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Background: Tissue levels of n-3 polyunsaturated fatty acids (PUFAs) have been inversely related with risk of myocardial infarction (MI). Whether ratios of n-3 to n-6 PUFAs, reflecting both dietary intake of n-3 PUFAs and competing n-6 PUFAs, are better predictors of future MI than n-3 PUFA fractions is unclear. We aimed at investigating whether such ratios in adipose tissue better predict MI than n-3 PUFA fractions.Methods: Subcutaneous adipose tissue biopsies were obtained in a random sample (n=3,500) of the Diet, Cancer and Health cohort (n=57,053). Adipose tissue content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), arachidonic acid (AA) and linoleic acid (LA) was determined using gas chromatography. Fractions of selected n-3 PUFAs and n-3/n-6 PUFA ratios were correlated to the 15-year occurrence of MI in a case-cohort design.Results: A total of 2,406 participants experienced an MI during follow-up. Adipose tissue total marine n-3 PUFAs, EPA+DHA, EPA, EPA/AA, DHA/AA and (EPA+DPA+DHA)/AA were all inversely associated with risk of incident MI. Evaluating the predictive power (Harrel's C-index) of the selected metrics, fractions of marine n-3 PUFAs and ratios of EPA/AA, DHA/AA, (EPA+DHA)/AA and (EPA+DPA+DHA)/AA all refined risk prediction over age and sex alone. At multivariable analyses, however, the above ratios were the only metrics providing additional risk prediction. Differences in ratios were related to differences in food intake.Conclusions: Both adipose tissue n-3 PUFAs fractions and ratios of n-3 PUFAs/AA were associated with a lower occurrence of MI, but ratios provided superior risk prediction. Dietary strategies affecting n-3/n-6 PUFA ratios should be further investigated for prediction of MI with dietary interventions at the population level and in intervention studies. Background: Tissue levels of n-3 polyunsaturated fatty acids (PUFAs) have been inversely related with risk of myocardial infarction (MI). Whether ratios of n-3 to n-6 PUFAs, reflecting both dietary intake of n-3 PUFAs and competing n-6 PUFAs, are better predictors of future MI than n-3 PUFA fractions is unclear. We aimed at investigating whether such ratios in adipose tissue better predict MI than n-3 PUFA fractions. Methods: Subcutaneous adipose tissue biopsies were obtained in a random sample (n = 3,500) of the Diet, Cancer and Health cohort (n = 57,053). Adipose tissue content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), arachidonic acid (AA) and linoleic acid was determined using gas chromatography. Fractions of selected n-3 PUFAs and n-3/n-6 PUFA ratios were correlated to the 15-year occurrence of MI in a case-cohort design. Results: A total of 2,406 participants experienced an MI during follow-up. Adipose tissue total marine n-3 PUFAs, EPA+DHA, EPA, EPA/AA, DHA/AA and (EPA + DPA + DHA)/AA were all inversely associated with risk of incident MI. Evaluating the predictive power (Harrel's C-index) of the selected metrics, fractions of marine n-3 PUFAs and ratios of EPA/AA, DHA/AA, (EPA + DHA)/AA and (EPA + DPA + DHA)/AA all refined risk prediction over age and sex alone. At multivariable analyses, however, the above ratios were the only metrics providing additional risk prediction. Differences in ratios were related to differences in food intake. Conclusions: Both adipose tissue n-3 PUFAs fractions and ratios of n-3 PUFAs/AA were associated with a lower occurrence of MI, but ratios provided superior risk prediction. Dietary strategies affecting n-3/n-6 PUFA ratios should be further investigated for prediction of MI with dietary interventions at the population level and in intervention studies.

Higher omega-3 fatty acid blood levels, as assessed by the Omega-3 Index (O3I, erythrocyte eicosapentaenoic [EPA] + docosahexaenoic [DHA] percentage), have been linked with lower risk for cardiovascular disease and total mortality. Because seafood is an excellent source of EPA and DHA, we reasoned that people living on the coast with direct access to fresh seafood might have higher O3I levels than people living inland. Using O3I data originally collected for other purposes and an observational design, we compared the mean O3I from people in Newport, RI, with that of people living from 5 inland US cities (Indianapolis, IN; Charleston, WV; Lexington, KY; Oklahoma City, OK; and Memphis, TN). The Newport samples were collected at free, industry-sponsored health fairs, whereas the inland city samples were collected at free public health screenings sponsored by the Seafood Nutrition Partnership in 2014 through 2015. The mean (standard deviation) O3I in the Newport sample (n = 226) was 5.13% (1.34%) and the mean of the 5 cities (n = 1109) was 4.48% (1.08%) (P.001). An O3I of ≥8% (considered optimal) was found in 3% of the Newport sample and in 1% of the pooled inland cities (P.05). An O3I of ≤4% (considered low) was found in 22% of the Newport sample and in 41% of the pooled inland cities (P.001). These data support our hypothesis, but because only 3% of those in the Newport sample had an O3I8%, even greater seafood intake (or the use of fortified foods or dietary supplements) is needed to attain optimal omega-3 status.

The effects of fish oil products containing docosahexaenoic acid (DHA) on LDL-C levels are controversial.To determine if changes in erythrocyte DHA are associated with changes in LDL-C levels.In this prospective observational study, erythrocyte DHA levels and LDL-C levels were measured in 9253 individuals who presented for at least two examinations at a medical clinic. Changes in DHA levels and the reported use of omega-3 dietary supplements were correlated with changes in LDL-C in multi-variable adjusted models including the use of LDL-C-lowering drugs.Mean (standard deviation) age at baseline was 52.6 (10.6) years, and the time between exams averaged 1.9 (1.4) years. As a group, erythrocyte DHA increased from 5.0% (1.3) to 5.3% (1.3) (p 0.001), and LDL-C was not significantly changed (109 (33) to 108 (33) mg/dL, p = 0.875). However, in multivariable-adjusted models of within-participant changes, a 1% increase in erythrocyte DHA was associated with a 1.9 mg/dL reduction in LDL-C (95% confidence interval (1.6, 2.2), p 0.001). Similar relationships were seen with changes in erythrocyte EPA and EPA + DHA. In adjusted analyses, an increased use of omega-3 supplements was associated with a significant increase in erythrocyte DHA and a decrease in LDL-C in both users and non-users of lipid-lowering drugs.In a predominantly male, normolipidemic, middle-aged cohort, increases in erythrocyte DHA were associated with decreases in LDL-C, and initiating fish oil supplement use did not increase LDL-C. These findings may serve to reassure individuals who, in adopting a more heart-healthy lifestyle, want to increase their omega-3 fatty acid intake.

