Eicosapentaenoic Acid In Patients Research Articles

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Omega-3 Eicosapentaenoic Acid Reduces Prostate Tumor Vascularity.

The impact of omega (ω)-3 fatty acids on prostate cancer is controversial in epidemiological studies but experimental studies suggest a protective effect. However, little is known about the mechanism of action. Here, we studied the effects of purified fatty acid molecules on prostate tumor progression using the TRAMP-C2 syngeneic immunocompetent mouse model. Compared with ω-6 or ω-9-supplemented animals, we observed that late-stage prostate tumor growth was reduced with a monoacylglyceride (MAG)-conjugated form of eicosapentaenoic acid (EPA) supplementation, whereas docosahexanenoic acid (DHA) caused an early reduction. MAG-EPA significantly decreased tumor blood vessel diameter (P < 0.001). RNA sequencing analysis revealed that MAG-EPA downregulated angiogenesis- and vascular-related pathways in tumors. We also observed this tissue vascular phenotype in a clinical trial testing MAG-EPA versus a high oleic sunflower oil placebo. Using anti-CD31 IHC, we observed that MAG-EPA reduced blood vessel diameter in prostate tumor tissue (P = 0.03) but not in normal adjacent tissue. Finally, testing autocrine and paracrine effects in an avascular tumor spheroid growth assay, both exogenous MAG-EPA and endogenous ω3 reduced VEGF secretion and in vitro endothelial cell tube formation and blocked tumor spheroid growth, suggesting that ω3 molecules can directly hinder prostate cancer cell growth. Altogether, our results suggest that fatty acids regulate prostate cancer growth and that a tumor-specific microenvironment is required for the anti-vascular effect of MAG-EPA in patients with prostate cancer. IMPLICATIONS: Increasing the amount of ingested EPA omega-3 subtype for patients with prostate cancer might help to reduce prostate tumor progression by reducing tumor vascularization.

High Baseline Lipoprotein(a) Level as a Risk Factor for Coronary Artery Calcification Progression: Sub-analysis of a Prospective Multicenter Trial.

Lipoprotein(a), or Lp(a), is a low-density lipoprotein-like particle largely independent of known risk factors for, and predictive of, cardiovascular disease (CVD). We investigated the association between baseline Lp(a) levels and the progression of coronary artery calcification (CAC) in patients with hypercholesterolemia undergoing statin therapy. This study was a sub-analysis of a multicenter prospective study that evaluated the annual progression of CAC under intensive and standard pitavastatin treatment with or without eicosapentaenoic acid in patients with an Agatston score of 1 to 999, and hypercholesterolemia treated with statins. We classified the patients into 3 groups according to CAC progression. A total of 147 patients (mean age, 67 years; men, 54%) were analyzed. The proportion of patients with Lp(a) > 30 mg/dL significantly increased as CAC progressed (non-progression; 5.4%, 0<CAC progression ≦100; 7.7%, and CAC progression >100; 23.6%). Logistic regression analysis showed that Lp(a) > 30 mg/dL was an independent predictor of the annual change in Agatston score > 100 (OR: 5.51; 95% CI: 1.28-23.68; p=0.02), even after adjusting for age, sex, hypertension, diabetes mellitus, current smoking, body mass index, and lipid-lowering medications. Baseline Lp(a) >30 mg/dL was a predictor of CAC progression in this population of patients with hypercholesterolemia undergoing statin therapy.

A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins

BackgroundThere is a residual risk of coronary heart disease (CHD) despite intensive statin therapy for secondary prevention. The aim of this study was to investigate whether coronary plaque regression and stabilization are reinforced by the addition of eicosapentaenoic acid (EPA) to high-dose pitavastatin (PTV). MethodsWe enrolled 193 CHD patients who underwent percutaneous coronary intervention (PCI) in six hospitals. Patients were randomly allocated to the PTV group (PTV 4mg/day, n=96) or PTV/EPA group (PTV 4mg/day and EPA 1800mg/day, n=97), and prospectively followed for 6–8 months. Coronary plaque volume and composition in nonstenting lesions were analyzed by integrated backscatter intravascular ultrasound (IB-IVUS). ResultsThe PTV/EPA group showed a greater reduction in total atheroma volume compared to PTV group. IB-IVUS analyses revealed that lipid volume was significantly decreased during follow-up period in only PTV/EPA group. The efficacy of additional EPA therapy on lipid volume reduction was significantly higher in stable angina pectoris (SAP) patients compared to acute coronary syndrome patients. EPA/AA ratio was significantly improved in PTV/EPA group compared to PTV group. There was no significant difference in the incidence of major adverse cardiovascular events and side effects. ConclusionsCombination EPA/PTV therapy significantly reduced coronary plaque volume compared to PTV therapy alone. Plaque stabilization was also reinforced by EPA/PTV therapy in particular SAP patients. The addition of EPA is a promising option to reduce residual CHD risk under intensive statin therapy.

