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Plasma Omega-3 Fatty Acids and the Risk of Cardiovascular Events in Patients After an Acute Coronary Syndrome in MERLIN-TIMI 36.
Zelniker, TA, Morrow, DA, Scirica, BM, Furtado, JD, Guo, J, Mozaffarian, D, Sabatine, MS, O'Donoghue, ML
Journal of the American Heart Association. 2021;(8):e017401
Abstract
Background Plasma omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been shown to be inversely correlated with the risk of cardiovascular death in primary prevention. The risk relationship in the setting of an acute coronary syndrome is less well established. Methods and Results Baseline plasma ω3-PUFA composition (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) was assessed through gas chromatography with flame ionization detection in a case-cohort study involving 203 patients with cardiovascular death, 325 with myocardial infarction, 271 with ventricular tachycardia, and 161 with atrial fibrillation, and a random sample of 1612 event-free subjects as controls from MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation-Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36), a trial of patients hospitalized with non-ST-segment-elevation -acute coronary syndrome. After inverse-probability-weighted multivariable adjustment including all traditional risk factors, a higher relative proportion of long-chain ω3-PUFAs (eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid) were associated with 18% lower odds of cardiovascular death (adjusted [adj] odds ratio [OR] per 1 SD, 0.82; 95% CI, 0.68-0.98) that was primarily driven by 27% lower odds of sudden cardiac death (adj OR per 1 SD, 0.73; 95% CI, 0.55-0.97). Long-chain ω3-PUFA levels in the top quartile were associated with 51% lower odds of cardiovascular death (adj OR 0.49; 95% CI, 0.27-0.86) and 63% lower odds of sudden cardiac death (adj OR, 0.37; 95% CI, 0.16-0.56). An attenuated relationship was seen for α-linolenic acid and subsequent odds of cardiovascular (adj OR, 0.92; 95% CI, 0.74-1.14) and sudden cardiac death (adj OR, 0.91; 95% CI, 0.67-1.25). No significant relationship was observed between any ω3-PUFAs and the odds of cardiovascular death unrelated to sudden cardiac death, myocardial infarction, atrial fibrillation, or early post-acute coronary syndrome ventricular tachycardia. Conclusions In patients after non-ST-segment-elevation-acute coronary syndrome, plasma long-chain ω3-PUFAs are inversely associated with lower odds of sudden cardiac death, independent of traditional risk factors and lipids. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00099788.
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Dietary supplementation with omega-3 fatty acids and oleate enhances exercise training effects in patients with metabolic syndrome.
Ortega, JF, Morales-Palomo, F, Fernandez-Elias, V, Hamouti, N, Bernardo, FJ, Martin-Doimeadios, RC, Nelson, RK, Horowitz, JF, Mora-Rodriguez, R
Obesity (Silver Spring, Md.). 2016;(8):1704-11
Abstract
OBJECTIVE We studied the effects of exercise training alone or combined with dietary supplementation of omega-3 polyunsaturated fatty acids (Ω-3PUFA) and oleate on metabolic syndrome (MSyn) components and other markers of cardiometabolic health. METHODS Thirty-six patients with MSyn underwent 24 weeks of high-intensity interval training. In a double-blind randomized design, half of the group ingested 500 mL/day of semi-skim milk (8 g of fat; placebo milk) whereas the other half ingested 500 mL/day of skim milk enriched with 275 mg of Ω-3PUFA and 7.5 g of oleate (Ω-3 + OLE). RESULTS Ω-3 + OLE treatment elevated 30% plasma Ω-3PUFA but not significantly (P = 0.286). Improvements in VO2peak (12.8%), mean blood pressure (-7.1%), waist circumference (-1.8%), body fat mass (-2.9%), and trunk fat mass (-3.3%) were similar between groups. However, insulin sensitivity (measured by intravenous glucose tolerance test), serum concentration of C-reactive protein, and high-density lipoprotein improved only in the Ω-3 + OLE group by 31.5%, 32.1%, and 10.3%, respectively (all P < 0.05). Fasting serum triacylglycerol, glucose, and plasma fibrinogen concentrations did not improve in either group after 24 weeks of intervention. CONCLUSIONS Diet supplementation with Ω-3PUFA and oleate enhanced cardiometabolic benefits of intense aerobic exercise training in patients with MSyn.