Insulin resistance early after acute myocardial infarction is associated with increased heart failure and mortality. OMEGA-REMODEL was a prospective double-blind 1:1 randomized control trial of patients with AMI. We reported that 6-month treatment with omega-3 fatty acid (O-3FA) 4 g/day attenuated cardiac remodeling accompanied by reduction in inflammation. We hypothesized that insulin resistance modifies the therapeutic effect of O-3FA on post-MI cardiac remodeling. The OMEGA-REMODEL study group was dichotomized according to cohort- and gender-specific median cutoff value of leptin-to-adiponectin ratio (LAR) at baseline (LAR-Hi vs LAR-Lo). Mixed model regression analyses were used to evaluate effect modification of O-3FA on reduction of left ventricular end-systolic volume index (LVESVI) by LAR status. Baseline LAR was evaluated on 325 patients (59 ± 11 years, 81% male). A total of 168 patients were categorized in LAR-Lo, and 157 in LAR-Hi. O-3FA treatment resulted in significant LVESVI reduction in patients with LAR-Lo but not with LAR-Hi (p = 0.0002 vs 0.66, respectively). Mixed model regression analysis showed significant modification of LAR on O-3FA's treatment effect in attenuating LVESVI (p = 0.021). In conclusion, this post-hoc efficacy analysis suggests that LAR status significantly modified O-3FA's treatment effect in attenuating cardiac remodeling. During the convalescent phase of acute infarct healing, patients with lower insulin resistance estimated by LAR appear to derive more therapeutic response from O-3FA toward improvement of LVESVI.

High red blood distribution width (RDW) is associated with decreased red blood cell deformability, and high neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and innate-adaptive immune system imbalance. Both RDW and NLR are predictors of chronic disease risk and mortality. Omega-3 index (O3I) values have previously been shown to be inversely associated with RDW and NLR levels. Our objective was to determine if total plasma long chain omega-3 fatty acids (Omega3%) measured in the UK Biobank cohort were associated with RDW and NLR values. RDW- and NLR-relationships with Omega3% were characterized in 109,191 adults (58.4% female). RDW- and NLR-Omega3% relationships were inversely associated with Omega3% (both p

Recently, 3 large randomized controlled trials (RCTs) have assessed the effects of supplementation with marine omega-3 fatty acids on the occurrence of cardiovascular disease (CVD) events. We reviewed this evidence and considered it in the context of the large and growing body of data on the CV health effects of marine omega-3s. One RCT examining 8179 patients, most with coronary heart disease (CHD), reported that 4 grams/day of a highly purified omega-3 product containing eicosapentaenoic acid (EPA) reduced the risk for major adverse CV events by 25% (P

Studies have linked an Omega-3 Index (O3I), which measures eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in red blood cell membranes, of ≥8% with improved health. Previous studies found that the American Heart Association (AHA) recommendation of 1-2 seafood meals per week does not achieve an O3I ≥8% even with an EPA + DHA supplement; however, these studies did not assess the frequency or amount of supplemental intake. Among participants in a predominantly US and Canadian cohort with high nutrient supplement use, we hypothesized that those adhering to the AHA guidelines would not have an average O3I ≥8% but that those taking a daily supplement would. Fish consumption and EPA + DHA supplement use were reported by 1795 participants; 985 also completed a blood spot test for O3I. A majority (71%) consumed2 servings per week of fatty fish, and 61% took an EPA + DHA supplement. The amount of EPA + DHA for 1 serving (based on the product label) significantly differed among the400 supplement products (50-3570 mg). O3I was ≥8.0% in 19% of participants. Among non-supplement takers, 3% of those consuming 1 fish serving per week and 17% consuming ≥2 achieved an O3I ≥8.0%. Among those consuming ≥2 fish servings per week, only those also taking an average of 1100 mg/d of supplemental EPA + DHA had a median O3I ≥8.0%. Based on the relationship between supplemental EPA + DHA intake and O3I for non-fish eaters (R

Ischemic heart disease (IHD) is a leading cause of mortality in the United States. There is substantial evidence that a sustained intake of industrially-produced trans fatty acids (IP-TFA) is associated with increased risk of fatal IHD. This has led many regulatory agencies to pressure dietary oil producers to remove IP-TFA from their products. That this has resulted in lower blood levels of IP-TFA in the United States is clear, but whether this has been accompanied by a reduction in the incidence of fatal IHD is unknown. To test the hypothesis that declining IP-TFA levels are associated with declining rates of fatal IHD, we compared the IP-TFA levels in red blood cells (RBC) analyzed in our laboratory between 2009 and 2016 (n = 53 194) with yearly US-specific IHD mortality rates. We found that decreasing RBC IP-TFA levels were strongly correlated with decreasing rates of fatal IHD (R2 = 0.9552, P

The REDUCE-IT study found that patients at elevated risk for cardiovascular disease (CVD) who were already taking statins obtained a marked benefit by taking 4 g/d of eicosapentaenoic acid ethyl esters (icosapent ethyl, IPE; Vascepa) over about 5 years. Although approved for triglyceride (TG) lowering, IPE had only a modest TG-lowering effect in REDUCE-IT, largely because median TG levels were relatively low already. Hence the question of what mechanisms IPE might be working through is of great interest. At present, it appears that the best mechanistic candidates would be anti-platelet effects and/or anti-inflammatory effects. Whatever the cause, the powerful effects of IPE on CVD risk have renewed interest in the clinical utility of omega-3 fatty acids.

An Omega-3 Index (O3I; EPA+DHA as a % of erythrocyte total fatty acids) in the desirable range (8%-12%) has been associated with improved heart and brain health.To determine the combination of fish intake and supplement use that is associated with an O3I of8%.Two cross-sectional studies comparing the O3I to EPA+DHA/fish intake.The first study included 28 individuals and assessed their fish and EPA+DHA intake using both a validated triple-pass 24-hr recall dietary survey and a single fish-intake question. The second study used de-identified data from 3,458 adults (84% from US) who self-tested their O3I and answered questions about their fish intake and supplement use.Study 1, chi-squared, one-way ANOVA, and Pearson correlations were computed. In Study 2, multi-variable regression models were used to predict O3I levels from reported fish/supplement intakes.The mean ± SD O3I was 4.87 ± 1.32%, and 5.99 ± 2.29% in the first and second studies, respectively. Both studies showed that for every increase in fish intake category the O3I increased by 0.50-0.65% (p 0.0001). In the second study, about half of the population was taking omega-3 supplements, 32% reported no fish intake and 17% reported eating fish2 times per week. Taking an EPA+DHA supplement increased the O3I by 2.2% (p 0.0001). The odds of having an O3I of ≥8% were 44% in the highest intake group (≥3 servings/week and supplementation) and 2% in the lowest intake group (no fish intake or supplementation); and in those consuming 2 fish meals per week but not taking supplements (as per recommendations), 10%.Current AHA recommendations are unlikely to produce a desirable O3I. Consuming at least 3 fish servings per week plus taking an EPA+DHA supplement markedly increases the likelihood of achieving this target level.

Recent trials in pregnant women on the effects of supplemental DHA on early preterm birth (ePTB) risk have shown that there is a maternal blood docosahexaenoic acid (DHA) level below which risk for ePTB was increased and supplemental DHA was effective at reducing risk. However, DHA levels were expressed in different terms across these trials making cross study comparisons impossible. The purposes of this study were 1) to report interlaboratory conversion factors from study-specific metrics to a common metric, red blood cell (RBC) DHA measured by OmegaQuant Analytics (OQA), and 2) to translate reported pre- and post-treatment DHA levels from these trials into a RBC DHA for comparison. Data from five published and one unpublished study are included. Across these studies, the effects on RBC DHA levels after supplementation with 0, 200, 600, 800 and 1000 mg of DHA were (as a% change from baseline): 0 mg, no change; 200 mg, 15-20% increase; 600 mg, 55-60% increase; 800 mg, 13-65% increase; and 1000 mg, 51% increase. Standardization of fatty acid analysis and reporting and a target omega-3 or DHA level for identifying those for which higher dose DHA supplementation is indicated to prevent ePTB are needed for clinical use.

