High-dose Eicosapentaenoic Acid Research Articles

Omega-3 polyunsaturated fatty acids in depression: insights from recent clinical trials

Purpose of review This review examines evidence from recent clinical trials on the therapeutic potential of omega-3 polyunsaturated fatty acids (PUFAs) in major depressive disorder (MDD). We focus on the effects in MDD with comorbidities, younger populations, and high-inflammation presentations. Recent findings PubMed, Cochrane, and Embase databases were systematically searched for studies published between May 2022 and May 2024. The search was conducted on randomized controlled trials using omega-3 PUFAs with participants with a clinical diagnosis of depression. Higher doses of eicosapentaenoic acid (EPA) (>1 g/day) improved measures of depression, particularly in MDD with elevated inflammation markers, comorbid cardiovascular diseases, late-life onset, and children and adolescent populations. Improvements in depressive symptoms were associated with increases in omega-3 PUFA-derived anti-inflammatory and proresolving lipid mediators. As adjuvant treatments, omega-3 PUFAs have potential benefits in mood, cognitive and metabolic functions, kynurenine and serotonin pathways, and alterations in corticolimbic functional connectivity. Summary While evidence suggests promise, particularly for high-dose EPA and in inflammatory MDD subtypes, more research is needed to establish optimal dosing regimens, treatment duration, and patient subgroups most likely to benefit. Future studies should focus on sex differences, long-term effects, and potential synergies with other treatments.

A 12-week randomized double-blind clinical trial of eicosapentaenoic acid intervention in episodic migraine

Omega-3 polyunsaturated fatty acids (PUFAs) may benefit migraine improvement, though prior studies are inconclusive. This study evaluated the effect of eicosapentaenoic acid (EPA) on episodic migraine (EM) prevention. Seventy individuals with EM participated in a 12-week randomized, double-blind, placebo-controlled trial from March 2020 and May 2022. They were randomly assigned to either the EPA (N = 35, 2 g fish oil with 1.8 g of EPA as a stand-alone treatment daily), or the placebo group (N = 35, 2 g soybean oil daily). Migraine frequency and headache severity were assessed using the monthly migraine days, visual analog scale (VAS), Migraine Disability Assessment (MIDAS), Hospital Anxiety and Depression Scale (HADS), Migraine-Specific Quality-of-Life Questionnaire (MSQ), and Pittsburgh Sleep Quality Index (PSQI) in comparison to baseline measurements. The EPA group significantly outperformed the placebo in reducing monthly migraine days (−4.4 ± 5.1 days vs. − 0.6 ± 3.5 days, p = 0.001), days using acute headache medication (−1.3 ± 3.0 days vs. 0.1 ± 2.3 days, p = 0.035), improving scores for headache severity (ΔVAS score: −1.3 ± 2.4 vs. 0.0 ± 2.2, p = 0.030), disability (ΔMIDAS score: −13.1 ± 16.2 vs. 2.6 ± 20.2, p = 0.001), anxiety and depression (ΔHADS score: −3.9 ± 9.4 vs. 1.1 ± 9.1, p = 0.025), and quality of life (ΔMSQ score: −11.4 ± 19.0 vs. 3.1 ± 24.6, p = 0.007). Notably, female particularly benefited from EPA, underscoring its potential in migraine management. In conclusion, high-dose EPA has significantly reduced migraine frequency and severity, improved psychological symptoms and quality of life in EM patients, and shown no major adverse events, suggesting its potential as a prophylactic for EM.

Eicosapentaenoic and docosahexaenoic acid supplementation and coronary artery calcium progression in patients with coronary artery disease: A secondary analysis of a randomized trial

Background and aimsWe previously reported that an omega-3 fatty acid index ≥4% with high-dose eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) prevented progression of noncalcified plaque. Higher coronary artery calcium (CAC) scores and progression of CAC are associated with increased cardiovascular events and mortality. We examined the effect of EPA + DHA on CAC score. MethodsA total of 242 patients with coronary artery disease (CAD) on statin therapy were randomized to 1.86 g EPA and 1.5 g DHA daily or none (control) for 30 months. The CAC score was measured at baseline and 30-months with non-contrast, cardiac computed tomography. ResultsBoth EPA + DHA and control groups had significant progression in CAC scores over 30 months (median change:183.5 vs 221.0, respectively, p < 0.001) despite a 13.6% reduction in triglyceride level with EPA + DHA. No significant difference was observed between groups for the total group, by baseline CAC scores of <100, 100–399, 400–999 and ≥1000 or quartiles of achieved levels of EPA, DHA and the omega-3 fatty acid index. Similar rates of CAC progression were noted in those on high-intensity statin compared to low- and moderate-intensity statin. ConclusionsEPA and DHA added to statin resulted in similar CAC progression over 30 months regardless of baseline CAC categories, statin intensity and achieved levels of EPA, DHA and the omega-3 fatty acid index.

Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events.

Long-chain omega-3 polyunsaturated fatty acids (OM3 PUFA) are commonly used for cardiovascular disease prevention. High-dose eicosapentaenoic acid (EPA) is reported to reduce major adverse cardiovascular events (MACE); however, a combined EPA and docosahexaenoic acid (DHA) supplementation has not been proven to do so. This study aimed to evaluate the potential interaction between EPA and DHA levels on long-term MACE. We studied a cohort of 987 randomly selected subjects enrolled in the INSPIRE biobank registry who underwent coronary angiography. We used rapid throughput liquid chromatography-mass spectrometry to quantify the EPA and DHA plasma levels and examined their impact unadjusted, adjusted for one another, and fully adjusted for comorbidities, EPA + DHA, and the EPA/DHA ratio on long-term (10-year) MACE (all-cause death, myocardial infarction, stroke, heart failure hospitalization). The average subject age was 61.5 ± 12.2 years, 57% were male, 41% were obese, 42% had severe coronary artery disease (CAD), and 311 (31.5%) had a MACE. The 10-year MACE unadjusted hazard ratio (HR) for the highest (fourth) vs. lowest (first) quartile (Q) of EPA was HR = 0.48 (95% CI: 0.35, 0.67). The adjustment for DHA changed the HR to 0.30 (CI: 0.19, 0.49), and an additional adjustment for baseline differences changed the HR to 0.36 (CI: 0.22, 0.58). Conversely, unadjusted DHA did not significantly predict MACE, but adjustment for EPA resulted in a 1.81-fold higher risk of MACE (CI: 1.14, 2.90) for Q4 vs. Q1. However, after the adjustment for baseline differences, the risk of MACE was not significant for DHA (HR = 1.37; CI: 0.85, 2.20). An EPA/DHA ratio ≥1 resulted in a lower rate of 10-year MACE outcomes (27% vs. 37%, adjusted p-value = 0.013). Higher levels of EPA, but not DHA, are associated with a lower risk of MACE. When combined with EPA, higher DHA blunts the benefit of EPA and is associated with a higher risk of MACE in the presence of low EPA. These findings can help explain the discrepant results of EPA-only and EPA/DHA mixed clinical supplementation trials.

Eicosapentaenoic acid supplementation modulates the osteoblast/osteoclast balance in inflammatory environments and protects against estrogen deficiency-induced bone loss in mice

An imbalance of osteoblasts (OBs) and osteoclasts (OCs) in a chronic inflammatory microenvironment is an important pathological factor leading to osteoporosis. Eicosapentaenoic acid (EPA) has been shown to suppress inflammation in macrophages and adipocytes. However, the effect of EPA on OBs and OCs has yet to be fully elucidated. We explored the roles of EPA in the differentiation of OBs and OCs, as well as the coupling between OBs and OCs in an inflammatory microenvironment. The effects of EPA on estrogen deficiency-induced osteoporosis were also evaluated. Mouse bone marrow mesenchymal stem cells (mBMSCs) and mouse bone marrow-derived macrophages (mBMMs) were used for invitro OBs and OCs differentiation. TNF-α was used to create an inflammatory microenvironment. We examined the effects of EPA on osteoblastogenesis in the absence or presence of TNF-α and collect OBs' culture medium as the conditioned medium (CM). Then we examined the effects of EPA and CM on RANKL-induced osteoclastogenesis. The invivo effects of EPA were determined using an ovariectomized (OVX) mouse model treated with EPA or vehicle. High-dose EPA was shown to promote osteoblastogenesis in an inflammatory environment invitro, as well as upregulate expression of OBs-specific proteins and genes. ARS and ALP staining also showed that high-dose EPA-treated groups restored mBMSCs' impaired osteogenic capacity caused by TNFa. Mechanistically, EPA suppressed the NF-κB pathway activated by TNF-α in mBMSCs and rescued TNF-α-mediated inhibition of osteoblastogenesis. EPA was also shown to inhibit expression of RANKL and decrease the RANKL/OPG ratio in OBs in an inflammatory environment. CM from TNF-α-stimulated OBs promoted osteoclastogenesis of mBMMs; EPA-treated CM prevented this. In the OVX mouse model, EPA supplementation prevented bone loss in an estrogen deficiency-induced inflammatory environment. EPA was demonstrated for the first time to restore mBMSCs' impaired osteogenic capacity caused by TNFa-induced inflammation and rescue the OBs/OCs balance via regulation of RANKL and OPG expression in OBs. EPA showed a remarkable ability to prevent bone loss in OVX mice, suggesting a potential application of EPA in postmenopausal osteoporosis.

