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Aspirin and omega-3 fatty acid status interact in the prevention of cardiovascular diseases in Framingham Heart Study.
Block, RC, Shearer, GC, Holub, A, Tu, XM, Mousa, S, Brenna, JT, Harris, WS, Tintle, N
Prostaglandins, leukotrienes, and essential fatty acids. 2021;:102283
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Abstract
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, <4.2%) in those who did not take aspirin (HR 0.54 (0.30, 0.98)), but in those reporting aspirin use, risk was significantly increased (HR 2.16 (1.19, 3.92)) in this quintile. This interaction remained significant when adjusting for confounders. Significant interactions were also present for coronary heart disease and stroke outcomes using the same quintiles. Similar findings were present for EPA and DHA alone but not for DPA and AA. CONCLUSIONS There is a complex interaction between aspirin use and RBC EPA+DHA levels on CVD outcomes. This suggests that aspirin use may be beneficial in one omega-3 environment but harmful in another, implying that a personalized approach to both aspirin use and omega-3 supplementation may be needed.
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Body surface area-based omega-3 fatty acids supplementation strongly correlates to blood concentrations in children.
Ljungblad, L, Gleissman, H, Hedberg, G, Wickström, M, Eissler, N, Pickova, J, Johnsen, JI, Tedroff, K, Strandvik, B, Kogner, P
Prostaglandins, leukotrienes, and essential fatty acids. 2021;:102285
Abstract
Omega-3 fatty acids have been suggested as a complement in cancer treatment, but doses are not established. We performed a dose-finding study in 33 children in remission from cancer. Participants were allocated to a body surface area (BSA) adjusted dose (mg/m2) of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (40:60), ranging 233-3448 mg/m2 daily for 90 days. Fatty acid concentration in plasma phospholipids and red blood cells were determined by GC. Supplementation was well tolerated and correlated strongly with blood ω3-fatty acid concentrations and EPA showed the highest increase. Using the ω3-index disregards docosapentaenoic acid (DPA), which increased 30-43% in our study motivating an EDD-index (∑EPA,DPA,DHA). The ratio between arachidonic acid and EPA or DHA showed negative exponential trends. Dose per BSA enabled an individualized omega-3 supplementation decreasing the variation referred to interindividual differences. Based on our results, we suggest a dose of 1500 mg/m2 BSA for further studies.
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Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Postmenopausal Women.
Fabian, CJ, Kimler, BF, Phillips, TA, Nydegger, JL, Kreutzjans, AL, Carlson, SE, Hidaka, BH, Metheny, T, Zalles, CM, Mills, GB, et al
Cancer prevention research (Philadelphia, Pa.). 2015;(10):922-31
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Abstract
Associational studies suggest higher intakes/blood levels of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) are associated with reduced breast cancer risk. We performed a pilot study of high-dose EPA + DHA in postmenopausal women to assess feasibility before initiating a phase IIB prevention trial. Postmenopausal women with cytologic evidence of hyperplasia in their baseline random periareolar fine needle aspiration (RPFNA) took 1,860 mg EPA +1500 mg DHA ethyl esters daily for 6 months. Blood and breast tissue were sampled at baseline and study conclusion for exploratory biomarker assessment, with P values uncorrected for multiple comparisons. Feasibility was predefined as 50% uptake, 80% completion, and 70% compliance. Trial uptake by 35 study entrants from 54 eligible women was 65%, with 97% completion and 97% compliance. Favorable modulation was suggested for serum adiponectin (P = 0.0027), TNFα (P = 0.016), HOMA 2B measure of pancreatic β cell function (P = 0.0048), and bioavailable estradiol (P = 0.039). Benign breast tissue Ki-67 (P = 0.036), macrophage chemoattractant protein-1 (P = 0.033), cytomorphology index score (P = 0.014), and percent mammographic density (P = 0.036) were decreased with favorable effects in a proteomics array for several proteins associated with mitogen signaling and cell-cycle arrest; but no obvious overall effect on proteins downstream of mTOR. Although favorable risk biomarker modulation will need to be confirmed in a placebo-controlled trial, we have demonstrated feasibility for development of high-dose EPA and DHA ethyl esters for primary prevention of breast cancer.
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Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a randomized, controlled, double-blind trial.