Objectives The goal of this study was to test the effects of long-chain omega-3 fatty acid supplementation on omega-3 levels, depressive symptoms, and other psychosocial factors, as well as other chronic heart failure (CHF)-related functional measures. Background Patients with CHF and depression had low blood omega-3 concentrations that were associated with an elevated risk of mortality. Methods This study was a randomized, double-blind, placebo-controlled pilot clinical trial using a 400/200 eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) fish oil at 2 g and an almost pure EPA at 2 g, compared with a matched placebo, daily for 12 weeks for patients with CHF and major depressive disorder. Statistical analyses included the intention-to-treat population and “completers” (defined as participants consuming ≥70% of the capsules and completing the final endpoint evaluation between 10 and 14 weeks). Results A total of 108 patients with CHF and major depressive disorder and a score ≥18 on the Hamilton Depression Scale who were randomized at 1:1:1 to the 3 interventions at 3 enrolling centers from June 12, 2014, to May 19, 2016; 80 (74.1%) qualified as completers. Intention-to-treat analyses revealed that the levels of all omega-3 variables were significantly elevated in the omega-3 groups, whereas the placebo group showed little change; there were no between-group differences with overall depression measurements. Per-protocol exploratory analyses showed that scores on the social functioning measurement of the 36-item Short Form Health Survey improved notably in the 400/200 EPA/DHA (p = 0.040) and EPA (p = 0.10) groups compared with the placebo group. Spearman correlation analysis indicated that increased omega-3 indices were associated with improved cognitive depressive symptoms. Conclusions Omega-3 supplementation resulted in significant increases in omega-3 levels in red blood cell counts, corresponding to a particular compound of omega-3. Changes in cognitive depressive symptoms and social function were in favor of the omega-3 supplementation. Further studies with larger sample sizes are necessary to confirm the benefits of omega-3 supplementation on modifying psychosocial factors for patients with CHF. (Omega-3 Supplementation for Co-Morbid Depression and Heart Failure Treatment [OCEAN]; NCT02057406)

As currently defined, the Omega-3 Index comprises eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), but not docosapentaenoic acid (DPA) in erythrocytes. In fish and many fish oils DPA is detectable (along with EPA and DHA), but sources rich in DPA are scarce. Purified DPA is available, and DPA is a precursor of biologically active molecules, but much remains to be learned about the effects of DPA in humans. In epidemiologic studies, erythrocyte DPA did not predict risk for total mortality, sudden cardiac death, or other relevant cardiovascular events, and, more importantly, did not improve prediction of these events when included along with EPA and DHA, the original Omega-3 Index. We conclude that current scientific evidence does not support including DPA into the Omega-3 Index.

Several studies demonstrate the importance of essential fatty acids (EFAs), and the long chain polyunsaturated FA docosahexaenoic acid (DHA), on cognition and brain development. The objective of this study was to investigate the relationship between whole-blood FAs and executive function in children from Northern Ghana. A total of 307, 2-to-6-year-old children attempted the dimensional change card sort (DCCS) task to assess executive function, and dried blood spot samples were collected and analyzed for FA content. Significant differences in mean % total whole-blood fatty acids were observed between children who could not follow directions on the DCCS test (49.8% of the sample) and those who could (50.2% of the sample). Positive associations with DCCS performance were observed for DHA (β=0.25, P=.06), total n-3 (β=0.17, P=.06) and dihomo-gamma-linolenic acid (DGLA; β=0.60, P=.06). Children with the highest levels of total n-3 and DHA were three and four times, respectively, more likely to pass at least one condition of the DCCS test of executive function than those with the lowest DHA levels. The results of this study indicate an association between n-3 FAs and high-level cognitive processes in children two to six years of age, providing impetus for further studies into possible interventions to improve EFA status of children in developing countries.

The well-known health effects of the long-chain, marine omega-3 (n-3) fatty acids (FAs) has led to a growing interest in the prognostic value that blood levels of these FAs might have vis-à-vis cardiovascular and neurocognitive diseases. The measurement and expression of n-3 FA levels is not straight-forward, however, and a wide variety of means of expression of n-3 FA status have been used in research and clinical medicine. This has led to considerable confusion as to what "optimal" n-3 FA status is. The n-6:n-3 ratio has enjoyed relatively widespread use, but this apparently simple metric has both theoretical and practical difficulties that have contributed to misunderstandings in this field. Just as the once-popular polyunsaturated:saturated FA ratio has largely disappeared from the nutritional and medical literature, it may be time to replace the n-6:n-3 ratio with a newer metric that focuses on the primary deficiency in Western diets - the lack of eicosapentaenoic and docosahexaenoic acids (EPA and DHA). The Omega-3 Index (red blood cell EPA+DHA) has much to recommend it in this regard.

The neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and measures innate-adaptive immune system balance. The omega-3-index (O3I) measures the amount of EPA+DHA in blood. Both a low O3I and an elevated NLR are associated with increased risk for chronic disease and mortality, including cardiovascular diseases and cancer. Hypothesizing that low O3I may partly contribute to systemic chronic inflammation, we asked if a relationship existed between O3I and NLR in healthy adults (≥18 y, n = 28,871, 51% female) without inflammation [C-reactive protein (CRP)3 mg/mL)] who underwent a routine clinical assessment. NLR was inversely associated with O3I before (p 0.0001) and after adjusting for age, sex, BMI, and CRP (p 0.0001). Pearson correlations of other variables with NLR were r = 0.06 (CRP), r = 0.14 (age), and r = 0.01(BMI). In this healthy population, an O3I 6.6% was associated with increasing NLR whereas NLR remained relatively constant (low) when O3I 6.6%, suggestive of a quiescent, balanced immune system.

SummaryLow red blood cell (RBC) membrane content of EPA and DHA, i.e., the omega-3 index (O3I), and elevated RBC distribution width (RDW) are risk factors for all-cause mortality. O3I and RDW are related with membrane fluidity and deformability. Our objective was to determine if there is a relationship between O3I and RDW in healthy adults. Subjects without inflammation or anemia, and with values for O3I, RDW, high-sensitivity C-reactive protein (CRP), body mass index (BMI), age and sex were identified (n=25,485) from a clinical laboratory dataset of >45,000 individuals. RDW was inversely associated with O3I in both sexes before and after (both p5.6% may help maintain normal RBC structural and functional integrity.

