Eicosapentaenoic acid/arachidonic acid ratio in Japanese junior high school students.

BACKGROUND: This epidemiological study investigated the eicosapentaenoic acid/arachidonic acid ratio (EAR) and docosahexaenoic acid/ arachidonic acid ratio (DAR) in ninth-graders in Japan. METHODS: A total of 175 ninth-grade children from Tsunan Town (115 boys and 60 girls) were enrolled in the study between 2015 and 2017. All participants were assessed during annual health checkups to determine their EAR and DAR. All data were compared between boys and girls using the Mann-Whitney test. Spearman's rank correlation coefficient was used to describe the strengths of correlations between the EAR, DAR, and relevant parameters. RESULTS: The median (minimum, maximum) EAR and DAR of all participants were 0.13 (0.05, 0.46) and 0.47 (0.25, 0.84), respectively. There was no significant difference in the EAR between boys and girls at 0.12 (0.05, 0.46) and 0.13 (0.06, 0.27) (P = 0.375), respectively. The DAR was not significantly different (P = 0.125). There was a significant positive correlation between EAR and triglyceride, body mass index, and homeostasis model assessment but a significantly negative correlation with HbA1c (r = -0.209, P = 0.006). In contrast, there was no significant correlation between DAR and any parameters. CONCLUSIONS: This is the first epidemiological study investigating the EAR using a population-based cohort of Japanese adolescents. The EAR in boys/girls in Japan is 0.12 (0.05, 0.46)/0.13 (0.06, 0.27). The study results suggest that children with a healthy diet may generally have a lower average blood glucose level.

Association between the ratio of serum n-3 to n-6 polyunsaturated fatty acids and acute coronary syndrome in non-obese patients with coronary risk factor: a multicenter cross-sectional study.

BACKGROUND: Previous studies have reported that being overweight, obese, or underweight is a risk factor for ischemic cardiovascular disease (CVD); however, CVD also occurs in subjects with ideal body mass index (BMI). Recently, the balance of n-3/n-6 polyunsaturated fatty acids (PUFAs) has received attention as a risk marker for CVD but, so far, no study has been conducted that investigates the association between BMI and the balance of n-3/n-6 PUFAs for CVD risk. METHODS: We evaluated the association between n-3/n-6 PUFA ratio and acute coronary syndrome (ACS) in three BMI-based groups (< 25: low BMI, 25-27.5: moderate BMI, and ≥ 27.5: high BMI) that included 1666 patients who visited the cardiovascular medicine departments of five hospitals located in urban areas in Japan. RESULTS: The prevalence of ACS events was 9.2, 7.3, and 10.3% in the low, moderate, and high BMI groups, respectively. We analyzed the relationship between ACS events and several factors, including docosahexaenoic acid/arachidonic acid (DHA/AA) ratio by multivariate logistic analyses. In the low BMI group, a history of smoking (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.40-4.35) and low DHA/AA ratio (OR: 0.30, 95% CI: 0.12-0.74) strongly predicted ACS. These associations were also present in the moderate BMI group but the magnitude of the association was much weaker (ORs are 1.47 [95% CI: 0.54-4.01] for smoking and 0.63 [95% CI: 0.13-3.10] for DHA/AA). In the high BMI group, the association of DHA/AA (OR: 1.98, 95% CI: 0.48-8.24) was reversed and only high HbA1c (OR: 1.46, 95% CI: 1.03-2.08) strongly predicted ACS. The interaction test for OR estimates (two degrees of freedom) showed moderate evidence for reverse DHA/AA ratio-ACS associations among the BMI groups (P = 0.091). CONCLUSIONS: DHA/AA ratio may be a useful marker for risk stratification of ACS, especially in non-obese patients.

Variations in the eicosapentaenoic acid-arachidonic acid ratio associated with age in acute myocardial infarction patients undergoing primary percutaneous coronary intervention.