Impact of Adding Eicosapentaenoic Acid to Statin Therapy on Plasma Pentraxin 3 Level in Patients with Stable Coronary Artery Disease: A 6-Month, Randomized Controlled Study.

We hypothesized that the additional administration of eicosapentaenoic acid (EPA) in patients with stable coronary artery disease (CAD) receiving statin has the potential to lower the serum pentraxin 3 (PTX3) level, an indicator of plaque stabilization. We randomly assigned CAD patients already receiving statin therapy to an EPA group (1800mg/day, n=53) or control group (n=53). No significant difference was found in the change in the plasma PTX3 level between the groups. However, in a subgroup analysis, a significant percentage reduction in the plasma PTX3 level was observed in patients receiving strong statin compared with the patients receiving moderate statin in the EPA group (-5.6 vs. 14.7%, p=0.0082), while no such difference in the percentage change in the plasma PTX3 level was noted between the two same statin subgroups in the control group. A multiple logistic regression analysis identified the addition of EPA to ongoing strong statin treatment as an independent predictor of PTX3 level reduction. Furthermore, even in patients with relatively well-controlled serum lipid levels, pretreatment with EPA added to ongoing statin therapy reduced serum non-high-density lipoprotein cholesterol and triglyceride-rich lipoproteins as residual risk factors. Through this study design, the results could not support the hypothesis that adding EPA in patients with stable CAD receiving varying degrees of statin treatment reduces the plasma PTX3 level comprehensively. However, addition of EPA to ongoing strong statin treatment, but not ongoing moderate statin treatment, may reduce the plasma PTX3 level, possibly leading to coronary plaque stabilization. UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010452.

Measurement of red blood cell eicosapentaenoic acid (EPA) levels in a randomised trial of EPA in patients with colorectal cancer liver metastases

We investigated red blood cell (RBC) PUFA profiles, and the predictive value of RBC EPA content for tumour EPA exposure and clinical outcomes, in the EMT study, a randomised trial of EPA in patients awaiting colorectal cancer (CRC) liver metastasis surgery (Cockbain et al., 2014) [8]. There was a significant increase in RBC EPA in the EPA group (n=43; median intervention 30 days; mean absolute 1.26[±0.14]% increase; P<0.001), but not in the placebo arm (n=45). EPA incorporation varied widely in EPA users and was not explained by treatment duration or compliance. There was little evidence of ‘contamination’ in the placebo group. The EPA level predicted tumour EPA content (r=0.36; P=0.03). Participants with post-treatment EPA≥1.22% (n=49) had improved OS compared with EPA <1.22% (n=29; HR 0.42[95%CI 0.16–0.95]). RBC EPA content should be evaluated as a biomarker of tumour exposure and clinical outcomes in future EPA trials in CRC patients.

Plasma and erythrocyte uptake of omega-3 fatty acids from an intravenous fish oil based lipid emulsion in patients with advanced oesophagogastric cancer

It has been demonstrated that short term intravenous (IV) administration of omega-3 polyunsaturated fatty acids (PUFAs) is more effective than oral supplementation at promoting incorporation of the bioactive omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into plasma, blood cells and tissues. The effect of repeated short term IV infusion of omega-3 PUFAs was investigated in patients with advanced oesophagogastric cancer during palliative chemotherapy. Patients with advanced oesophagogastric cancer (n=21) were recruited into a phase II pilot clinical trial. All patients were scheduled for an intravenous infusion of Omegaven® (fish oil supplement containing EPA and DHA) at a rate of 2ml/kg body weight for 4h once a week for up to six months. Blood samples were collected to assess omega-3 PUFA uptake into plasma non-esterified fatty acids (NEFAs) and phosphatidylcholine (PC) and into red blood cell (RBC) membranes. Fatty acid profiles were analysed by gas chromatography. Twenty patients received at least one Omegaven® treatment and were included in the analysis. Each infusion of omega-3 PUFAs resulted in increased EPA and DHA in plasma NEFAs, but there was little effect on PUFAs within plasma PC during the infusions. However, with repeated weekly infusion of omega-3 PUFAs, the EPA content of plasma PC and of RBC membranes increased. Repeated weekly omega-3 PUFA infusion is effective in enriching plasma PC and RBC membranes in EPA in patients with advanced oesophagogastric cancer receiving palliative chemotherapy. Clinical Trials.Gov NCT01870791.