Indications for omega-3 fatty acid supplementation in prevention of cardiovascular disease: From fish to pharmaceuticals.

To explore the evidence for omega-3 fatty acid (O3FA) supplementation in primary and secondary prevention of cardiovascular disease (CVD). PubMed, Cochrane reviews, and Google Scholar were searched for meta-analyses and reviews related to O3FAs and CVD. Salient, recent randomized controlled trials referenced in these reviews were retrieved. Current lipid guidelines were reviewed. Most O3FAs are derived from marine or aquatic microalgae, which are consumed by fish. The essential fatty acids eicosapentaenoic acid and docosahexaenoic acid are mainly sourced from fish, with a small fraction coming from plants. Omega-3 fatty acids modestly lower triglyceride levels, but the major impact on CVD is through a variety of other mechanisms related to cell membrane function, antioxidant properties, and reduction of atherogenic small low-density lipoprotein cholesterol particles. Guidelines continue to recommend eating 2 servings of fish per week. There is little evidence of benefit of O3FAs in primary prevention of CVD. Given that 40% of Canadians have insufficient levels and that these low levels may be associated with other chronic diseases over time, supplementation with O3FAs could be considered, particularly in those with hypertriglyceridemia, in those who eat no fish, or for vegetarians or vegans. Doses up to 1 g daily are considered safe. For secondary prevention after statin optimization, if triglyceride levels are between 1.5 and 5.6 mmol/L, guidelines recommend with level 1A evidence taking 2 g of icosapent ethyl twice a day. This is also recommended in primary prevention for patients with diabetes and hypertriglyceridemia and additional CVD risk factors. As fish stocks dwindle over time, preserving fisheries for developing countries and obtaining O3FA from microalgal or genetically modified plant sources may become important. All guidelines recommend at least 2 servings of oily fish per week, although benefit from O3FAs is mostly seen in secondary prevention. Fish oil and combination preparations of eicosapentaenoic acid and docosahexaenoic acid have failed to show benefit at any dose at any level of prevention in patients who are appropriately prescribed statins. High-dose eicosapentaenoic acid shows substantial benefit in selected patients taking statins who have high triglyceride levels.

Abstract 11150: The Effect of Eicosapentaenoic Acid and Docosahexaenoic Acid on Neutrophil/Lymphocyte Ratio, a Marker of Inflammation, in Subjects With Coronary Artery Disease: Results of a Randomized Trial

Background: The neutrophil/lymphocyte (N/L) ratio increases with the systemic inflammatory response due to an increase in neutrophils and decrease in lymphocytes with systemic inflammation. An elevated N/L ratio has been associated with an increased risk of cardiovascular disease (CVD), cancer and mortality. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease levels of high sensitivity C-reactive protein (hs-CRP), the gold standard inflammatory marker, when levels of hs-CRP are elevated. Randomized trials have also reported a decrease in CVD events with EPA. The mechanism for this benefit is unclear. Objective: To examine the effect of high-dose EPA and DHA supplementation on inflammation as measured by the N/L ratio in the setting of low levels of hs-CRP. Methods: A total of 242 subjects with stable coronary artery disease on statin treatment were randomized to 3.36 g EPA+DHA daily or none. N/L ratio and the monocyte to lymphocyte (M/L) ratio were measured at baseline and 1 year. Results: Mean (SD) age was 63.1 years (7.7); mean (SD) LDL-C: 77.8 mg/dL (27.3); median [IQR] TG: 117.5 mg/dL [81.3,166.8] and median [IQR] hs-CRP: 0.75 mg/L [0.40,2.5]. Those on EPA+DHA had a 2.2% reduction in N/L ratio (P=0.014) at 1 year compared to those not on EPA+DHA who had a 12.2% increase (Figure) (between group P= 0.007). There was a trend toward benefit with the M/L ratio (P=0.078). Conclusion: High-dose EPA+DHA decreases systemic inflammation as reflected in the N/L ratio even with low hs-CRP levels. This is a new finding which suggests that under conditions of generally low levels of inflammation in terms of hs-CRP levels, the N/L ratio may be a more sensitive measure of underlying inflammation than hs-CRP and should be considered as an additional marker in future studies of omega-3 fatty acids. If a decrease in inflammation by N/L ratio were accompanied by a clinical decrease in CVD events, this would assist in determining a plausible mechanism of action.