Acute myocardial infarction (AMI) is a life-threatening disease, and its incidence has been increasing even in the young population. Although a low eicosapentaenoic acid (EPA)-arachidonic acid (AA) ratio is associated with an increased risk of coronary artery disease, the effect of age on EPA/AA ratios in AMI patients remains unclear. This study aimed to clarify the independent polyunsaturated fatty acid (PUFA)-related determinants of age in younger and older AMI patients. A total of 153 consecutive patients who underwent primary percutaneous coronary interventions (PCIs) for de novo AMIs were enrolled in this study. Patients' background data, including PUFA and lipid profiles during PCI, were evaluated retrospectively. The EPA/AA ratio correlated positively with age (r = 0.21; P = 0.011) and increased markedly from age 60 years. Patients aged < 60 years (n = 35) had a lower mean EPA/AA ratio (0.25 ± 0.16) than patients aged ≥ 60 years (n = 118) (0.38 ± 0.25) (P < 0.001). The AA level was more dependent on age than on EPA level (r = - 0.34, P < 0.001 vs. r = 0.12, P = 0.16). The multivariate analysis revealed that a 0.1 EPA/AA ratio increase (odds ratio 1.50; 95% confidence interval 1.09-2.06), body mass index, triglyceride level, and aspirin administration were independently associated with the age stratification of AMI patients. The EPA/AA ratio was higher in younger AMI patients who have undergone primary PCIs than in older patients. Younger population at risk for AMI should be managed with multiple interventions including PUFA profiling.

A lower eicosapentaenoic acid/arachidonic acid ratio is associated with in-hospital fatal arrhythmic events in patients with acute myocardial infarction: a J-MINUET substudy.

The ratio of serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) is significantly associated with long-term clinical outcomes in patients with acute myocardial infarction (AMI). However, it has not been conclusively demonstrated that higher serum EPA/AA ratio fares better clinical outcomes in the early phase of AMI. The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry conducted in 28 Japanese medical institutions between July 2012 and March 2014. We enrolled 3,283 consecutive AMI patients who were admitted to participating institutions within 48 h of symptom onset. A serum EPA/AA ratio was available for 629 of these patients. The endpoints were in-hospital mortality and major adverse cardiac events (MACE), defined as a composite of all cause death, cardiac failure, ventricular tachycardia (VT) and/or ventricular fibrillation (VF) and bleeding during hospitalization. Although similar rates of in-hospital mortality, cardiac failure, bleeding, and MACE were found in the lower serum EPA/AA group and higher serum EPA/AA group, the incidence of VT/VF during hospitalization was significantly higher in the low ratio group (p = 0.008). Receiver operating characteristic curve analysis showed that an EPA/AA ratio < 0.35 could predict the incidence of VT/VF with 100% sensitivity and 64.0% specificity. A lower serum EPA/AA ratio was associated with a higher frequency of fatal arrhythmic events in the early phase of AMI.

Clinical implications of eicosapentaenoic acid/arachidonic acid ratio (EPA/AA) in adult patients with congenital heart disease.

Recent studies showed that a low ratio between the levels of eicosapentaenoic acid and those of arachidonic acid (EPA/AA) is associated with higher incidence of coronary artery disease and poor prognosis of heart failure, arrhythmia, and cardiac sudden death. However, the clinical implications of EPA/AA in adult patients with congenital heart disease remain unclear. We aimed to assess the prognostic value of EPA/AA regarding cardiac events in adult patients with congenital heart disease. We measured the serum levels of eicosapentaenoic acid and arachidonic acid in 130 adult patients (median age, 31 years) stratified into two groups according to their EPA/AA (low, ≤0.22; high, >0.22). We prospectively analyzed the association between EPA/AA and incidence of cardiac events during a mean observation period of 15 months, expressed in terms of hazard ratio (HR) with 95% confidence interval (95% CI). In the subgroup of patients with biventricular circulation (2VC) (n = 76), we analyzed the same clinical endpoints. In our study population, EPA/AA was not associated with the incidence of arrhythmic events (HR, 1.52; 95% CI, 0.82-2.85; p = 0.19), but low EPA/AA was a predictor of heart failure hospitalization (HR, 2.83; 95% CI, 1.35-6.30; p < 0.01). Among patients with 2VC, an EPA/AA of ≤0.25 was associated with a significantly higher risk of arrhythmic events (HR, 2.55; 95% CI, 1.11-6.41; p = 0.03) and heart failure hospitalization (HR, 5.20; 95% CI, 1.78-18.1; p < 0.01). EPA/AA represents a useful predictor of cardiac events in adult patients with congenital heart disease.

Association and Implications of Blood and Plaque n-3 Polyunsaturated Fatty Acid Composition in Patients Treated with Oral Eicosapentaenoic Acid before Carotid Endarterectomy.