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Insulin resistance determines a differential response to changes in dietary fat modification on metabolic syndrome risk factors: the LIPGENE study.
Yubero-Serrano, EM, Delgado-Lista, J, Tierney, AC, Perez-Martinez, P, Garcia-Rios, A, Alcala-Diaz, JF, Castaño, JP, Tinahones, FJ, Drevon, CA, Defoort, C, et al
The American journal of clinical nutrition. 2015;(6):1509-17
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Abstract
BACKGROUND Previous data support the benefits of reducing dietary saturated fatty acids (SFAs) on insulin resistance (IR) and other metabolic risk factors. However, whether the IR status of those suffering from metabolic syndrome (MetS) affects this response is not established. OBJECTIVE Our objective was to determine whether the degree of IR influences the effect of substituting high-saturated fatty acid (HSFA) diets by isoenergetic alterations in the quality and quantity of dietary fat on MetS risk factors. DESIGN In this single-blind, parallel, controlled, dietary intervention study, MetS subjects (n = 472) from 8 European countries classified by different IR levels according to homeostasis model assessment of insulin resistance (HOMA-IR) were randomly assigned to 4 diets: an HSFA diet; a high-monounsaturated fatty acid (HMUFA) diet; a low-fat, high-complex carbohydrate (LFHCC) diet supplemented with long-chain n-3 polyunsaturated fatty acids (1.2 g/d); or an LFHCC diet supplemented with placebo for 12 wk (control). Anthropometric, lipid, inflammatory, and IR markers were determined. RESULTS Insulin-resistant MetS subjects with the highest HOMA-IR improved IR, with reduced insulin and HOMA-IR concentrations after consumption of the HMUFA and LFHCC n-3 diets (P < 0.05). In contrast, subjects with lower HOMA-IR showed reduced body mass index and waist circumference after consumption of the LFHCC control and LFHCC n-3 diets and increased HDL cholesterol concentrations after consumption of the HMUFA and HSFA diets (P < 0.05). MetS subjects with a low to medium HOMA-IR exhibited reduced blood pressure, triglyceride, and LDL cholesterol levels after the LFHCC n-3 diet and increased apolipoprotein A-I concentrations after consumption of the HMUFA and HSFA diets (all P < 0.05). CONCLUSIONS Insulin-resistant MetS subjects with more metabolic complications responded differently to dietary fat modification, being more susceptible to a health effect from the substitution of SFAs in the HMUFA and LFHCC n-3 diets. Conversely, MetS subjects without IR may be more sensitive to the detrimental effects of HSFA intake. The metabolic phenotype of subjects clearly determines response to the quantity and quality of dietary fat on MetS risk factors, which suggests that targeted and personalized dietary therapies may be of value for its different metabolic features. This study was registered at clinicaltrials.gov as NCT00429195.
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The effects of vitamin E and omega-3 PUFAs on endothelial function among adolescents with metabolic syndrome.