Recent Updates in Hypertriglyceridemia Management for Cardiovascular Disease Prevention.

Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia. The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefit on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors.

Effect of Omega-3 Fatty Acids on Coronary Plaque Morphology - A Serial Computed Tomography Angiography Study.

Omega-3 fatty acids have been proposed to be useful in the prevention of cardiac events. High-risk plaque (HRP) and plaque progression on serial coronary computed tomography angiography (CTA) have been suggested to be the predecessor of acute coronary syndrome (ACS). The purpose of this study was to investigate whether addition of omega-3 fatty acids to statin therapy for secondary prevention would lead to change in plaque characteristics detected by using serial CTA. This study enrolled 210 patients with ACS: no eicosapentaenoic acid (EPA)/ docosahexaenoic acid (DHA; EPA/DHA), low-dose EPA+DHA, high-dose EPA+DHA, and high-dose EPA alone. HRP was significantly more frequent in patients with plaque progression (P=0.0001). There was a significant interaction between plaque progression and EPA dose regardless of the DHA dose; 20.3% in EPA-none (no EPA/DHA), 15.7% in EPA-low (low-dose EPA+DHA), and 5.6% in EPA-high (high-dose EPA+DHA and high-dose EPA alone). On multivariate logistic regression analysis, HRP (OR 6.44, P<0.0001), EPA-high (OR 0.13, P=0.0004), and Rosvastatin (OR 0.24, P=0.0079) were the independent predictors for plaque progression. In quantitative analyses (n=563 plaques), the interval change of low attenuation plaque (LAP) volume was significantly different based on EPA dose; LAP was significantly increased in the EPA-none group and significantly decreased in the EPA-high group. In patients with ACS, addition of high-dose EPA (EPA-high) to statin therapy, compared to statin therapy without EPA, was associated with a lower rate of plaque progression.

WITHDRAWN: Differential Effects of Omega-3 Fatty Acids on HO-1, VCAM-1, and Cytotoxicity in Endothelial Cells

<h2>ABSTRACT</h2><h3>Introduction</h3> : Omega-3-fatty acids are considered to have beneficial effects on the initiation and progression of atherosclerosis beyond lowering blood lipids. Clinical trials demonstrated that treatment with high-dose eicosapentaenoic acid (EPA) reduced the incidence of cardiovascular events in at-risk patients, yet not with an EPA and docosahexaenoic acid (DHA) combination treatment. <h3>Objectives</h3> : This <i>in-vitro</i> experiment evaluates molecular mechanisms for the observed differential pleiotropic cardioprotective effects of DHA and EPA on endothelial cells. <h3>Materials and Methods</h3> : Human umbilical vein endothelial cells (HUVEC) were stimulated with 25 ng/ml tumor necrosis factor alpha (TNF-α) and (pre-)treated with 125 µmol/l DHA or EPA. Vascular cell adhesion molecule-1 (VCAM-1) and hemoxygenase-1 (HO-1) mRNA fold change were measured in HUVEC. HUVEC cell viability was determined by MTT assay. <h3>Results</h3> : Pre-treating HUVEC with 125 μmol/l EPA 24 hours before the TNF-α stimulus significantly reduced VCAM-1 mRNA expression by -17.5% (<i>p</i>=.011), yet not DHA (+7.4%, <i>p</i>=.060). Treating HUVEC at the time of the TNF-α stimulus lowered VCAM-1 expression by -22.8% for DHA and -56.7% for EPA (<i>p</i>=.002). Treating HUVEC simultaneous to the TNF-α stimulus increased HO-1 expression for DHA (+571.4%, <i>p</i>=.007) and EPA (+581.4%, <i>p</i>=.003). Repeated treatment of HUVEC with DHA or EPA further reduced VCAM-1 expression, whilst HO-1 expression surged by +3,133.4% for DHA and +919.1% for EPA (<i>p</i>=.002). MTT assays displayed DHA and EPA were cytotoxic on HUVEC beyond concentrations of 250 µmol/l. <h3>Conclusions</h3> : (Pre-)treatment of HUVEC with EPA reduces VCAM-1 expression, which is known to impact the initiation and progression of arteriosclerosis, to a greater extent than DHA. In contrast, DHA displays a greater effect on HO-1 expression than EPA. These results offer potential molecular mechanisms for the clinically observed different pleiotropic effects in cardiometabolic treatment of omega-3 fatty acids.

