Objective

To test whether red blood cell (RBC) levels of marine omega-3 fatty acids measured in the Women's Health Initiative Memory Study were related to MRI brain volumes measured 8 years later.

Methods

RBC eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and MRI brain volumes were assessed in 1,111 postmenopausal women from the Women's Health Initiative Memory Study. The endpoints were total brain volume and anatomical regions. Linear mixed models included multiple imputations of fatty acids and were adjusted for hormone therapy, time since randomization, demographics, intracranial volume, and cardiovascular disease risk factors.

Results

In fully adjusted models, a 1 SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm(3) larger brain volume (p = 0.048). DHA was marginally correlated (p = 0.063) with total brain volume while EPA was less so (p = 0.11). There were no correlations between ischemic lesion volumes and EPA, DHA, or EPA + DHA. A 1 SD greater omega-3 index was correlated with greater hippocampal volume (50 mm(3), p = 0.036) in fully adjusted models. Comparing the fourth quartile vs the first quartile of the omega-3 index confirmed greater hippocampal volume (159 mm(3), p = 0.034).

Conclusion

A higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured 8 years later. While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy. Future studies should examine whether maintaining higher RBC EPA + DHA levels slows the rate of hippocampal or overall brain atrophy.

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.

Background

Oxylipins mediate inflammation, vascular tension, and more. Their presence in lipoproteins could explain why lipoproteins mediate nearly identical activities.

Methods

To determine how oxylipins are distributed in the lipoproteins of hypertriglyceridemic subjects, and whether omega-3 fatty acids alter them in a manner consistent with improved cardiovascular health, we recruited 15 dyslipidemic subjects whose levels of low density lipoprotein cholesterol (LDL-C) were at goal but who remained hypertriglyceridemic (200-499 mg/dL). They were treated them with the indicated dose of 4 g/d omega-3 acid ethyl esters (P-OM3) for 8 weeks. Measured oxylipins included mid-chain alcohols (HETEs, HEPEs and HDoHEs), ketones (KETEs), epoxides (as EpETrEs, EpETEs, and EpDPEs).

Results

At baseline, arachidonate-oxylipins (HETEs, KETEs, and EpETrEs) were most abundant in plasma with the greatest fraction of total abundance (mean |95% CI|) being carried in high density lipoproteins (HDL); 42% |31, 57| followed by very low density lipoproteins (VLDL); 27% |20, 36|; and LDL 21% |16, 28|. EPA- and DHA-derived oxylipins constituted less than 11% of total. HDL carried alcohols and epoxides but VLDL was also rich in ketones. Treatment decreased AA-derived oxylipins across lipoprotein classes (-23% |-33, -12|, p = 0.0003), and expanded EPA-(322% |241, 422|, p<0.0001) and DHA-derived oxylipins (123% |80, 176|, p<0.0001).

Conclusions

Each lipoprotein class carries a unique oxylipin complement. P-OM3 treatment alters the oxylipin content of all classes, reducing pro-inflammatory and increasing anti-inflammatory species, consistent with the improved inflammatory and vascular status associated with the treatment.

Trial registration

ClinicalTrials.gov NCT00959842.

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.

Population-based data suggest that individuals who consume large dietary amounts of n-3 polyunsaturated fatty acids (PUFA) have lower odds of peripheral artery disease (PAD); however, clinical studies examining n-3 PUFA levels in patients with PAD are sparse. The objective of this study is to compare erythrocyte membrane fatty acid (FA) content between patients with PAD and controls. We conducted a cross-sectional study of 179 vascular surgery outpatients (controls, 34; PAD, 145). A blood sample was drawn and the erythrocyte FA content was assayed using capillary gas chromatography. We calculated the ratio of the n-3 PUFA eicosapentaenoic acid (EPA) to the n-6 PUFA arachidonic acid (ARA) as well as the omega-3 index (O3I), a measure of erythrocyte content of the n-3 PUFA, EPA, and docosahexaenoic acid (DHA), expressed as a percentage of total erythrocyte FA. Compared with controls, patients with PAD smoked more and were more likely to have hypertension and hyperlipidemia (p < 0.05). Patients with PAD had a lower mean O3I (5.0 ± 1.7% vs 6.0 ± 1.6%, p < 0.001) and EPA:ARA ratio (0.04 ± 0.02 vs 0.05 ± 0.05, p < 0.001), but greater mean total saturated fats (39.5 ± 2.5% vs 38.5 ± 2.6%, p = 0.01). After adjusting for several patient characteristics, comorbidities, and medications, an absolute decrease of 1% in the O3I was associated with 39% greater odds of PAD (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.03-1.86, and p = 0.03). PAD was associated with a deficiency of erythrocyte n-3 PUFA, a lower EPA:ARA ratio, and greater mean total saturated fats. These alterations in FA content may be involved in the pathogenesis or development of poor outcomes in PAD.