Ahmadi, A, Gharipour, M, Arabzadeh, G, Moin, P, Hashemipour, M, Kelishadi, R
BioMed research international. 2014;:906019
Abstract
AIM: The present study aims to explore the effects of vitamin E and omega-3 on endothelial function indicators among adolescents with metabolic syndrome. METHOD In a randomized, double blind, and placebo-controlled trial, 90 young individuals, aged 10 to 18 years, with metabolic syndrome were randomly assigned to receive either vitamin E tablets (400 IU/day) or omega-3 tablets (2.4 gr/day) or placebo. For assessing endothelial functional state, the serum level of vascular endothelial growth factor (VEGF) was measured by ELISA test. RESULTS The use of omega-3 supplementation for eight weeks led to significant increase in serum HDL level compared with the group treated with vitamin E or placebo group. In this regard, no significant correlations were found between the change in VEGF and baseline levels of other markers including anthropometric indices and serum lipids. Omega-3 could significantly reduce VEGF with the presence of other baseline variables (Beta = -12.55; P = 0.012). CONCLUSION The administration of omega-3 can effectively improve endothelial function in adolescents with metabolic syndrome by reducing the level of serum VEGF, as a major index for atherosclerosis progression and endothelial destabilization. Omega-3 can be proposed as a VEGF antagonist for improving endothelial function in metabolic syndrome. The clinical implications of our findings should be assessed in future studies.
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A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia.
Bentsen, H, Osnes, K, Refsum, H, Solberg, DK, Bøhmer, T
Translational psychiatry. 2013;(12):e335
Abstract
Membrane lipid metabolism and redox regulation may be disturbed in schizophrenia. We examined the clinical effect of adding an omega-3 fatty acid and/or vitamins E+C to antipsychotics. It was hypothesized that lower baseline levels of polyunsaturated fatty acids (PUFAs) would predict more benefit from the add-on treatment. The trial had a multicenter, randomized, double-blind, placebo-controlled 2 × 2 factorial design. Patients aged 18-39 years with schizophrenia or related psychoses were consecutively included at admission to psychiatric departments in Norway. They received active or placebo ethyl-eicosapentaenoate (EPA) 2 g day⁻¹ and active or placebo vitamin E 364 mg day⁻¹+vitamin C 1000 mg day⁻¹ (vitamins) for 16 weeks. The main outcome measures were Positive and Negative Syndrome Scale (PANSS) total and subscales scores, analyzed by linear mixed models. Ninety-nine patients were included. At baseline, erythrocyte PUFA were measured in 97 subjects. Given separately, EPA and vitamins increased drop-out rates, whereas when combined they did not differ from placebo. In low PUFA patients, EPA alone impaired the course of total PANSS (Cohen's d=0.29; P=0.03) and psychotic symptoms (d=0.40; P=0.003), especially persecutory delusions (d=0.48; P=0.0004). Vitamins alone impaired the course of psychotic symptoms (d= 0.37; P=0.005), especially persecutory delusions (d=0.47; P=0.0005). Adding vitamins to EPA neutralized the detrimental effect on psychosis (interaction d=0.31; P=0.02). In high PUFA patients, there were no significant effects of trial drugs on PANSS scales. In conclusion, given separately during an acute episode, EPA and vitamins E+C induce psychotic symptoms in patients with low levels of PUFA. Combined, these agents seem safe.
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Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome.
Mohammadi, E, Rafraf, M, Farzadi, L, Asghari-Jafarabadi, M, Sabour, S
Asia Pacific journal of clinical nutrition. 2012;(4):511-8
Abstract
OBJECTIVE Polycystic ovary syndrome (PCOS) is a common female endocrine disorder associated with several risk factors of type 2 diabetes and cardiovascular diseases. The objectives of this study were to investigate the effects of omega-3 fatty acids on serum adiponectin levels and some metabolic risk factors in PCOS patients. METHODS This double-blind randomized controlled clinical trial was conducted on 64 overweight or obese PCOS patients; aged 20-35 years. Subjects in omega-3 fatty acids (n=32) and placebo (n=32) groups were given 4 omega- 3 fatty acids capsules (each one contained 180 mg eicosapentaenoic acid and 120 mg docosahexanoic acid) or placebo daily for 8 weeks. Fasting blood samples, anthropometric measurements and 3-day, 24-hour dietary recalls were collected at the baseline and at the end of the trial. RESULTS The study was completed by 61 subjects. Omega-3 fatty acids significantly increased serum levels of adiponectin (p=0.003) and decreased glucose (p<0.001), insulin (p=0.002), homeostatic model assessment for insulin resistance (p<0.001), total cholesterol (p=0.002) and low-density lipoprotein cholesterol (p=0.003) compared with placebo. Serum levels of triglyceride significantly decreased (p=0.024) and high-density lipoprotein cholesterol increased (p=0.018) in the omega-3 fatty acids group, in comparison with baseline values. No significant changes were shown in serum high sensitive C-reactive protein (hs-CRP) levels in both groups. CONCLUSION Omega-3 fatty acids had some beneficial effects on serum adiponectin levels, insulin resistance and lipid profile in PCOS patients and may contribute to the improvement of metabolic complications in these patients.