New targets for treating hypertriglyceridemia.

Elevated fasting and postprandial plasma triglyceride concentrations are associated with an increased risk for atherosclerotic cardiovascular disease in patients on and off low-density lipoprotein (LDL) lowering therapy. This association is not mediated by triglycerides directly. Other components of triglyceride rich lipoproteins, such as cholesterol and apolipoproteins B and -CIII can directly induce and enhance atherosclerosis. In addition, an elevated concentration of triglyceride rich lipoproteins affects the concentration, composition, function, and metabolism of LDL and high-density lipoprotein (HDL), which contributes to the risk. Especially in patients with hypertriglyceridemia, apolipoprotein B and non-HDL-cholesterol (encompassing cholesterol of all atherogenic lipoproteins) predict risk better than LDL-cholesterol and/or triglycerides. Therefore, current guidelines have stated secondary goals relating to non-HDL-cholesterol and apolipoprotein B (in addition to the primary goal relating to LDL-cholesterol). These secondary goals can be achieved by further reducing LDL-cholesterol or by decreasing triglyceride rich lipoproteins. However, only further LDL reduction has so far proven to be beneficial in outcome trials. In addition, high dose eicosapentaenoic acid (EPA) can reduce atherosclerotic cardio-vascular disease risk in patients with hypertriglyceridemia, although benefit is not (or not only) related to apolipoprotein B or non-HDL-cholesterol reduction. Non-HDL-cholesterol and apoB represent novel targets for patients with hypertriglyceridemia, but achieving LDL-cholesterol targets remains the first step for cardio-vascular risk reduction.

Clinical Management of Hypertriglyceridemia in the Prevention of Cardiovascular Disease and Pancreatitis.

Purpose of ReviewHypertriglyceridemia (HTG) is common and is a significant contributor to atherosclerosis and pancreatitis risk. Specific HTG treatments have had variable success in reducing atherosclerosis risk. Novel therapies for severe HTG treatment and pancreatitis risk reduction are likely to be available soon. These novel therapies are expected to have broader applications for more moderate HTG and atherosclerosis risk reduction as well.Recent FindingsNHANES 2012 data has confirmed a reduction in average triglyceride (TG) levels in the US population. Dietary modification and weight reduction when needed remain the core treatment elements for all individuals with HTG, while statin therapy is a foundational pharmacologic care for atherosclerotic cardiovascular disease (ASCVD) event risk reduction. In addition, the REDUCE-IT study provides evidence for additional benefit from the use of high-dose icosapent ethyl (IPE) on top of background medical therapy in adults with moderate HTG and ASCVD or type 2 diabetes mellitus (T2D) and additional ASCVD risk factors. However, treatment with eicosapentaenoic acid (EPA) combined with docosahexanoic acid (DHA) did not reduce ASCVD in a similar population studied in the STRENGTH trial. Furthermore, novel therapeutics targeting PPAR-ɑ, as well as ApoC-III and AngPTL3, effectively lower TG levels in individuals with moderate and severe HTG, respectively. These treatments may have applicability for reducing risk from ASCVD among individuals with chylomicronemia; in addition, ApoC-III and AngPTL3 treatments may have a role in treating individuals with the rare monogenic familial chylomicronemia syndrome (FCS) at risk for acute pancreatitis (AP).SummaryResidual ASCVD risk in individuals treated with contemporary care may be due in part to non-LDL lipid abnormalities including HTG. The findings from REDUCE-IT, but not STRENGTH, confirm that consumption of high-dose EPA may reduce ASCVD risk, while combination therapy of EPA plus DHA does not reduce ASCVD in a similar population. TG lowering likely reduces ASCVD risk in individuals with HTG, but ASCVD risk is multifactorial; the added benefit of IPE to contemporary preventive therapy is the consequence of differential non-TG biologic properties between the two fatty acids. Acute pancreatitis is more difficult to study prospectively since it is less common; however, TG lowering is likely critical for the care of at-risk individuals. Additional benefit from novel therapy that has an impact on this otherwise refractory condition is anticipated.

