antibiotic requirement in the EPA group were significantly decreased compared to the untreated control group (p＜0.05). We suggest that EPA administration may exert anti-inflammatory effects in patients with hyperlipidemia and in those undergoing cardiac surgery, possibly through an increase in plasma adiponectin levels.

Levels of eicosapentaenoic acid in obese schoolchildren with and without insulin resistance.

Obesity in children is now an increasing health risk worldwide in which the insulin-resistance can be present. Studies have linked a diet rich in n-3 fatty acids with a lower prevalence of insulin-resistance. To compare the levels of eicosapentaenoic acid among obese children with and without insulin-resistance. In 56 randomly school-age children with obesity, insulin-resistance was determined by the homeostasis model assessment for insulin-resistance index and the serum levels of eicosapentaenoic acid were determined by gas chromatography. Insulin-resistance was established when the index was >6.0, non- insulin- resistance when that index was within the range of 1.4-5.9. The serum levels of eicosapentaenoic acid were compared with the Kruskal-Wallis and Mann-Whitney U tests, as needed. No differences in age or sex were identified among the groups studied. The anthropometric parameters were significantly higher in the group of children with insulin-resistance than in the other two groups. The children with insulin- resistance had significantly lower levels of eicosapentaenoic acid than the non- insulin-resistance group [12.4% area under the curve vs. 37.4%, p = 0.031], respectively. Obese primary school-aged children with insulin-resistance had lower plasma levels of eicosapentaenoic acid.

Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder

Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n = 48) and healthy volunteers (HV, n = 35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n = 39; HV, n = 33) completed the Barratt Impulsiveness Scale. Plasma PUFAs eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6) were quantified and ln-transformed to mitigate distributional skew. Ln-transformed PUFA (lnPUFA) levels were predictors in regression models, with aggression or impulsivity scores as outcomes, and cofactors of sex and diagnostic status (MDD with or without a history of substance use disorder [SUD], or HV). Interactions were tested between relevant PUFAs and diagnostic status. Additional analyses explored possible confounds of depression severity, self-reported childhood abuse history, and, in MDD patients, suicide attempt history. Among PUFA, lnEPA but not lnDHA predicted aggression (F1,76 = 12.493, p = 0.001), and impulsivity (F1,65 = 5.598, p = 0.021), with interactions between lnEPA and history of SUD for both aggression (F1,76 = 7.941, p = 0.001) and impulsivity (F1,65 = 3.485, p = 0.037). Results remained significant when adjusted for childhood abuse, depression severity, or history of suicide attempt. In conclusion, low EPA levels were associated with aggression and impulsivity only in patients with MDD and comorbid SUD, even though in most cases SUD was in full sustained remission.

Transfer of omega‐3 fatty acids across the blood–brain barrier after dietary supplementation with a docosahexaenoic acid‐rich omega‐3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study

Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF). A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation. At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers. Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.