Long-chain n-3 polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), have been shown to prevent atherosclerosis-related cardiovascular disease, including stroke. Recently, the ratio of serum EPA to arachidonic acid (AA; EPA/AA ratio) has been reported to be a biomarker to prevent cardiovascular disease. In this study, we evaluate whether the serum EPA/AA ratio would be a useful biomarker for determining the efficacy of orally administered EPA in preventing stroke by investigating tissue and serum EPA/AA ratios, serum inflammatory markers, and carotid artery intimamedia thickness (IMT). Patients with dyslipidemia, as the primary illness scheduled for carotid endarterectomy (CEA), were included and randomly assigned to the EPA group (EPA: 1,800 mg/day plus statin; 10 patients) or non-EPA group (statin only; 15 patients). PUFA fraction was evaluated in the tissue (post-CEA) and serum (pre-CEA and 6 months thereafter). As for the tissue PUFA fraction in the plaque, the EPA group had a significantly higher EPA/AA ratio (EPA group, 0.46; non-EPA group, 0.28; p = 0.01). At 6 months postoperatively, the EPA group had a significantly higher serum EPA/AA ratio (baseline, 0.83; follow-up, 1.60; p = 0.05). No significant differences were found for inflammatory markers and IMT. Both serum and tissue EPA/AA ratios were higher in patients treated with oral EPA. Serum EPA/AA ratio might be a useful biomarker for the efficacy of orally administered EPA.

Proportions of long-chain ω-3 fatty acids in erythrocyte membranes of Canadian adults: Results from the Canadian Health Measures Survey 2012-2015.

BACKGROUND: The Omega-3 Index (OI) is a proposed marker of coronary artery disease (CAD) risk. Another index, the EPA/arachidonic acid (AA) ratio has also been proposed as a possible risk marker for CAD. OBJECTIVE: Our primary objective was to characterize the Canadian population subgroups that have an undesirable OI (<4%, associated with high CAD risk) and to identify the participants' characteristics most strongly associated with the OI. Our secondary objective was to identify the characteristics most strongly associated with the EPA/AA ratio. DESIGN: Data from 4025 adult participants of cycles 3 and 4 (2012-2015) of the cross-sectional Canadian Health Measures Survey were pooled. Adjusted mean proportions of erythrocyte membrane ω-3 (n-3) fatty acids, total ω-6 fatty acids, and ratios were analyzed by sociodemographic, health, and lifestyle characteristics using covariate-adjusted models. RESULTS: The mean OI was 4.5%. Almost 40% of Canadians had an undesirable (<4%) OI. ω-3 supplement use, fish intake, and race were the variables most strongly associated with OI scores. The prevalence of undesirable OI was significantly higher among participants consuming fish less than twice a week (43.8%; 95% CI: 39.0%, 48.6%) than among those consuming more fish (12.7%; 95% CI: 7.8%, 19.9%), among smokers (62.7%; 95% CI: 52.9%, 71.7%) than nonsmokers (33.4%; 95% CI: 29.4%, 37.7%), in whites (42.7%; 95% CI: 38.2%, 47.4%) than in Asians (23.0%; 95% CI: 15.4%, 33.0%), and in adults aged 20-39 y (49.6%; 95% CI: 42.3%, 56.9%) than in those aged 60-79 y (24.4%; 95% CI: 21.0%, 28.1%). ω-3 supplement intake and fish intake were the characteristics most strongly associated with EPA/AA. All P ≤ 0.05. CONCLUSIONS: An important proportion of Canadian adults has an undesirable (<4%) OI, with higher prevalence in some subgroups. Further assessment is required to determine the value and feasibility of an increase in the population's OI to the currently proposed target of ≥8% as a potential public health objective.

Administration of eicosapentaenoic acid may alter high-density lipoprotein heterogeneity in statin-treated patients with stable coronary artery disease: A 6-month randomized trial.

BACKGROUND: Combined statin plus eicosapentaenoic acid (EPA) therapy might be a potentially effective treatment option to prevent coronary artery disease (CAD). The serum EPA/arachidonic acid (AA) ratio has been identified as a potential new risk marker for CAD. Few data exist whether administration of EPA could affect high-density lipoprotein (HDL) particle size. We hypothesized that the addition of EPA to ongoing statin therapy may result in altered HDL heterogeneity. METHODS: We conducted this 6-month, single-center, prospective, randomized open-label clinical trial to investigate the effect of the additional administration of EPA on the HDL heterogeneity (HDL2, HDL3, and HDL2/HDL3 ratio) in stable CAD patients receiving treatment with statins. We assigned stable CAD patients already receiving statin therapy to the EPA group (1800mg/day: n=50) or the control group (n=50). RESULTS: A significant decrease in the serum HDL3 level (-4.7% vs. -0.5%, p=0.037), but not of the serum HDL2 level, and a significant increase in the HDL2/HDL3 ratio (5.5% vs. -5.1%, p=0.032) were observed in the EPA group as compared to the control group. Multiple regression analysis with adjustments for coronary risk factors identified the achieved EPA/ AA ratio as an independent and significant predictor of an increase of the HDL2/HDL3 ratio (ß=0.295, p=0.001). Furthermore, the change in the serum cholesterol ester transfer protein mass was positively correlated with the change in the EPA/AA ratio in the EPA group (r=0.286, p=0.044), but not in the control group (r=0.121, p=0.401). CONCLUSION: Administration of EPA might decrease the serum HDL3 level, resulting in an increase in the HDL2/HDL3 ratio. Furthermore, increased EPA/AA ratio by the addition of EPA to ongoing statin therapy might be an indicator of an increase in the HDL2/HDL3 ratio, thereby regulating HDL particle size. CLINICAL TRIAL REGISTRATION: UMIN (http://www.umin.ac.jp/) Study ID: UMIN000010452.