Aspirin and omega-3 polyunsaturated fatty acid use and their interaction in cardiovascular diseases and colorectal adenomas.

Aspirin (acetylsalicylic acid, ASA) is inexpensive and is established in preventing cardiovascular disease (CVD) and colorectal adenomas. Omega-3 (n3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have also shown benefit in preventing CVD. The combination could be an effective preventative measure in patients with such diseases. ASA and n3 PUFA reduced the risk of CVD in ASA-resistant or diabetic patients. EPA- and DHA-deficient patients also benefited the most from n3 PUFA supplementation. Synergistic effects between ASA and EPA and DHA are 'V-shaped' such that optimal ASA efficacy is dependent on EPA and DHA concentrations in blood. In colorectal adenomas, ASA (300 mg/d) and EPA reduced adenoma burden in a location- and subtype-specific manner. Low doses of ASA (75-100 mg/d) were used in CVD prevention; however, ultra-low doses (30 mg/d) can also reduce thrombosis. EPA-to-DHA ratio is also important with regard to efficacy. DHA is more effective in reducing blood pressure and modulating systemic inflammation; however, high-dose EPA can lower CVD events in high-risk individuals. Although current literature has yet to examine ASA and DHA in preventing CVD, such combination warrants further investigation. To increase adherence to ASA and n3 PUFA supplementation, combination dosage form may be required to improve outcomes.

Omega-3 fatty acids ameliorate vascular inflammation: A rationale for their atheroprotective effects

Background and aimsClinical trials have demonstrated reductions in major adverse cardiovascular events with purified high-dose eicosapentaenoic acid (EPA), independent of effects on lipids. We aimed to investigate whether omega-3 fatty acids reduce vascular inflammation, a critical mediator of atherosclerosis, and hypothesised that EPA is superior to docosahexaenoic acid (DHA). MethodsIn a double-blind randomised controlled trial and cell-culture study, 40 healthy volunteers were supplemented with 4 g daily of either EPA, DHA, fish oil (2:1 EPA:DHA), or placebo for 30 days. Serum was incubated with TNF-stimulated human umbilical vein endothelial cells (HUVECs), and markers of acute vascular inflammation (AVI) were measured. The effects of EPA, DHA (600 mg/kg/day), olive oil, or no treatment were also measured in preclinical models of [1] AVI using a periarterial collar (C57Bl/6J; n = 40 mice) and [2] atherosclerosis where ApoE−/− mice (n = 40) were fed a 16-week atherogenic diet. ResultsEPA supplementation reduced expression of C–C motif chemokine ligand 2 (CCL2) by 25% compared to placebo (p = 0.03). In the AVI model, EPA reduced vascular expression of VCAM1 by 43% (p = 0.02) and CCL2 by 41% (p = 0.03). Significant inverse correlations were observed between EPA levels and vascular expression of VCAM1 (r = −0.56, p = 0.001) and CCL2 (r = −0.56, p = 0.001). In ApoE−/- mice, EPA reduced aortic expression of Il1b by 44% (p = 0.04) and Tnf by 49% (p = 0.04), with similar inverse correlations between EPA levels and both Il1b (r = −0.63, p = 0.009) and Tnf (r = −0.50, p = 0.04). ConclusionsSupplementation with EPA, more so than DHA, ameliorates acute and chronic vascular inflammation, providing a rationale for the cardiovascular benefit observed with high dose omega-3 fatty acid administration.

Differential effects of EPA and DHA on DSS-induced colitis in mice and possible mechanisms involved.