Metabolic syndrome (MetSyn) is characterized by chronic inflammation which mediates the associated high risk for cardiovascular and other diseases. Oxylipins are a superclass of lipid mediators with potent bioactivities in inflammation, vascular biology, and more. While their role as locally produced agents is appreciated, most oxylipins in plasma are found in lipoproteins suggesting defective regulation of inflammation could be mediated by the elevated VLDL and low HDL levels characteristic of MetSyn. Our objective was to compare the oxylipin composition of VLDL, LDL, and HDL in 14 optimally healthy individuals and 31 MetSyn patients, and then to determine the effects of treating MetSyn subjects with 4g/day of prescription omega-3 fatty acids (P-OM3) on lipoprotein oxylipin profiles. We compared oxylipin compositions of healthy (14) and MetSyn (31) subjects followed by randomization and assignment to 4g/d P-OM3 for 16 weeks using LC/MS/MS. Compared to healthy subjects, MetSyn is characterized by abnormalities of (1) pro-inflammatory, arachidonate-derived oxylipins from the lipoxygenase pathway in HDL; and (2) oxylipins mostly not derived from arachidonate in VLDL. P-OM3 treatment corrected many components of these abnormalities, reducing the burden of inflammatory mediators within peripherally circulating lipoproteins that could interfere with, or enhance, local effectors of inflammatory stress. We conclude that MetSyn is associated with a disruption of lipoprotein oxylipin patterns consistent with greater inflammatory stress, and the partial correction of these dysoxylipinemias by treatment with omega-3 fatty acids could explain some of their beneficial effects.

Background and aims A recent 19-cohort meta-analysis examined the relationships between biomarkers of omega-3 fatty acids and risk for coronary heart disease (CHD). That study did not, however, report hazard ratios (HRs) specifically as a function of erythrocyte eicosapentaenoic (EPA) plus docosahexaenoic (DHA) levels, a metric called the Omega-3 Index in which EPA + DHA content is expressed as a percent of total fatty acids. The Omega-3 Index has been used in several recent studies and is a validated biomarker of omega-3 fatty acid tissue levels, but additional data are needed to confirm (or refute) the originally-proposed clinical cut-points of Methods The present study was therefore undertaken using published data from this meta-analysis to estimate HRs per 1-SD increase in the Omega-3 Index and median quintile values for this metric across 10 of the cohorts for which the needed data were available. Results The overall mean (SD) for the Omega-3 Index in these 10 cohort studies was 6.1% (2.1%), and the HR for a 1-SD increase was 0.85 (95% confidence interval, 0.80–0.91). Median quintile 1 and 5 levels were 4.2% vs. 8.3%, respectively. Based on these values, we estimate that risk for fatal CHD would have been reduced by about 30% moving from an Omega-3 Index of 4%–8%. Conclusions These findings support the use of 8% as reasonable therapeutic targets for the Omega-3 Index.

To assess whether red blood cell (RBC) docosahexaenoic acid and eicosapentaenoic acid (DHA+EPA) levels have a protective association with the risk of dementia in older women.RBC DHA+EPA levels were assessed at baseline, and cognitive status was evaluated annually in a cohort of 6706 women aged ≥65 years who participated in the Women's Health Initiative Memory Study (WHIMS). Cox regression was used to quantify the association between RBC DHA+EPA and the risk of probable dementia, independent of major dementia risk factors.During a median follow-up period of 9.8 years, 587 incident cases of probable dementia were identified. After adjusting for demographic, clinical, and behavioral risk factors, a one standard deviation increase in DHA+EPA levels was associated with a significantly lower risk of dementia (HR = 0.92, 95% CI: 0.84, 1.00; p0.05). This effect estimate did not meaningfully change after further adjustment for baseline cognitive function and APOE genotype. For women with high DHA+EPA exposure (1SD above mean) compared to low exposure (1SD below mean), the adjusted 15-year absolute risk difference for dementia was 2.1% (95% CI: 0.2%, 4.0%). In secondary analyses, we also observed a protective association with longitudinal change in Modified Mini-Mental State (3MS) Exam scores, but no significant association with incident MCI, PD/MCI, or baseline 3MS scores.Higher levels of DHA+EPA may help protect against the development of dementia. Results from prospective randomized controlled trials of DHA+EPA supplementation are needed to help clarify whether this association is causal.

Recent studies suggest that eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids have distinct effects on cardiometabolic risk factors. The Omega-3 Index (O3I), which is calculated as the proportion of EPA and DHA in red blood cell (RBC) membranes, has been inversely associated with the risk of coronary heart diseases and coronary mortality. The objective of this study was to compare the effects of EPA and DHA supplementation on the O3I in men and women with abdominal obesity and subclinical inflammation.In a double-blind controlled crossover study, 48 men and 106 women with abdominal obesity and subclinical inflammation were randomized to a sequence of three treatment phases: 1-2.7g/d of EPA, 2-2.7g/d of DHA, and 3-3g/d of corn oil (0g of EPA+DHA). All supplements were provided as 3×1g capsules for a total of 3g/d. The 10-week treatment phases were separated by nine-week washouts. RBC membrane fatty acid composition and O3I were assessed at baseline and the end of each phase. Differences in O3I between treatments were assessed using mixed models for repeated measures.The increase in the O3I after supplementation with DHA (+5.6% compared with control, P0.0001) was significantly greater than after EPA (+3.3% compared with control, P0.0001; DHA vs. EPA, P0.0001). Compared to control, DHA supplementation decreased (-0.8%, P0.0001) while EPA increased (+2.5%, P0.0001) proportion of docosapentaenoic acid (DPA) in RBCs (DHA vs. EPA, P0.0001). The baseline O3I was higher in women than in men (6.3% vs. 5.8%, P=0.011). The difference between DHA and EPA in increasing the O3I tended to be higher in men than in women (+2.6% vs. +2.2% respectively, P for the treatment by sex interaction=0.0537).The increase in the O3I is greater with high dose DHA supplementation than with high dose EPA, which is consistent with the greater potency of DHA to modulate cardiometabolic risk factors. The extent to which such differences between EPA and DHA in increasing the O3I relates to long-term cardiovascular risk needs to be investigated in the future.

The omega-3 index represents the red blood cell (RBC) content of two major long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid, and docosahexaenoic acid. We sought to determine factors associated with a favorable response to fish oil treatment and to characterize changes in RBC PUFAs associated with fish oil supplementation.This study was a secondary analysis of the OMEGA-PAD I trial, a randomized, double-blinded, placebo-controlled trial investigating short-duration, high-dose n-3 PUFA oral supplementation on endothelial function and inflammation in subjects with peripheral arterial disease. Patients with mild to severe claudication received either 4.4 g of fish oil providing 2.6 g of eicosapentaenoic acid and 1.8 g of docosahexaenoic acid daily (n = 40) or placebo capsules (n = 40) for 1 mo. The RBC fatty acid content was measured by gas chromatography and expressed as a percent of total fatty acids. The change in omega-3 index was calculated as the difference between pre- and post-supplementation in the fish oil and placebo groups. Univariate analysis identified predictors of change in omega-3 index, with these variables included in our multivariable model.In the fish oil group, there was an increase in the omega-3 index (5.1± 1.3% to 9.0± 1.8%; P 0.0001), whereas there was no change in the control group. Factors associated with a favorable response (i.e., greater than the median change of 4.06%) included a lower body mass index and higher concentrations of low-density lipoproteins. Other demographic and/or lifestyle factors such as age, race, or smoking status were unrelated to the response. Oral n-3 PUFA supplementation also decreased the n-6 PUFA content in RBCs.Short-term, high-dose n-3 PUFA supplementation increases the omega-3 index to a greater extent in patients with a lower body mass index and higher total and low-density lipoprotein cholesterol levels.