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Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial.
Shearer, GC, Pottala, JV, Hansen, SN, Brandenburg, V, Harris, WS
Journal of lipid research. 2012;(11):2429-35
Abstract
The metabolic syndrome includes both dyslipidemia and impaired vascular function. Because extended-release niacin (ERN) and prescription omega-3 acid ethyl-esters (P-OM3) independently improve these characteristics, we tested their effects in combination. Sixty metabolic syndrome subjects were randomized to 16 weeks of treatment on dual placebo, P-OM3 (4 g/day), ERN (2 g/day), or combination in a double-blind trial. Lipoprotein subfractions and vascular endpoints were measured and tested using ANCOVA. ERN increased HDL cholesterol by 5.4 mg/dl from baseline (P = 0.04), decreased triglycerides (TG) by 39 mg/dl (-21%, P = 0.003), and decreased the augmentation index, which is a measure of vascular stiffness, by 3.5 units (P = 0.04). P-OM3 reduced TG by 26 mg/dl (-13%, P = 0.04). Combination treatment increased HDL cholesterol by 7.8 mg/dl (P = 002) and decreased TG by 72 mg/dl (-34%) but there was no improvement in vascular stiffness. Detailed analysis of lipoprotein subfractions revealed increased large, bouyant HDL(2) (3.3 mg/dl; P = 0.002) and decreased VLDL(1+2) (-32%; P < 0.0001), among subjects treated with combination therapy, that were not present with either therapy alone. ERN and P-OM3 alone improved characteristics of metabolic syndrome; however, whereas subjects on combination therapy did not have improved vascular stiffness, TG and HDL levels improved as did certain lipoprotein subfractions.
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Transcriptomic coordination in the human metabolic network reveals links between n-3 fat intake, adipose tissue gene expression and metabolic health.
Morine, MJ, Tierney, AC, van Ommen, B, Daniel, H, Toomey, S, Gjelstad, IM, Gormley, IC, Pérez-Martinez, P, Drevon, CA, López-Miranda, J, et al
PLoS computational biology. 2011;(11):e1002223
Abstract
Understanding the molecular link between diet and health is a key goal in nutritional systems biology. As an alternative to pathway analysis, we have developed a joint multivariate and network-based approach to analysis of a dataset of habitual dietary records, adipose tissue transcriptomics and comprehensive plasma marker profiles from human volunteers with the Metabolic Syndrome. With this approach we identified prominent co-expressed sub-networks in the global metabolic network, which showed correlated expression with habitual n-3 PUFA intake and urinary levels of the oxidative stress marker 8-iso-PGF(2α). These sub-networks illustrated inherent cross-talk between distinct metabolic pathways, such as between triglyceride metabolism and production of lipid signalling molecules. In a parallel promoter analysis, we identified several adipogenic transcription factors as potential transcriptional regulators associated with habitual n-3 PUFA intake. Our results illustrate advantages of network-based analysis, and generate novel hypotheses on the transcriptomic link between habitual n-3 PUFA intake, adipose tissue function and oxidative stress.
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Low omega-6 vs. low omega-6 plus high omega-3 dietary intervention for chronic daily headache: protocol for a randomized clinical trial.