The anti-inflammatory effect of n-3 PUFAs has been widely documented. Emerging evidence suggests that the main component of n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects in ulcerative colitis (UC). It was aimed to clarify their differential effects in UC. Eight-week-old male C57BL/6J mice were randomly divided into 7 groups, namely control, UC model, salicylazosulfapyridine (SASP), low-dose DHA, high-dose DHA, low-dose EPA, and high-dose EPA. DHA, EPA and SASP treatment groups were orally treated accordingly for 9 weeks. During the 5th to 9th week the control group was given distilled water, while other groups were given distilled water with 2% dextran sodium sulfate (DSS) to induce UC. Body weight loss, diarrhea, and stool bleeding were recorded to calculate the disease activity index (DAI). The level of tight junction proteins Claudin-1 and Occludin, and cytokines including TNF-α, IL-6, and IL-1β as well as inflammatory cell markers such as MPO, F4/80, and MCP-1 in the intestinal epithelium were measured using western blotting. Activation of IL-6/STAT3 and NLRP3/IL-1β inflammatory pathways was also assessed. Levels of proliferation-related proteins of the Wnt/β-catenin pathway with c-myc, Cyclin-D1, and PCNA were detected. EPA, superior to DHA, significantly attenuated DSS-induced colitis evidenced by reduced DAI scores, cytokine production and inflammatory cell infiltration. Mechanically, EPA triggered a marked up-regulation of Claudin-1 and Occludin with down-regulation of their up-stream Akt and ERK. EPA also inhibited NLRP3/IL-1β and IL-6/STAT3 inflammatory pathways and up-regulated the Wnt/β-catenin pathway. EPA is more suitable to be used for the treatment of UC than DHA.

Abstract 16407: Plasma Omega-3 Fatty Acids Predict Cardiovascular Events Stratified by Coronary Artery Calcium

Background: In REDUCE-IT, high-dose eicosapentaenoic acid (EPA) was beneficial in high-risk patients without clinical CVD independent of triglyceride levels. Whether the benefit of higher plasma EPA extends to those without subclinical CVD is unclear. Hypothesis: In those without clinical CVD, plasma omega-3 fatty acid (O3FA) levels predict long-term CVD events, and subclinical CVD measured by coronary artery calcium (CAC) modifies the effect such that individuals with the highest CAC attain the greatest benefit from higher O3FA. Methods: We examined 6568 MESA participants with plasma EPA and docosahexaenoic acid (DHA) levels measured at baseline and classified them by tertiles of EPA and DHA and by CAC category (0, 1-99, ≥100). Our outcome was time to CVD event (myocardial infarction, angina, cardiac arrest, stroke, CVD death). Cox regression models were used to assess the associations between log-transformed EPA and DHA and CVD events adjusted for demographic factors, CVD risk factors, and medication use. Results: Mean age was 62.1±10.2 and 52.9% were females. Higher log(EPA) (adjusted hazard ratio, aHR = 0.83; 95% CI, 0.74-0.93; P = 0.002) and log(DHA) (aHR = 0.80; 95% CI, 0.66-0.96; P = 0.019) were independently associated with fewer CVD events. The difference in absolute CVD event rates between the lowest and highest EPA tertile increased at higher CAC levels (Figure). The adjusted HR for highest compared to lowest EPA tertile within CAC 0 was 1.02 (95% CI, 0.72-1.45), CAC 1-99 was 0.71 (95% CI, 0.51-0.98), and CAC≥100 was 0.66 (95% CI, 0.52-0.83). A similar association was seen in tertiles of DHA by CAC category. These findings were consistent by sex and race category and after adjusting for O3FA supplement use. Conclusion: In an ethnically diverse population free of clinical CVD at baseline, higher plasma O3FA levels were associated with fewer CVD events. The absolute reduction in CVD events with higher O3FA levels was more apparent at higher CAC scores.

Effect of eicosapentaenoic acid/docosahexaenoic acid on coronary high-intensity plaques detected with non-contrast T1-weighted imaging: subgroup analysis of the AQUAMARINE EPA/DHA study