Changes in plasma chemokine C-C motif ligand 2 levels during treatment with eicosapentaenoic acid predict outcome in patients undergoing surgery for colorectal cancer liver metastasis.

The mechanism of the anti-colorectal cancer (CRC) activity of the omega-3 fatty acid eicosapentaenoic acid (EPA) is not understood. We tested the hypothesis that EPA reduces expression of chemokine C-C motif ligand 2 (CCL2), a pro-inflammatory chemokine with known roles in metastasis.We measured CCL2 in clinical samples from a randomized trial of EPA in patients undergoing liver surgery for CRC liver metastasis (LM) and preclinical models. Genome-wide transcriptional profiling of tumors from EPA-treated patients was performed.EPA decreased CCL2 synthesis by CRC cells in a dose-dependent manner. CCL2 was localized to malignant epithelial cells in human CRCLM. EPA did not reduce CCL2 content in human or mouse tumors compare to control. However, EPA treatment was associated with decreased plasma CCL2 levels compared with controls (P=0.04). Reduction in plasma CCL2 following EPA treatment predicted improved disease-free survival (HR 0.32; P=0.003). Lack of ‘CCL2 response’ was associated with a specific CRCLM gene expression signature.In conclusion, reduction in plasma CCL2 in patients with CRCLM treated with EPA predicts better clinical outcome and a specific tumor gene expression profile. Further work is needed to validate CCL2 as a therapeutic response biomarker for omega-3 fatty acid treatment of CRC patients.

The effect of eicosapentaenoic acid in patients with nasopharyngeal cancer receiving concurrent chemoradiotherapy in an outpatient clinic: An open-label prospective randomized trial.

e19550 Background: Evaluating the benefit of esicosapentaenoic acid (EPA) nutrition supplement in nasopharyngeal cancer (NPC) patients who receiving concomitant chemoradiotherapy Methods: Patients ...

Effects of Eicosapentaenoic Acid Supplementation on Immunoglobulin A Nephropathy

Eicosapentaenoic acid (EPA), which is purified from fish oil, attenuates inflammatory responses by decreasing eicosanoid and cytokine production. EPA reportedly improves renal survival in patients with immunoglobulin (Ig)A nephropathy; however, this is unconfirmed. We studied the effects of EPA on IgA nephropathy patients. Eighteen biopsy-confirmed IgA nephropathy patients (aged 31 +/- 3 years) were enrolled. The prognoses based on glomerular findings were good (N = 5), relatively poor (N = 12), and poor (N = 1). EPA was administered at 1.8 g/day for 12 months. Five biopsy-confirmed IgA nephropathy patients were enrolled as control subjects. Administration of other drugs used to treat IgA nephropathy was not changed. The estimated creatinine clearance (eCCr), serum creatinine (Cr) concentration, urinary protein creatinine ratio (U/P), and other clinical parameters were checked. In the EPA group, the Cr went from 0.8 +/- 0.2 mg/dL to 0.7 +/- 0.2 mg/dL after 12 months of EPA treatment, and the U/P went from 550 +/- 580 mg/g Cr to 330 +/- 920 mg/g Cr. The values did not differ significantly; however, Cr and U/P tended to improve, with no adverse effects from the EPA. The eCCr improved significantly (99 +/- 7-110 +/- 8 mL/min, P = 0.001) in the EPA group, but not in the control group (126 +/- 12-120 +/- 13, P > 0.05). The effect of EPA in patients with IgA nephropathy is not pronounced, but these results suggest that EPA is a safe and worthwhile supplement to the drugs used to treat this disease.

Omega-3 fatty acids: antiarrhythmic, proarrhythmic or both?