Objective

Despite available medical therapies, patients with peripheral arterial disease (PAD) remain at high risk for cardiovascular events. The n-3 polyunsaturated fatty acids (PUFA), derived from marine sources, have been shown to improve cardiovascular mortality. The Omega-3 Index (O3I), a proportion of the n-3 PUFA eicosapentaenoic acid and docosahexaenoic acid in the red blood cell membrane, correlates with cardiovascular risk. Previous investigations have found that n-3 PUFA supplementation, fish consumption, older age, and smoking history affect the O3I in different patient populations, although similar correlations have never been explored in PAD. We hypothesized that in our PAD cohort, blood content of omega-3 fatty acids would directly and positively correlate with a history of fish oil supplementation and older age and inversely correlate with a smoking history and obesity.

Methods

This cross-sectional study included 111 patients who had an ankle-brachial index of <0.9 associated with claudication symptoms. We used linear regression to determine the association between clinical factors and the O3I.

Results

The mean age of the cohort was 69 ± 8 years; 37% had diabetes mellitus (hemoglobin A1c, 7% ± 1%), and 94% reported current smoking or a history of smoking. The mean O3I was 5% ± 2%. In multivariate linear regression analysis, the O3I was associated with older age, increasing body mass index, and a history of smoking and fish oil intake.

Conclusions

This is the first report of the relation between blood content of omega-3 fatty acids and clinical factors in a PAD population. In patients with PAD, older age, elevated body mass index, and prior fish oil supplementation predicted a higher O3I. A history of smoking correlated with a lower O3I. These results demonstrate that the O3I is a reliable measure of dietary n-3 PUFA intake and that clinical factors related to the O3I in PAD are similar to those observed in other populations.

Background

Oral supplementation with n-3 polyunsaturated fatty acids (PUFA) increases the omega-3 index, a biomarker of red blood cell eicosapentaenoic acid and docosahexaenoic acid, and plasma levels of biosynthesis pathway markers and potent lipid mediators involved in the resolution of inflammation among patients with peripheral arterial disease (PAD).

Objective

We aimed to quantify the association between an upstream change in the omega-3 index and downstream changes in lipid mediator production.

Methods

We conducted a secondary analysis of the OMEGA-PAD I Trial, a randomized, placebo controlled trial investigating high-dose n-3 PUFA oral supplementation in PAD patients. Eighty subjects were randomized to either 4.4 g of fish oil or placebo for 1 month. Regression analyses using generalized estimating equation techniques were used to investigate the relationship between changes in the omega-3 index and changes in lipid mediators, pre- and post-intervention.

Results

In the fish oil group, there was a significant increase in the omega-3 index (5 ± 1% to 9 ± 2%, P < .001) as well as in the plasma levels of several downstream lipid mediator pathway markers of resolution, which are involved with the regulation of leukocyte effector function and host defense. A doubling of the omega-3 index correlated with increases of 2.3-fold in 18-hydroxy-eicosapentaenoic acid (HEPE; P < .0001), 1.7-fold in 15-HEPE (P = .03), 1.9-fold in 5-HEPE (P = .04), and 3.6-fold in 4-hydroxy-docosahexaenoic acid (P < .001).

Conclusion

Among subjects with symptomatic PAD who took oral fish oil supplements for 1 month, observed changes in the omega-3 index were strongly associated with increases in downstream mediators in the biochemical pathways of resolution.

Background and objectives

Diet may be a key contributor to brain health in midlife. In particular, omega-3 fatty acids have been related to better neurologic outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults and further explore effect modification by APOE genotype.

Methods

We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs noncarrier) on MRI and cognitive outcomes.

Results

We included 2,183 dementia-free and stroke-free participants (mean age of 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ± 0.001, p = 0.013) and better abstract reasoning (0.17 ± 0.07, p = 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers.

Discussion

Our results, albeit exploratory, suggest that higher omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-aged populations are warranted to confirm these findings.

Background

Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear.

Objective

The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I.

Methods

Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion.

Results

Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products.

Conclusions

Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.

Background

n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.

Objectives

We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.

Methods

Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.

Results

In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.

Conclusions

Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.