OBJECTIVES: Higher omega-3 fatty acid blood levels, as assessed by the Omega-3 Index (O3I, erythrocyte EPA + DHA expressed as a % of total fatty acids), have been linked with lower risk for cardiovascular disease and total mortality. Seafood is an excellent source of EPA and DHA. The purpose of this study was to determine if individuals living in a coastal US city (Newport, RI) with direct access to fresh seafood have higher O3I levels than people living in inland cities. METHODS: Dried blood spot samples were collected from a convenience sample of people attending a sponsored health fair on the boardwalk in Newport, RI between July and August 2019. Attendees interested in obtaining their O3I signed a consent form before testing and then provided a drop of blood for testing. As a comparator inland group, we used published data (Harris et al. PLEFA 2019;148:30–34) from 7 US cities in the “stroke belt” (note, only one of the 7 cities was coastal, Jacksonville, FL). Dried blood samples were analyzed for the O3I by gas chromatography in both settings. RESULTS: The Newport sample included 234 individuals, 50/50 male/female, with a mean (SD) age of 46 (16) years. The 7 cities comparator cohort contained 2177 subjects, with a mean age of 48 (16) years and of those reporting gender, 78% were female. The mean (SD) O3I in Newport was 5.15% (1.37%), whereas in the 7 cities study it was 4.42% (1.12%; P 8% (considered optimal) was found in 3% of the Newport sample compared to 1.2% in the 7 cities study (P = 0.19). CONCLUSIONS: These data support our hypothesis that the O3I is higher in populations living in a coastal city than those living inland. Still, only 3% of individuals with immediate access to fresh seafood had O3I levels in the optimal zone. Given the documented health benefits of having an optimal O3I, increased intakes of EPA and DHA from fish and other dietary sources or supplementation should be recommended. FUNDING SOURCES: RB Health (US) LLC.

BACKGROUND: The roles of omega-3 (n3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and low-dose aspirin in the primary prevention of ischemic cardiovascular disease (CVD) are controversial. Since omega-3 (n3) fatty acids and aspirin affect cyclooxygenase activity in platelets, there could be a clinically-relevant effect of aspirin combined with a particular n3 fatty acid level present in each individual. METHODS: RBC EPA+DHA, arachidonic acid (AA) and docosapentaenoic acid (DPA) were measured in 2500 participants without known CVD in the Framingham Heart Study. We then tested for interactions with reported aspirin use (1004 reported use and 1494 did not) on CVD outcomes. The median follow-up was 7.2 years. RESULTS: Having RBC EPA+DHA in the second quintile (4.2–4.9% of total fatty acids) was associated with significantly reduced risk for future CVD events (relative to the first quintile

Background The importance of providing the newborn infant with docosahexaenoic acid (DHA) from breast milk is well established. However, women in the United States, on average, have breast milk DHA levels of 0.20%, which is below the worldwide average (and proposed target) of >0.32%. Additionally, the relationship between maternal red blood cell (RBC) and breast milk DHA levels may provide insight into the sufficiency of DHA recommendations during lactation. Whether the standard recommendation of at least 200 mg/day of supplemental DHA during lactation is sufficient for most women to achieve a desirable RBC and breast milk DHA status is unknown. Methods Lactating women (n = 27) at about 5 weeks postpartum were enrolled in a 10–12 week controlled feeding study that included randomization to 480 or 930 mg choline/d (diet plus supplementation). As part of the intervention, all participants were required to consume a 200 mg/d of microalgal DHA. RBC and breast milk DHA levels were measured by capillary gas chromatography in an exploratory analysis. Results Median RBC DHA was 5.0% (95% CI: 4.3, 5.5) at baseline and 5.1% (4.6, 5.4) after 10 weeks of supplementation (P = 0.6). DHA as a percent of breast milk fatty acids increased from 0.19% (0.18, 0.33) to 0.34% (0.27, 0.38) after supplementation (P 5% was unchanged (52% at baseline and week 10). The proportion of women achieving a breast milk DHA level of >0.32% approximately doubled from 30% to 56% (p = 0.06). Baseline RBC and breast milk DHA levels affected their responses to supplementation. Those with baseline RBC and breast milk DHA levels above the median (5% and 0.19%, respectively) experienced no change or a slight decrease in levels, while those below the median had a significant increase. Choline supplementation did not significantly influence final RBC or breast milk DHA levels. Conclusions On average, the standard prenatal DHA dose of 200 mg/d did not increase RBC DHA but did increase breastmilk DHA over 10 weeks in a cohort of lactating women in a controlled-feeding study. Baseline DHA levels in RBC and breast milk affected the response to DHA supplementation, with lower levels being associated with a greater increase and higher levels with no change or a slight decrease. Additional larger, dose-response DHA trials accounting for usual intakes and baseline DHA status are needed to determine how to best achieve target breast milk DHA levels and to identify additional modifiers of the variable breast milk DHA response to maternal DHA supplementation.

We sought to determine the associations between plasma eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels and various cardiovascular risk factors and with the use of fish oil supplements (FOS).Patients with suspected coronary artery disease (CAD) undergoing cardiac catheterization (n=433) were studied. Serum fatty acid (FA) composition, the concentrations of lipids and biomarkers of oxidative stress, and dietary/lifestyle factors were measured.FOS use was associated with a higher plasma EPA+DHA levels (3.7±1.5 vs. 2.6±1.1%, p0.0001). However, there was no relationship between FOS dose (mg/day) and EPA+DHA levels in 76 patients reporting FOS use (r=-0.21, p=0.07). Lower levels were inversely associated with risk factor profiles including lower ApoB100/ApoA1 ratios (p0.001).Higher EPA+DHA levels characterized patients with lower CAD risk. The lack of relations between FOS dose and plasma EPA+DHA levels likely reflects uncaptured variability in EPA+DHA content of supplements.

BACKGROUND Long-chain ω-3 (n-3) polyunsaturated fatty acids (PUFAs) may reduce the risk of atherosclerosis. The association between n-3 PUFAs and cardiovascular disease may vary across different populations, and there is limited information on Hispanic individuals with mixed Amerindian and European origin. OBJECTIVE We evaluated the cross-sectional relations between whole blood n-3 PUFAs and carotid intima-media thickness (IMT) in Mexican women living in Mexico and assessed whether this relation was different in women who spoke an indigenous language compared with women who did not. METHODS In 2012-2013, we assessed the association between blood n-3 PUFAs and IMT in 1306 women free of disease in Chiapas and Yucatan, Mexico. We categorized blood n-3 PUFAs (% of total FAs) in quartiles and adjusted linear regression models by age, indigenous language, site, socioeconomic status, education, smoking, menopause, diabetes, hypertension, hypercholesterolemia, body mass index, physical activity, and diet. We stratified analyses by indigenous/nonindigenous language speakers (n = 315 of 991). RESULTS Whole blood n-3 PUFAs (means ± SDs) were 3.58% ± 0.78% of total FAs. We did not observe a significant association between n-3 PUFAs and IMT in the overall study population. However, the adjusted mean difference of IMT was -6.5% (95% CI: -10.7%, -2.3%; P-trend < 0.0001) for indigenous women in the highest quartile compared with the lowest quartile of blood n-3 PUFAs. In nonindigenous women, we did not observe an association (-0.6%; 95% CI: -3.0%, 1.8%, comparing extreme quartiles; P-trend = 1.00). CONCLUSIONS Overall, circulating n-3 PUFAs were not associated with IMT. However, we observed a strong statistically significant inverse association with IMT in indigenous Mexican women. Future studies should evaluate genetic markers that may reflect differences in n-3 PUFA metabolism across populations.

