Christopher E. Ramsden

Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century

BACKGROUND The consumption of omega-3 (n-3) and omega-6 (n-6) essential fatty acids in Western diets is thought to have changed markedly during the 20th century. OBJECTIVE We sought to quantify changes in the apparent consumption of essential fatty acids in the United States from 1909 to 1999. DESIGN We calculated the estimated per capita consumption of food commodities and availability of essential fatty acids from 373 food commodities by using economic disappearance data for each year from 1909 to 1999. Nutrient compositions for 1909 were modeled by using current foods (1909-C) and foods produced by traditional early 20th century practices (1909-T). RESULTS The estimated per capita consumption of soybean oil increased >1000-fold from 1909 to 1999. The availability of linoleic acid (LA) increased from 2.79% to 7.21% of energy (P < 0.000001), whereas the availability of α-linolenic acid (ALA) increased from 0.39% to 0.72% of energy by using 1909-C modeling. By using 1909-T modeling, LA was 2.23% of energy, and ALA was 0.35% of energy. The ratio of LA to ALA increased from 6.4 in 1909 to 10.0 in 1999. The 1909-T but not the 1909-C data showed substantial declines in dietary availability (percentage of energy) of n-6 arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Predicted net effects of these dietary changes included declines in tissue n--3 highly unsaturated fatty acid status (36.81%, 1909-T; 31.28%, 1909-C; 22.95%, 1999) and declines in the estimated omega-3 index (8.28, 1909-T; 6.51, 1909-C; 3.84, 1999). CONCLUSION The apparent increased consumption of LA, which was primarily from soybean oil, has likely decreased tissue concentrations of EPA and DHA during the 20th century.

Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: Evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

Objective To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death. Design Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data. Setting Ambulatory, coronary care clinic in Sydney, Australia. Participants 458 men aged 30-59 years with a recent coronary event. Interventions Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups. Outcome measures All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group. Results The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07). Conclusions Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats. Trial registration Clinical trials NCT01621087.

Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)

Objective To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic review and meta-analysis. Design The MCE (1968-73) is a double blind randomized controlled trial designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduces coronary heart disease and death by lowering serum cholesterol. Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators. Further, a systematic review and meta-analyses of randomized controlled trials that lowered serum cholesterol by providing vegetable oil rich in linoleic acid in place of saturated fat without confounding by concomitant interventions was conducted. Setting One nursing home and six state mental hospitals in Minnesota, United States. Participants Unpublished documents with completed analyses for the randomized cohort of 9423 women and men aged 20-97; longitudinal data on serum cholesterol for the 2355 participants exposed to the study diets for a year or more; 149 completed autopsy files. Interventions Serum cholesterol lowering diet that replaced saturated fat with linoleic acid (from corn oil and corn oil polyunsaturated margarine). Control diet was high in saturated fat from animal fats, common margarines, and shortenings. Main outcome measures Death from all causes; association between changes in serum cholesterol and death; and coronary atherosclerosis and myocardial infarcts detected at autopsy. Results The intervention group had significant reduction in serum cholesterol compared with controls (mean change from baseline −13.8% v −1.0%; P<0.001). Kaplan Meier graphs showed no mortality benefit for the intervention group in the full randomized cohort or for any prespecified subgroup. There was a 22% higher risk of death for each 30 mg/dL (0.78 mmol/L) reduction in serum cholesterol in covariate adjusted Cox regression models (hazard ratio 1.22, 95% confidence interval 1.14 to 1.32; P<0.001). There was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts. Systematic review identified five randomized controlled trials for inclusion (n=10 808). In meta-analyses, these cholesterol lowering interventions showed no evidence of benefit on mortality from coronary heart disease (1.13, 0.83 to 1.54) or all cause mortality (1.07, 0.90 to 1.27). Conclusions Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. Findings from the Minnesota Coronary Experiment add to growing evidence that incomplete publication has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid.

Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial.

Summary A dietary intervention increasing n‐3 and reducing n‐6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality of life in a chronic headache population. Abstract Omega‐3 and n‐6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single‐blinded, parallel‐group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n‐3 and n‐6 fatty acids for treatment of chronic headaches. After a 4‐week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food‐based 12‐week dietary interventions: a high n‐3 plus low n‐6 (H3‐L6) intervention, or a low n‐6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT‐6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n‐6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n‐3 and n‐6 derivatives. Fifty‐six of 67 patients completed the intervention. Both groups achieved targeted intakes of n‐3 and n‐6 fatty acids. In intention‐to‐treat analysis, the H3‐L6 intervention produced significantly greater improvement in the HIT‐6 score (−7.5 vs −2.1; P < 0.001) and the number of Headache Days per month (−8.8 vs −4.0; P = 0.02), compared to the L6 group. The H3‐L6 intervention also produced significantly greater reductions in Headache Hours per day (−4.6 vs −1.2; P = 0.01) and the n‐6 in HUFA score (−21.0 vs −4.0%; P < 0.001), and greater increases in antinociceptive n‐3 pathway markers 18‐hydroxy‐eicosapentaenoic acid (+118.4 vs +61.1%; P < 0.001) and 17‐hydroxy‐docosahexaenoic acid (+170.2 vs +27.2; P < 0.001). A dietary intervention increasing n‐3 and reducing n‐6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality‐of‐life in this population.

Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans

Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in human diets, a major component of human tissues, and the direct precursor to the bioactive oxidized LA metabolites (OXLAMs), 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). These four OXLAMs have been mechanistically linked to pathological conditions ranging from cardiovascular disease to chronic pain. Plasma OXLAMs, which are elevated in Alzheimers dementia and non-alcoholic steatohepatitis, have been proposed as biomarkers useful for indicating the presence and severity of both conditions. Because mammals lack the enzymatic machinery needed for de novo LA synthesis, the abundance of LA and OXLAMs in mammalian tissues may be modifiable via diet. To examine this issue in humans, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced the abundance of plasma OXLAMs, and reduced the LA content of multiple circulating lipid fractions that may serve as precursor pools for endogenous OXLAM synthesis. These results show that lowering dietary LA can reduce the synthesis and/or accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions. Future studies evaluating the clinical implications of diet-induced OXLAM reductions are warranted.

Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools.

BACKGROUND Dietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations. OBJECTIVE To evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. DESIGN Secondary analysis of a randomized trial. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. RESULTS Compared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3-L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations. CONCLUSION Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA.

Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression

BACKGROUND Trials evaluating efficacy of omega-3 highly unsaturated fatty acids (HUFAs) in major depressive disorder report discrepant findings. AIMS To establish the reasons underlying inconsistent findings among randomised controlled trials (RCTs) of omega-3 HUFAs for depression and to assess implications for further trials. METHOD A systematic bibliographic search of double-blind RCTs was conducted between January 1980 and July 2014 and an exploratory hypothesis-testing meta-analysis performed in 35 RCTs including 6665 participants receiving omega-3 HUFAs and 4373 participants receiving placebo. RESULTS Among participants with diagnosed depression, eicosapentaenoic acid (EPA)-predominant formulations (>50% EPA) demonstrated clinical benefits compared with placebo (Hedges G = 0.61, P<0.001) whereas docosahexaenoic acid (DHA)-predominant formulations (>50% DHA) did not. EPA failed to prevent depressive symptoms among populations not diagnosed for depression. CONCLUSIONS Further RCTs should be conducted on study populations with diagnosed or clinically significant depression of adequate duration using EPA-predominant omega-3 HUFA formulations.

Low- n -6 and low- n -6 plus high- n -3 diets for use in clinical research

Few trials have evaluated the metabolic effects and health outcomes of lowering dietary n-6 PUFA. The objectives of the present paper were (1) to report the methods employed to lower dietary n-6 PUFA, while either increasing or maintaining n-3 PUFA intake and (2) to validate our methods with 24 h recalls and erythrocyte fatty acid analyses. A total of sixty-seven subjects were randomised to either (1) an average-n-3 PUFA, low-n-6 PUFA (L6) intervention designed to lower linoleic acid (LA; #2·5% of energy (en%)) and arachidonic acid (#60 mg/d), while maintaining an average US intake of n-3 PUFA or (2) a high-n-3 PUFA, low-n-6 PUFA (H3-L6) intervention designed to lower n-6 LA, while increasing the n-3 PUFA a-linolenic acid (ALA;

Low omega-6 vs. low omega-6 plus high omega- 3 dietary intervention for Chronic Daily Headache: Protocol for a randomized clinical trial

1·5 en%) and EPA þ DHA (

A low omega-6 polyunsaturated fatty acid (n-6 PUFA) diet increases omega-3 (n-3) long chain PUFA status in plasma phospholipids in humans.

1000 mg/d). Pre- and intraintervention nutrient intakes were estimated with six 24 h dietary recalls per subject. Both groups achieved the targeted reductions in dietary LA to #2·5 en% (median LA 2·45 (2·1, 3·1); P,0·001). Intakes of n-3 PUFA did not change for the L6 group. Target increases in n-3 ALA (median 1·6 en%, (1·3, 2·0), P,0·001) and EPA þ DHA (1482 mg, (374, 2558), P,0·001) were achieved in the H3-L6 group. Dietary changes were validated by corresponding changes in erythrocyte n-6 and n-3 fatty acid composition. Dietary LA can be lowered to #2·5 en%, with or without concurrent increases in dietary n-3 PUFA, in an outpatient clinical trial setting using this integrated diet method.