Dunbar, RL, Nicholls, SJ, Maki, KC, Roth, EM, Orloff, DG, Curcio, D, Johnson, J, Kling, D, Davidson, MH
Lipids in health and disease. 2015;:98
Abstract
BACKGROUND This study examined the effects of a mixture of highly bioavailable omega-3 carboxylic acids (OM3-CA) on nuclear magnetic resonance spectroscopy-assessed lipoprotein particle concentrations and sizes and other cardiovascular risk markers in statin-treated patients with fasting triglycerides (TG) ≥ 2.3 mmol/L (200 mg/dL) and <5.6 mmol/L (500 mg/dL) and at high cardiovascular risk. METHODS After a diet lead-in and statin-stabilization period, 647 patients were randomly assigned to receive capsules of control (olive oil, OO) 4 g/d, OM3-CA 2 g/d (plus OO 2 g/d), or OM3-CA 4 g/d for 6 weeks. RESULTS Compared with OO, low-density lipoprotein (LDL) particle size was increased with OM3-CA 2 g/d (p < 0.01) and 4 g/d (p < 0.001), and very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) particle sizes were decreased with both OM3-CA dosages vs. OO (p < 0.001 and p < 0.05 for VLDL and HDL, respectively). Total VLDL/chylomicron remnant particle concentration was reduced by 8.5 and 16.0 % with OM3-CA 2 and 4 g/d, respectively, vs. a 6.9 % reduction with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Total HDL particle concentration was also reduced by 1.5 and 3.2 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.6 % increase with OO (at least p < 0.05 for both comparisons). Changes in total LDL particle concentration were not significantly different for OO vs. OM3-CA at either dosage. Apolipoprotein (Apo) CIII levels decreased by 7.6 and 13.1 % with OM3-CA 2 and 4 g/d, respectively, vs. 3.2 % with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass was reduced by 6.2 and 10.7 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.1 % increase with OO (p < 0.001 for both vs. OO). There were no significant differences between treatments in high-sensitivity C-reactive protein responses. CONCLUSION OM3-CA were associated with shifts in lipoprotein particle sizes and concentrations, and reductions in Apo CIII and Lp-PLA2, in patients with hypertriglyceridemia while taking a statin. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT01408303.
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Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Premenopausal Women.
Fabian, CJ, Kimler, BF, Phillips, TA, Box, JA, Kreutzjans, AL, Carlson, SE, Hidaka, BH, Metheny, T, Zalles, CM, Mills, GB, et al
Cancer prevention research (Philadelphia, Pa.). 2015;(10):912-21
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Abstract
Higher intakes of the omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) have been variably associated with reduced risk of premenopausal breast cancer. The purpose of this pilot trial was to assess feasibility and explore the effects of high-dose EPA and DHA on blood and benign breast tissue risk biomarkers before design of a placebo-controlled phase IIB trial. Premenopausal women with evidence of hyperplasia ± atypia by baseline random periareolar fine needle aspiration were given 1860 mg of EPA + 1500 mg of DHA ethyl esters daily for 6 months. Blood and benign breast tissue were sampled during the same menstrual cycle phase prestudy and a median of 3 weeks after last dose. Additional blood was obtained within 24 hours of last dose. Feasibility, which was predefined as 50% uptake, 85% retention, and 70% compliance, was demonstrated with 46% uptake, 94% completion, and 85% compliance. Cytologic atypia decreased from 77% to 38% (P = 0.002), and Ki-67 from a median of 2.1% to 1.0% (P = 0.021) with an increase in the ratio of EPA + DHA to AA in erythrocyte phospholipids but no change in blood hormones, adipokines, or cytokines. Exploratory breast proteomics assessment showed decreases in several proteins involved in hormone and cytokine signaling with mixed effects on those in the AKT/mTOR pathways. Further investigation of EPA plus DHA for breast cancer prevention in a placebo-controlled trial in premenopausal women is warranted.
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Low levels of serum n-3 polyunsaturated fatty acids are associated with worse heart failure-free survival in patients after acute myocardial infarction.
Hara, M, Sakata, Y, Nakatani, D, Suna, S, Usami, M, Matsumoto, S, Hamasaki, T, Doi, Y, Nishino, M, Sato, H, et al
Circulation journal : official journal of the Japanese Circulation Society. 2013;(1):153-62
Abstract
BACKGROUND Intake of long-chain n-3 polyunsaturated fatty acids (n-3 PUFA), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), is associated with a lower risk of atherosclerotic cardiovascular events, particularly acute myocardial infarction (AMI). However, limited data are available regarding the association between serum n-3 PUFA levels and heart failure (HF) events in survivors of AMI. METHODS AND RESULTS We evaluated whether serum DHA and EPA levels were associated with HF-free survival and HF hospitalization rates after AMI. A total of 712 patients were divided into 3 groups according to their tertile serum levels of DHA and EPA (Low, Middle, and High). Propensity-score-stratified Cox regression analysis revealed that DHA- and EPA-Low groups presented statistically significant worse HF-free survival (hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.03-2.72, P=0.0358, and HR 1.69, 95% CI 1.05-2.72, P=0.0280, respectively), with the EPA-Low group having a higher risk of HF hospitalization (HR 2.40, 95% CI 1.21-4.75, P=0.0097) than the DHA-Low group (HR 1.72, 95% CI 0.86-3.45, P=0.1224). The relationship between a low DHA or EPA level and decreased HF-free survival was almost common to all subgroups; however, the effect of low serum EPA on HF hospitalization was prominent in male patients, and those with low levels of high-density lipoprotein cholesterol or without statin therapy. CONCLUSIONS Low levels of circulating n-3 PUFA are associated with decreased HF-free survival in post-AMI patients.