In contrast to earlier long-chain (LC) omega-3 (i.e. EPA and DHA) investigations, some recent studies have not demonstrated significant effects of EPA and DHA on cardiovascular disease (CVD) outcomes. The neutral findings may have been due to experimental design issues, such as: maintenance on aggressive cardiovascular drug treatment overshadowing the benefits of LC omega-3s, high background LC omega-3 intake, too few subjects in the study, treatment duration too short, insufficient LC omega-3 dosage, increase in omega-6 fatty acid intake during the study, failure to assess the LC omega-3 status of the subjects prior to and during treatment and lack of clarity concerning which mechanisms were expected to produce benefits. At the 11th ISSFAL Congress, a workshop was held on conducting LC omega-3 clinical trials with cardiovascular outcomes, with the goal of gaining a better understanding concerning aspects of experimental design that should be considered when planning clinical studies related to EPA and DHA and potential cardiovascular benefits.

BACKGROUND Synergistic or additive effects or both on cardiometabolic risk may be missed by examining individual fatty acids (FAs). A pattern analysis may be a more useful approach. In addition, it remains unclear whether erythrocyte FA composition relates to insulin resistance among Hispanics/Latinos. OBJECTIVE We derived erythrocyte FA patterns for a Puerto Rican cohort and examined their association with diet and insulin resistance in cross-sectional and prospective analyses. DESIGN At baseline, principal components analysis was used to derive factor patterns with the use of 24 erythrocyte FAs from 1157 participants of the Boston Puerto Rican Health Study (aged 45-75 y). Dietary intake was assessed with a validated semiquantitative food-frequency questionnaire. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated at baseline and at the 2-y follow-up. Relations between FA patterns and HOMA-IR were analyzed in a sample of 922 participants with available data. RESULTS Five FA patterns were derived, differentiated by 1) relatively high de novo lipogenesis (DNL) FAs and low n-6 (ω-6) FAs, 2) high very-long-chain saturated FAs, 3) high n-3 (ω-3) FAs, 4) high linoleic acid and low arachidonic acid, and 5) high trans FAs. The DNL pattern was positively correlated with sugar and inversely with n-6 and monounsaturated FA intakes. Only the DNL pattern was positively related to baseline HOMA-IR [adjusted geometric means (95% CIs) for quartiles 1 and 4: 1.72 (1.58, 1.87) and 2.20 (2.02, 2.39); P-trend < 0.0001]. Similar associations were observed at 2 y, after adjustment for baseline status [quartiles 1 and 4 means (95% CIs): 1.61 (1.48, 1.76) and 1.84 (1.69, 2.00); P-trend = 0.02]. These results remained consistent after the exclusion of participants with diabetes (n = 485). CONCLUSION Our findings suggest that upregulated DNL associated with a diet high in sugar and relatively low in unsaturated FAs may adversely affect insulin sensitivity in a Hispanic/Latino cohort.

Previous studies have suggested that omega-3 polyunsaturated fatty acids (n-3 PUFA) can favorably influence cardiac autonomic tone. However, data regarding n-3 PUFA status and heart rate recovery (HRR) in healthy adults are sparse.To examine the association between n-3 PUFA status and HRR.Participants included 13,912 patients who underwent a comprehensive examination at the Cooper Clinic, Dallas TX. Fitness was determined from a maximal exercise test. HRR was calculated by subtracting the heart rate at 1, 3, and 5 min of an active recovery period from the maximal heart rate. Participants were categorized as having a low (4%), normal (4-8%) or optimal (8%) Omega-3 Index (O3I) (i.e., erythrocyte levels of eicosapentaenoic and docosahexaenoic acids). Multiple linear regression was used to model the association between O3I and HRR adjusting for age, maximal METs, body mass index, and smoking by sex.Higher categories of O3I were associated with greater HRR at 1 min (men: 23.7, 23.9, 24.6 beats/min; women: 23.9, 24.6, 25.9 and 3 min (men: 52.4, 52.9, 53.6 beats/min; women: 51.9, 53.4, 54.6), p trend0.01 for all. Corresponding HRR at 5 min were (men: 60.0, 60.2, 60.7 beats/min, p trend=0.09; women: 59.4, 60.8, 61.6, p trend0.001). The HRR gradients across O3I categories were steeper in women than men at 1, 3, and 5 min (p0.03 for all sex x O3I category interactions with HRR).A direct relationship between HRR and O3I values was observed in both men and women, with a steeper gradient in women. These findings suggest a potential cardioprotective mechanism for n-3 PUFA.

Background Clinical laboratory patient databases are an untapped source of valuable diagnostic and prognostic information. However, the lack of associated clinical and/or demographic information and questionable generalizability to nonpatient populations often limit utility of these data. Objectives This study compared levels of cardiometabolic biomarkers between a national clinical laboratory patient cohort (Health Diagnostic Laboratory [HD Lab]) and the US population as inferred from the National Health and Nutrition Examination Survey (NHANES, 2011–2012). Methods Sample sizes for HD Lab ranged from 199,000 to 739,000 and for NHANES from 2200 to 5300. The latter were weighted to represent the adult US population (∼220 million). Descriptive statistics were compared for body mass index, 5 lipid biomarkers, and 3 glycemic biomarkers. Results Using age- and sex-matched data, mean biomarker values (mg/dL unless noted) and percent differences (%) for HD Lab vs NHANES were body mass index (kg/m 2 ), 29.1 vs 28.6 (1.7%); total cholesterol, 185 vs 193 (–4.1%); apolipoprotein B, 92 vs 90 (2.2%); low-density lipoprotein cholesterol, 107 vs 115 (–7%); high-density lipoprotein cholesterol, 53 vs 53 (0%); triglycerides, 128 vs 127 (0.8%); glucose, 99 vs 108 (–8.3%); insulin (uU/mL), 13.7 vs 13.4 (2.2%); and hemoglobin A1c (%), 5.6 vs 5.8 (–3.4%). Although all differences were statistically significant, only low-density lipoprotein cholesterol and glucose differed by more than 5%. These may reflect a greater use of medications among HD Lab patients and/or preanalytical factors. Conclusions Cardiometabolic risk markers from a national clinical laboratory were broadly similar to those of the US population; thus, with certain caveats, data from the former may be generalizable to the latter.