Recent publications seem to indicate no or an untoward effect of the marine omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid on cardiac rhythm. This review puts these developments into perspective. In-vitro or in animal models, little pro-arrhythmic effect, but many antiarrhythmic mechanisms of omega-3 fatty acids have been documented. In intervention studies in humans, eicosapentaenoic acid plus docosahexaenoic acid suppressed new atrial fibrillation in patients undergoing coronary bypass grafting. More importantly, in systematic reviews, it has been demonstrated that eicosapentaenoic acid plus docosahexaenoic acid reduce sudden cardiac death by 50%. In a recently published intervention study with eicosapentaenoic acid in patients at high cardiovascular risk in Japan, sudden cardiac death was rare. Sudden cardiac death is even rarer in the general population of Japan: it occurs 20 times less frequently than in the general population in Europe, e.g. Germany. In Japan, levels of eicosapentaenoic acid plus docosahexaenoic acid are high (omega-3 index estimated around 11%), whereas in Germany levels of eicosapentaenoic acid plus docosahexaenoic acid acids are low (omega-3 index around 4%). These and other data strengthen the concept that a low omega-3 index is a risk factor for sudden cardiac death, as a tool to assess the status of a person in terms of eicosapentaenoic acid plus docosahexaenoic acid, and as a means to monitor therapy with eicosapentaenoic acid plus docosahexaenoic acid. Concerns about pro-arrhythmic effects of eicosapentaenoic acid plus docosahexaenoic acid are largely theoretical. The evidence in favour of an antiarrhythmic effect is overwhelming, especially, when factoring in the omega-3 index.

The Triglyceride-Lowering Effects of a Modest Dose of Docosahexaenoic Acid Alone Versus in Combination with Low Dose Eicosapentaenoic Acid in Patients with Coronary Artery Disease and Elevated Triglycerides

Background: Hypertriglyceridemia is a risk factor for coronary artery disease (CAD). The American Heart Association recommends 1000 mg of omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), daily for cardioprotection and higher doses for triglyceride-lowering in patients with CAD.Methods: This was a prospective, randomized, double-blind study comparing DHA to DHA + EPA in patients with CAD and triglycerides greater than 200 mg/dL. Subjects were randomized to either 1000 mg of DHA or 1252 mg of DHA + EPA for eight weeks. Baseline and eight-week laboratories were drawn to assess changes in the fasting lipid profile. The primary objective was to evaluate the change in triglycerides between the two groups at eight weeks.Results: A total of 116 subjects were enrolled; 57 in the DHA group and 59 in the DHA + EPA group. Baseline characteristics were similar between groups. The mean age was 69.4 ± 9.1 years and 70.7% were male. Triglycerides decreased by an average of 21.8% in the DHA group (p < 0.001) and 18.3% in the DHA + EPA group (p < 0.001). The difference between groups was not significant. A greater proportion of subjects in the DHA group achieved triglyceride goal (less than 150 mg/dL) compared to the DHA + EPA group (24.6% versus 10.2%, p < 0.05).Conclusions: Our results indicate that the American Heart Association recommended cardioprotective dose of omega-3 fatty acids can also significantly lower triglycerides in patients with CAD. There do not appear to be significant differences in triglyceride-lowering between DHA only and DHA + EPA combination products when dosing is based on DHA.

Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: A systematic review

The aim of this systematic review was to determine the efficacy and potential benefits of enteral nutritional support [oral nutritional supplements (ONS) or enteral tube feeding (ETF)], and eicosapentaenoic acid (EPA, free acid, ethyl esters or fish oil; provided as capsules or enriched ONS or ETF) in patients with cancer. Clinical studies were identified using electronic databases, and studies were selected according to predetermined criteria. For each treatment modality (chemo/radiotherapy, surgery, and palliative care), the comparisons of interest were nutritional support vs. routine care (no nutritional support), EPA supplement (capsule or enriched ONS or ETF) vs. routine care (no supplement or standard supplement), ETF vs. parenteral nutrition (PN). The reviewed outcomes were dietary intake, anthropometry, clinical (mortality, length of hospital stay, complications, and quality of life) and haematological/biochemical (white blood cell count, serum transferrin and albumin, CD3-positive lymphocytes, and inflammatory markers). Meta-analyses were performed where possible. In patients undergoing radiotherapy, meta-analysis showed that ONS significantly increase dietary intake (381 kcal/day, 95% CI 193 to 569 in 3 RCTs) compared to routine care. In patients undergoing surgery, meta-analyses showed that ETF results in a significantly shorter length of hospital stay (1.72 fewer days, 95% CI 0.90 to 2.54 in 8 RCTs), lower incidence of any complications (OR 0.62, 95% CI 0.50 to 0.77 in 4 RCTs) and infectious complications (OR 0.67, 95% CI 0.55 to 0.82 in 11 RCTs) and lower sepsis scores (2.21 points, 95% CI 1.49 to 2.92 in 2 RCTs), but no difference in mortality (OR 0.72, 95% CI 0.40 to 1.29 in 7 RCTs) compared to PN. There was also no difference in mortality between ONS or ETF vs. routine care in patients undergoing chemotherapy/radiotherapy (OR 1.00, 95% CI 0.62-1.61 in 4 RCTs) or surgery (OR 2.44, 95% CI 0.75 to 7.95 in 4 RCTs). Individual studies of EPA supplementation as capsules showed improvements in survival, complications and inflammatory markers in patients undergoing bone marrow transplant (BMT). In palliative care patients receiving EPA-enriched ONS or capsules, there were inconsistent positive effects on survival and quality of life. In those undergoing surgery, EPA-enriched ETF had no effect. Further research is required to elucidate the clinical efficacy of enteral nutrition support, including the potential benefits of EPA supplementation, in patients with cancer.

Eicosapentaenoic acid protects endothelial cells against anoikis through restoration of cFLIP.

Dietary supplementation with eicosapentaenoic acid (EPA) improves the prognosis of chronic inflammatory diseases, including atherosclerosis. The mechanism underlying these beneficial effects, however, remains to be elucidated. Here we show that EPA protects endothelial cells from anoikis through upregulation of the cellular FLICE (Fas-associating protein with death domain-like interleukin-1-converting enzyme)-inhibitory protein (cFLIP), an endogenous inhibitor of caspase-8. EPA-induced upregulation of cFLIP expression was partially suppressed by the phosphatidylinositol-3-kinase inhibitor wortmannin. Conversely, treatment with insulinlike growth factor-1 (IGF-1), an activator of phosphatidylinositol-3-kinase/Akt signaling, or infection with an adenoviral construct expressing the constitutively active Akt gene induced upregulation of cFLIP expression. In addition, pretreatment of endothelial cells with either EPA or IGF-1 protected them from anoikis, suggesting that EPA-induced protection against anoikis is partially mediated through activation of Akt. On the other hand, when endothelial cells were already detached, treatment of these cells with EPA but not with IGF-1 protected them against anoikis. Importantly, EPA restored cFLIP expression without activating Akt signaling in detached endothelial cells, whereas IGF-1 had no effect. Additionally, exogenously restored expression of cFLIP by the tetracycline-regulated adenovirus system protected endothelial cells against anoikis. Furthermore, EPA was protective against the loss of endothelium in an organ culture of rat aortas. These findings suggest that EPA protects against endothelial cell anoikis through restoration of cFLIP expression, which might contribute to the mechanism underlying the beneficial effects of EPA in patients with hypertension.

I015 Dynamics of prostacyclin, thromboxane A 2, and F 2-isoprostanes and influence of eicosapentaenoic acid in patients with hyperlipidemia

I015 Dynamics of prostacyclin, thromboxane A 2, and F 2-isoprostanes and influence of eicosapentaenoic acid in patients with hyperlipidemia

Effects of eicosapentaenoic acid in patients with bronchial asthma

Eicosapentaenoic acid (EPA) is composed of 20 unsaturated fatty acids and is similar to arachidonic acid. Epadel, the drug made from EPA, is reported not only to reduce levels of serum lipids, but also to have antiinflammatory and antiallergic effects. EPA may exert these effects via control of the production of prostanoids and leukotrienes. We studied the effects of EPA in patients with bronchial asthma who had hyperlipidemia. The patents were given EPA at 1800 mg/day and they recorded signs and symptoms in an asthma diary during a 2-week observation period and the 8 weeks during which they took the drug. Peak flow, leukotriene B4 concentration in urine, Leukotriene E4 concentration in urine, IgE level, total cholesterol level, and triglyceride level were measured before and after the 8 weeks of medication. Administration of EPA was associated with improvements in symptom score, therapeutic score, asthma score, and peak flow. EPA may be useful in patients with asthma complicated by hyperlipidemia.