Abstract Background In the recent the Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT), statin therapy plus high-dose eicosapentaenoic acid (EPA) significantly reduced the risk of cardiovascular death in patients with coronary artery disease (CAD) with elevated triglyceride (TG) levels. An epidemiologic study has shown that increasing the intake of long-chain n-3 polyunsaturated fatty acids, especially EPA and docosahexaenoic acid (DHA), are associated with a lower risk of fatal CAD. However, the anti-atherosclerotic effect of high-dose EPA/DHA has not be clarified. We reported that coronary high-intensity plaques (HIPs) detected with non-contrast T1-weighted imaging (T1WI) on cardiac magnetic resonance (CMR), which can be uniquely quantitative assessed using the plaque-to-myocardium signal intensity ratio (PMR) of ≥1.4, are significantly associated with future coronary events. Moreover, we demonstrated that intensive statin therapy reduces the PMR of coronary HIPs by 19% but is unlikely to completely resolve HIP (PMR&amp;lt;1.0). In the AQUAMARINE EPA/DHA study, our goal was to assess the anti-atherogenic effect of EPA/DHA in an exploratory manner by examining the change in PMR of coronary HIPs after 12 months of EPA/DHA therapy in patients with CAD on statin therapy. Methods This study was designed as a single-center, triple-arm, parallel-group, randomized controlled, open-label, superiority trial examining the effect of 12 months of additional EPA/DHA therapy on coronary HIPs in patients with CAD who receiving statin therapy. Eligible subjects are randomly assigned to the 2 g/day EPA/DHA group (n=26), the 4 g/day group (n=23), or the no EPA/DHA (statin-only) group (n=24) between May 2014 and December 2017. The PMR was defined as the signal intensity of the coronary plaque divided by that of nearby left ventricular myocardium. The primary endpoint is the change in PMR after EPA/DHA treatment. Results These 3 groups were well matched at baseline, with no statistically significant differences in age, male sex, conventional coronary risk factors, TG level, medications, and PMR. Figure 1 shows subgroup analysis of patients with high triglyceride levels (&amp;gt;150mg/dl). In the patient-based analysis (A), 12 months of EPA/DHA therapy significantly reduced the PMR of primary lesions. In the segment-based analysis (B), additional reduction of PMR was observed in the high-dose EPA/DHA group compared with the no EPA/DHA treatment group. Discussion The present study of patients with high triglyceride levels demonstrated that EPA/DHA had a dose-dependent anti-atherosclerotic effect. This finding may provide additional information of EPA/DHA for lowering the residual risk in patients with CAD on statin therapy. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Takeda Pharmaceutical Co., Ltd.

Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites.

Patients with well-controlled low-density lipoprotein cholesterol levels, but persistent high triglycerides, remain at increased risk for cardiovascular events as evidenced by multiple genetic and epidemiologic studies, as well as recent clinical outcome trials. While many trials of low-dose ω3-polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have shown mixed results to reduce cardiovascular events, recent trials with high-dose ω3-PUFAs have reignited interest in ω3-PUFAs, particularly EPA, in cardiovascular disease (CVD). REDUCE-IT demonstrated that high-dose EPA (4 g/day icosapent-ethyl) reduced a composite of clinical events by 25% in statin-treated patients with established CVD or diabetes and other cardiovascular risk factors. Outcome trials in similar statin-treated patients using DHA-containing high-dose ω3 formulations have not yet shown the benefits of EPA alone. However, there are data to show that high-dose ω3-PUFAs in patients with acute myocardial infarction had reduced left ventricular remodelling, non-infarct myocardial fibrosis, and systemic inflammation. ω3-polyunsaturated fatty acids, along with their metabolites, such as oxylipins and other lipid mediators, have complex effects on the cardiovascular system. Together they target free fatty acid receptors and peroxisome proliferator-activated receptors in various tissues to modulate inflammation and lipid metabolism. Here, we review these multifactorial mechanisms of ω3-PUFAs in view of recent clinical findings. These findings indicate physico-chemical and biological diversity among ω3-PUFAs that influence tissue distributions as well as disparate effects on membrane organization, rates of lipid oxidation, as well as various receptor-mediated signal transduction pathways and effects on gene expression.

SIGNIFICANT CARDIOVASCULAR BENEFITS OF ICOSAPENT ETHYL FROM REDUCE-IT

Statin-treated patients with established cardiovascular disease or diabetes remain at high risk for ischemic events. We explored if icosapent ethyl (IPE), a stable, prescription high-dose eicosapentaenoic acid (EPA) ethyl ester, reduces major cardiovascular events in such patients, and if serum EPA correlated with risk reductions

The fish-oil paradox.

Increasing interest has focused on the potential cardioprotective effects of the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the basis of findings from epidemiology and cohort studies. This review will summarize the findings of contemporary clinical trials of omega-3 fatty acids. Although a large clinical trial performed prior to the widespread use of statins demonstrated cardiovascular benefit with fish oils, subsequent studies have failed to reproduce this result. More recent studies have demonstrated a reduction in cardiovascular risk with administration of high-dose EPA, but not a carboxylic acid formulation containing both EPA and DHA or with lower doses of omega-3 fatty acids. Administration of omega-3 fatty acids differing in either composition or dose produce variable effects on cardiovascular outcomes. This has implications for both the public health and pharmacological approach to cardiovascular prevention.