Adequate long-chain polyunsaturated fatty acid (LCPUFA) intake is critical during the fetal and infant periods. We quantified fatty acid content of breast milk (n=718) and plasma from six month old infants (n=412) in southern Malawi, and in usipa (n=3), a small dried fish from Lake Malawi. Compared to global norms, Malawian breast milk fatty acid content (% of total fatty acids) was well above average levels of arachidonic acid [ARA] (0.69% vs. 0.47%) and docosahexaenoic acid [DHA] (0.73% vs. 0.32%). Average Malawian infant plasma ARA (7.5%) and DHA (3.8%) levels were comparable to those reported in infants consuming breast milk with similar fatty acid content. The amounts (mg) of DHA, EPA and ARA provided by a 3 oz (85 g) portion of dried usipa (1439, 659 and 360, respectively) are considerably higher than those for dried salmon. Usipa may be an important source of LCPUFA for populations in this region.

BACKGROUND & AIMS: Several studies have demonstrated that vegetarians and vegans have much lower plasma concentrations of omega-3 fatty acids (i.e., docosahexaenoic and eicosapentaenoic acids) when compared to those who eat fish. The purposes of this study were 1) to define the age and/or sex-specific docosahexaenoic plus eicosapentaenoic acids levels in red blood cell membranes (expressed as a percent of total fatty acids; hereafter the omega-3 index) in long-term vegans, and 2) to determine the effects of a vegetarian omega-3 supplement (254 mg docosahexaenoic plus eicosapentaenoic acids/day for 4 months) on the omega-3 index. METHODS: A sample (n = 165) of vegans was recruited, and their omega-3 index was determined using a dried blood spot methodology. A subset of 46 subjects with a baseline omega-3 index of

The long-chain omega-3 polyunsaturated (n-3 PUFA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), may have anti-inflammatory effects. We evaluated the dose-response effect of EPA+DHA supplementation on circulating TNF-α, IL-6, and CRP and explored associations between red blood cell (RBC) membrane PUFA content and TNF-α, IL-6, and CRP. Young adults with low fish intake (n = 116) received one of five doses (0, 300, 600, 900, or 1,800 mg/d EPA+DHA) for 5 months. There were no significant effects of supplemental EPA+DHA on IL-6 or CRP; however, there was a marginal treatment effect for TNF-α (p < 0.08). At baseline, higher quartiles of RBC DHA were associated with lower TNF-α (p = 0.001); higher quartiles of arachidonic acid were associated with higher TNF-α (p = 0.005). EPA+DHA supplementation had no dose-response effect on TNF-α, IL-6, or CRP in healthy young adults; however, associations between inflammatory markers and RBC PUFA warrant further investigation.

The long chain n-3 (omega-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), although originally synthesized by microorganisms in the oceans, are primarily obtained from the consumption of fish. Vegetarians, by definition, do not eat fish and thus consume virtually no EPA and DHA. Because conversion of the plant-derived n-3 fatty acid α-linolenic acid (ALA) to EPA and DHA is very low, n-3 tissue concentrations in vegetarians are lower than in omnivores. This review asks 2 questions: what is the evidence that increased n-3 concentrations reduce the risk of cardiovascular disease in vegetarians, and, if it does, how can vegetarians increase their blood and tissue concentrations of these animal-derived fatty acids? At present, both cardiovascular risk markers and cardiovascular events appear to be significantly reduced in vegetarians compared with those in omnivores. If so, and in the absence of data to show that risk in vegetarians could be even lower with higher n-3 concentrations, then the second question becomes moot. However, the absence of evidence is not evidence of absence; therefore, at our present state of knowledge, increasing n-3 concentrations is not an unreasonable goal for vegetarians. This can be accomplished by a variety of approaches, including increased intakes of ALA, consumption of stearidonic acid-enriched soybean oil (if and when it comes to the market), and the use of supplements containing EPA, DHA, or both derived from nonanimal sources (microalgae, biotech yeast, and, in the future, biotech plant oils).

Background The Omega-3 Index [red blood cell (RBC) content of eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA)] is inversely related to risk of cardiovascular disease in humans. In the U.S., the average Omega-3 Index is about 4–6% of RBC fatty acids, whereas in Japan it is 9–10%. The range of physiologically-possible levels for the Omega-3 Index in other mammals is unknown. Objective To compare the RBC fatty acid composition of a common piscivorous mammal, the bottlenose dolphin ( Tursiops truncatus ), with that of (U.S.) humans, and to examine the extent to which dietary fatty acid patterns were reflected in RBCs. Methods RBCs were isolated from routine blood samples collected from 35 healthy dolphins at two display facilities and were analyzed by gas chromatography. For humans, historic, deidentified RBC fatty acid data from our laboratory were used ( n =11,329; mean age 58). Results The mean Omega-3 Index of the dolphins was 19.9% compared with 6.0% for humans. EPA levels were 15.3% vs 1.2%, respectively, but DHA levels were virtually identical (4.6% vs 4.8%). Linoleic acid (LNA) levels were much lower in dolphins vs humans (0.5% vs 12.5%) whereas arachidonic acid (ARA) levels were similar (12.3% vs 14.5%). In a subgroup of humans with an Omega-3 Index in the >99.2 percentile, the mean index was similar to that of the dolphins. Based on an analysis of their food, the dolphins consumed about 60g of EPA+DHA per day as compared to about 0.1g in humans. Conclusion Dolphins have an Omega-3 Index that is (only) 3–4× higher than that of U.S. adults despite their intake of EPA+DHA being about 165× higher (as a percent of kcal). RBC, EPA and LNA levels are relatively more reflective of dietary intakes than are DHA and ARA levels. The mechanisms by which certain fatty acid levels appear to be fixed and others may vary in RBC membranes are unknown.

Objective The n-3 polyunsaturated fatty acids are dietary components derived from fish oil with beneficial cardiovascular effects that may relate in part to anti-inflammatory properties. Peripheral artery disease (PAD) is characterized by a marked proinflammatory state. We hypothesized that the n-3 polyunsaturated fatty acids content of red blood cells (omega-3 index) would be correlated with biomarkers of inflammation and vascular function in a PAD cohort. Methods This was a cross-sectional study of subjects who presented to an outpatient vascular surgery clinic for evaluation of PAD. We used linear regression to evaluate the independent association between the omega-3 index, inflammatory biomarkers (C-reactive protein [CRP], intercellular adhesion molecule-1, interleukin-6, and tumor-necrosis-factor-α) and endothelial function (brachial artery flow mediated dilation). Results 64 subjects (61 claudicants and three with critical limb ischemia) were recruited for the study. The mean CRP level was 5.0 ± 5.0 mg/L, and the mean omega-3 index was 5.0% ± 1.8%. In an unadjusted model, the omega-3 index was negatively associated with CRP (38% increase in CRP for one standard deviation decrease in the omega-3 index; P = .007), which remained significant after adjustment for age, body mass index, smoking, ankle-brachial index, and high-density lipoprotein (33%; P = .04). There was also evidence for independent associations between the omega-3 index and IL-6 ( P = .001). There were no significant associations between the omega-3 index and vascular function tests. Conclusions In a cohort of patients with PAD, the omega-3 index was inversely associated with biomarkers of inflammation even after adjustment for covariates including the ankle-brachial index. Because patients with PAD have a high inflammatory burden, further studies should be conducted to determine if manipulation of omega-3 index via dietary changes or fish oil supplementation could improve inflammation and symptoms in these patients.