Ramsden, CE, Mann, JD, Faurot, KR, Lynch, C, Imam, ST, MacIntosh, BA, Hibbeln, JR, Loewke, J, Smith, S, Coble, R, et al
Trials. 2011;:97
Abstract
BACKGROUND Targeted analgesic dietary interventions are a promising strategy for alleviating pain and improving quality of life in patients with persistent pain syndromes, such as chronic daily headache (CDH). High intakes of the omega-6 (n-6) polyunsaturated fatty acids (PUFAs), linoleic acid (LA) and arachidonic acid (AA) may promote physical pain by increasing the abundance, and subsequent metabolism, of LA and AA in immune and nervous system tissues. Here we describe methodology for an ongoing randomized clinical trial comparing the metabolic and clinical effects of a low n-6, average n-3 PUFA diet, to the effects of a low n-6 plus high n-3 PUFA diet, in patients with CDH. Our primary aim is to determine if: A) both diets reduce n-6 PUFAs in plasma and erythrocyte lipid pools, compared to baseline; and B) the low n-6 plus high n-3 diet produces a greater decline in n-6 PUFAs, compared to the low n-6 diet alone. Secondary clinical outcomes include headache-specific quality-of-life, and headache frequency and intensity. METHODS Adults meeting the International Classification of Headache Disorders criteria for CDH are included. After a 6-week baseline phase, participants are randomized to a low n-6 diet, or a low n-6 plus high n-3 diet, for 12 weeks. Foods meeting nutrient intake targets are provided for 2 meals and 2 snacks per day. A research dietitian provides intensive dietary counseling at 2-week intervals. Web-based intervention materials complement dietitian advice. Blood and clinical outcome data are collected every 4 weeks. RESULTS Subject recruitment and retention has been excellent; 35 of 40 randomized participants completed the 12-week intervention. Preliminary blinded analysis of composite data from the first 20 participants found significant reductions in erythrocyte n-6 LA, AA and %n-6 in HUFA, and increases in n-3 EPA, DHA and the omega-3 index, indicating adherence. TRIAL REGISTRATION ClinicalTrials.gov (NCT01157208).
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Acute ingestion of long-chain (n-3) polyunsaturated fatty acids decreases fibrinolysis in men with metabolic syndrome.
Montegaard, C, Tulk, HM, Lauritzen, L, Tholstrup, T, Robinson, LE
The Journal of nutrition. 2010;(1):38-43
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Abstract
Individuals with metabolic syndrome (MetS) often have elevated plasma plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA), contributing to an increased risk of cardiovascular disease. PAI-1 and t-PA may be affected by chronic (n-3) long-chain PUFA [(n-3)LCPUFA] supplementation; however, the acute impact of fat ingestion on these risk factors has not been established. Our objective was to investigate the acute effect of (n-3)LCPUFA on plasma PAI-1, t-PA, and platelet aggregation. We conducted a randomized crossover study in which men (n = 8, > or =45 y) with MetS consumed water or a high-saturated fat beverage (1 g fat/kg body weight) with either a high or low content of (n-3)LCPUFA. Blood samples were collected over 8 h to measure triacylglycerol (TAG), PAI-1, t-PA, and platelet aggregation. Both fat loads resulted in a significant increase in whole blood TAG concentration, plasma PAI-1 and t-PA concentrations, and PAI-1 activity, as well as a significant decrease in t-PA activity during the postprandial period. Interestingly, PAI-1 concentration and activity increased more following the high (n-3)LCPUFA compared with the low (n-3)LCPUFA beverage (P < 0.05). Furthermore, the high (n-3)LCPUFA beverage resulted in a lower t-PA activity (P < 0.05), whereas the effects of the 2 fat loads on the plasma t-PA concentration and platelet aggregation did not differ. Overall, acute intake of a high (n-3)LCPUFA beverage shifted the balance between plasma PAI-1 and t-PA, which might indicate a lower capacity for fibrinolysis.