Daisy Zamora

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.

Intakes of long-chain omega-3 (n-3) PUFAs and fish in relation to incidence of asthma among American young adults: the CARDIA study.

BACKGROUND Although long-chain ω-3 (n-3) PUFAs (LCω3PUFAs) have been linked to the prevention of some inflammatory disorders, little is known about the association between these fatty acids and incidence of asthma. OBJECTIVE The objective was to prospectively investigate the association between LCω3PUFAs and fish intake and incidence of asthma among American young adults. DESIGN A 20-y follow-up longitudinal analysis was conducted in a biracial cohort of 4162 Americans, aged 18-30 y, with a history of asthma at baseline in 1985. Diet was assessed by a validated interviewer-administered quantitative food-frequency questionnaire at the examinations in 1985, 1992, and 2005. Incident self-reported asthma was defined as having a physician diagnosis of asthma and/or the use of asthma medications between 1985 and 2005. RESULTS During the 20-y follow-up, 446 incident cases of asthma were identified. LCω3PUFA intake was significantly inversely associated with incidence of asthma after adjustment for sociodemographic, major lifestyle, and dietary confounders. The multivariable-adjusted HR for the highest quintile of LCω3PUFA intake as compared with the lowest quintile was 0.46 (95% CI: 0.33, 0.64; P-trend < 0.01). However, a higher frequency of nonfried fish consumption was not significantly associated with the risk of asthma. DHA showed a greater inverse association than did EPA. The association between LCω3PUFAs and incident asthma was not appreciably modified by sex, race, BMI, smoking status, or atopic status. CONCLUSION This study showed that intakes of LCω3PUFAs are inversely longitudinally associated with the incidence of asthma in American young adults.

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;

Are the 2005 Dietary Guidelines for Americans Associated With reduced risk of type 2 diabetes and cardiometabolic risk factors? Twenty-year findings from the CARDIA study.

1·5 en%) and EPA þ DHA (

Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: A secondary analysis of a randomized trial

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.

Raloxifene Plus Antipsychotics Versus Placebo Plus Antipsychotics in Severely Ill Decompensated Postmenopausal Women With Schizophrenia or Schizoaffective Disorder: A Randomized Controlled Trial

OBJECTIVE To examine the prospective association between accordance with the 2005 Dietary Guidelines for Americans (DGA) and subsequent diabetes incidence and changes in cardiometabolic risk factors. RESEARCH DESIGN AND METHODS The sample consisted of 4,381 black and white young adults examined repeatedly from 1985 to 2005. We used the 2005 Diet Quality Index (DQI) to rate participants’ diets based on meeting key dietary recommendations conveyed by the 2005 DGA. RESULTS Overall, we found no association between DQI score and diabetes risk using Cox models adjusted for potential confounders. Higher DQI scores were associated with favorable changes in HDL cholesterol and blood pressure overall (P for trend <0.05), but with increased insulin resistance among blacks (P for trend <0.01). CONCLUSIONS Our findings highlight the need for evaluation of the DGA’s effectiveness, particularly among ethnic minority populations. Clinicians should be aware that following the DGA might not lower diabetes risk.

Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid

Abstract Omega-3 and omega-6 fatty acids are precursors of bioactive lipid mediators posited to modulate both physical pain and psychological distress. In a randomized trial of 67 subjects with severe headaches, we recently demonstrated that targeted dietary manipulation—increasing omega-3 fatty acids with concurrent reduction in omega-6 linoleic acid (the H3-L6 intervention)—produced major reductions in headache compared with an omega-6 lowering (L6) intervention. Because chronic pain is often accompanied by psychological distress and impaired health-related quality of life (HRQOL), we used data from this trial to examine whether the H3-L6 intervention favorably impacted these domains. Additionally, we examined the effect of the interventions on the number of cases with substantial physical or mental impairments as defined by cutoff values in the Brief Symptom Inventory (BSI-18), Medical Outcomes Study Short Forms 12 (SF-12), Headache Impact Test (HIT-6), and the number of headache days per month. In the intention-to-treat analysis, participants in the H3-L6 group experienced statistically significant reductions in psychological distress (BSI-18 mean difference: −6.56; 95% confidence interval [CI]: −11.43 to −1.69) and improvements in SF-12 mental (mean difference: 6.01; 95% CI: 0.57 to 11.45) and physical (mean difference: 6.65; 95% CI: 2.14 to 11.16) health summary scores. At 12 weeks, the proportion of subjects experiencing substantial impairment according to cutoff values in the BSI-18, SF-12 physical, HIT-6, and headache days per month was significantly lower in the H3-L6 group. Dietary manipulation of n-3 and n-6 fatty acids, previously shown to produce major improvements in headache, was found to also reduce psychological distress and improve HRQOL and function.

Lipidomic Analysis of Oxidized Fatty Acids in Plant and Algae Oils

OBJECTIVE Several single-center studies have found raloxifene, an estrogen agonist, to be effective in ameliorating symptoms of schizophrenia in stable patients as augmentation of antipsychotics. This multicenter study assessed whether raloxifene plus antipsychotic treatment, in comparison to placebo plus antipsychotics, improves symptoms or cognition in severely ill decompensated schizophrenia patients. METHODS In this 16-week, double-blind, randomized, placebo-controlled study, 200 severely ill, decompensated postmenopausal women who met DSM-IV-TR criteria for schizophrenia or schizoaffective disorder were recruited from January 2011 to December 2012 and were randomized to receive either raloxifene 120 mg/d plus antipsychotics or placebo plus antipsychotics. The primary outcome measure was Positive and Negative Syndrome Scale (PANSS) total score at the end of the trial. RESULTS The placebo plus antipsychotics group experienced statistically significant improvement in PANSS total score (P < .001) compared to the raloxifene plus antipsychotics group, using mixed models for repeated measures, with results favoring placebo by 4.5 points (95% CI, 2.3-6.7). These results were clearly outside the 95% confidence interval. This negative effect was more pronounced in patients who had more frequent relapses and in those with baseline PANSS scores of 100 or higher. There were no differences between groups in Clinical Global Impression Scale-Severity scores or Composite Brief Assessment of Cognition in Schizophrenia scores at 16 weeks (P > .3). Baseline follicle-stimulating hormone and estradiol levels did not alter the drug-placebo differences. CONCLUSIONS Individuals in the active treatment arm showed worse outcome than those in the placebo arm, most likely as a result of chance variation, but the results unequivocally show no benefit of antipsychotics plus raloxifene versus antipsychotics plus placebo in this large randomized, double-blind, placebo-controlled trial in postmenopausal women. These data do not support the use of raloxifene in severely decompensated schizophrenia patients until reliable research identifies what subgroup of patients or domain of outcome is benefited. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01280305.