Long chain omega-3 fatty acids (FAs) are effective for reducing plasma triglyceride (TG) levels. At the pharmaceutical dose, 3.4g/day, they reduce plasma TG by about 25-50% after one month of treatment, resulting primarily from the decline in hepatic very low density lipoprotein (VLDL-TG) production, and secondarily from the increase in VLDL clearance. Numerous mechanisms have been shown to contribute to the TG overproduction, but a key component is an increase in the availability of FAs in the liver. The liver derives FAs from three sources: diet (delivered via chylomicron remnants), de novo lipogenesis, and circulating non-esterified FAs (NEFAs). Of these, NEFAs contribute the largest fraction to VLDL-TG production in both normotriglyceridemic subjects and hypertriglyceridemic, insulin resistant patients. Thus reducing NEFA delivery to the liver would be a likely locus of action for fish oils (FO). The key regulator of plasma NEFA is intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), which increases as insulin sensitivity worsens. FO counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation. In addition, FO increases extracellular lipolysis by lipoprotein lipase (LpL) in adipose, heart and skeletal muscle and enhances hepatic and skeletal muscle β-oxidation which contributes to reduced FA delivery to the liver. FO could activate transcription factors which control metabolic pathways in a tissue specific manner regulating nutrient traffic and reducing plasma TG. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

Objective The purpose of this randomized, controlled, parallel group study was to characterize the relationships between dosages of stearidonic acid (SDA) and eicosapentaenoic acid (EPA), and incorporation of EPA into red blood cell (RBC) membranes over time. Methods Healthy subjects ( n =131) received capsules with placebo (safflower oil), SDA (0.43, 1.3, 2.6, or 5.2g/d) or EPA (0.44, 1.3, or 2.7g/d) for 12 weeks. RBC fatty acids were analyzed biweekly. Results RBC %EPA increased in all EPA and SDA groups ( p p =0.187). For theoretical intakes of EPA of 0.25, 0.5, and 0.89g/d, the amounts of SDA needed to achieve equivalent RBC EPA enrichment were 0.61, 1.89, and 5.32g/d (conversion efficiencies of 41%, 26%, and 17%), respectively. Conclusions SDA increased RBC %EPA in a dosage and time-dependent manner at intakes as low as 1.3g/d.

To identify the patient and dietary characteristics associated with low omega-3 levels in patients with acute myocardial infarction (AMI) and determine whether these characteristics are useful to identify patients who may benefit from omega-3 testing and treatment.Dietary habits of 1487 patients in the 24-center Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health status (TRIUMPH) registry between April 11, 2005, and September 28, 2007, were assessed by asking about the frequency of fast food and nonfried fish consumption. All patients had erythrocyte omega-3 index measured at the time of hospital admission for AMI. We used multivariable linear regression to identify independent correlates of the omega-3 index and modified Poisson regression to predict risk of a low omega-3 index (4%).The proportion of patients with a low omega-3 index increased with more frequent fast food intake (18.9% for1 time monthly, 28.6% for 1-3 times monthly, 28.8% for 1-2 times weekly, and 37.6% for ≥ 3 times weekly; P.001). In contrast, a low omega-3 index was less common among patients with more frequent fish intake (35.1% for1 time monthly, 24.9% for 1-3 times monthly, 16.1% for 1-2 times weekly, and 21.1% for ≥ 3 times weekly; P.001). Fish intake, older age, race other than white, and omega-3 supplementation were independently associated with a higher omega-3 index, whereas frequent fast food intake, smoking, and diabetes mellitus were associated with a lower omega-3 index.Potentially modifiable factors, such as patient-reported fast food intake, fish intake, and smoking, are independently associated with the omega-3 index in patients with AMI. These characteristics may be useful to identify patients who would benefit most from omega-3 supplementation and lifestyle modification.

Dietary intake of n-3 polyunsaturated fatty acids is associated with a lower incidence of cardiovascular events. Mechanisms underlying this association are poorly understood but may include beneficial effects on physical conditioning and vagal tone. We investigated the association of n-3 fatty acid levels to exercise parameters in 992 subjects with stable coronary artery disease. Cross-sectional associations of heart rate recovery time, treadmill exercise capacity, and exercise time with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels were evaluated in multivariable linear and logistic regression models adjusted for demographics, cardiovascular risk factors, co-morbidities, self-reported physical activity, medication use, and left ventricular function. After multivariable adjustment, n-3 fatty acid levels (DHA + EPA) were strongly associated with heart rate recovery (beta 2.1, p = 0.003), exercise capacity (beta 0.8, p0.0001), and exercise time (beta 0.9, p0.0001). Increasing levels of (DHA + EPA) were also associated with decreased risk of impaired heart rate recovery (odds ratio 0.8, p = 0.004) and exercise time (odds ratio 0.7, p = 0.01) and trended toward significance for exercise capacity (odds ratio 0.8, p = 0.07). These associations were not modified by demographics, body mass index, smoking, co-morbid conditions, statin use, or β-blocker use (p for interaction0.1 for all comparisons). In conclusion, an independent association exists between n-3 fatty acid levels and important exercise parameters in patients with stable coronary artery disease. These findings support the hypothesis that n-3 fatty acids may increase vagal tone and physical conditioning.

Background: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce cardiovascular mortality at a dose of ≈1 g/d. Studies using higher doses have shown evidence of reduced inflammation and improved endothelial function. Few studies have compared these doses. Objective: The objective of this study was to compare the effects of a nutritional dose of EPA+DHA (0.85 g/d) with those of a pharmaceutical dose (3.4 g/d) on serum triglycerides, inflammatory markers, and endothelial function in healthy subjects with moderately elevated triglycerides. Design: This was a placebo-controlled, double-blind, randomized, 3-period crossover trial (8 wk of treatment, 6 wk of washout) that compared the effects of 0.85 and 3.4 g EPA+DHA/d in 23 men and 3 postmenopausal women with moderate hypertriglyceridemia (150–500 mg/dL). Results: The higher dose of EPA+DHA lowered triglycerides by 27% compared with placebo (mean ± SEM: 173 ± 17.5 compared with 237 ± 17.5 mg/dL; P = 0.002), whereas no effect of the lower dose was observed on lipids. No effects on cholesterol (total, LDL, and HDL), endothelial function [as assessed by flow-mediated dilation, peripheral arterial tonometry/EndoPAT (Itamar Medical Ltd, Caesarea, Israel), or Doppler measures of hyperemia], inflammatory markers (interleukin-1β, interleukin-6, tumor necrosis factor-α, and high-sensitivity C-reactive protein), or the expression of inflammatory cytokine genes in isolated lymphocytes were observed. Conclusion: The higher dose (3.4 g/d) of EPA+DHA significantly lowered triglycerides, but neither dose improved endothelial function or inflammatory status over 8 wk in healthy adults with moderate hypertriglyceridemia. The trial was registered at clinicaltrials.gov as NCT00504309.