Administration of eicosapentaenoic acid may alter lipoprotein particle heterogeneity in statin-treated patients with stable coronary artery disease: A pilot 6-month randomized study.

BACKGROUND: We hypothesized that the addition of eicosapentaenoic acid (EPA) to ongoing statin therapy could change the particle heterogeneity of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles, even in stable coronary artery disease (CAD) patients. METHODS: We assigned CAD patients already receiving statin therapy to one of two groups: an EPA group (1800 mg/day; n = 30) and a control group (n = 30). A gel permeation high-performance liquid chromatography method was used to measure the particle concentration and number of lipoprotein subclasses. RESULTS: In the EPA group, significant decreases of both the concentration and number of medium LDL (p = 0.0002 and 0.0001), small LDL (p = 0.0004 and 0.0005) and very small LDL (p = 0.0005 and 0.002) particles were observed. Conversely, the concentration and number of large HDL particles increased significantly (p = 0.024 and 0.048). The concentration of very large HDL particles also increased significantly (p = 0.028). Furthermore, significant correlations between the variables that showed significant changes in the LDL and HDL particle subclasses, and the EPA/arachidonic acid (AA) ratio were found. No other significant associations of lipoprotein particle heterogeneity with the serum EPA/AA ratio were noted in either the control group or the EPA group. Interestingly, univariate and multivariate regression analyses revealed that increased serum lecithin-cholesterol acyltransferase activity, a key enzyme of HDL cholesterol efflux, was a predictor for increased above-mentioned HDL particles subclasses. CONCLUSIONS: Administration of EPA might alter both LDL and HDL particle heterogeneity, causing decreased concentration and number of smaller LDL particles and increased concentration and number of larger HDL particles. Furthermore, addition of EPA to ongoing statin therapy appears to be capable of increasing the EPA/AA ratio, which might have an anti-atherosclerotic effect on lipoprotein particle heterogeneity, even in stable CAD patients with well-controlled serum lipid levels. CLINICAL TRIAL REGISTRATION: UMIN (http://www.umin.ac.jp/) Study ID: UMIN000010452.

Optimal Dose of n-3 Polyunsaturated Fatty Acids for Cardiovascular Event Prevention.

Background: The n-3 polyunsaturated fatty acids (PUFA), represented by eicosapentaenoic acid (EPA) and docosahexaenoic acid, have anti-atherogenic effects (e.g., neutral fat-lowering effects) and other beneficial effects such as antiplatelet, anti-inflammatory, plaque stabilizing, vascular endothelial function ameliorative, antihypertensive, and anti-arrhythmic effects. Epidemiological studies and clinical trials have assessed the inhibitory effects of n-3 PUFA on cardiovascular events. Methods and Results: Studies that reported positive outcomes, such as the Japan EPA Lipid intervention Study (JELIS) and the Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (REDUCE-IT), noted a tendency toward the use of high-dose n-3 PUFA (1.8-4 g/day). The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Prevenzione (GISSI-Prevenzione) trial and the JELIS had high EPA/arachidonic acid (AA) baseline ratios. In contrast, negative outcome studies, such as the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, Risk and Prevention study, A Study of Cardiovascular Events in Diabetes (ASCEND), and the Vitamin D and Omega-3 Trial (VITAL) had participants who tended to use low-dose n-3 PUFA (0.84-1 g/day) and to have low baseline EPA/AA. Conclusions: Differences in baseline EPA/AA ratio and the EPA/AA ratio threshold for the prevention of cardiovascular events seem to contribute to the different outcomes, together with the dose of n-3 PUFA.

Intestinal Failure-Associated Liver Disease and Eicosapentaenoic Acid/Arachidonic Acid Ratio.

Intestinal failure-associated liver disease (IFALD) is a fatal complication of short bowel syndrome managed with parenteral nutrition. A clinical cohort study reported the usefulness of parenteral administration of fish-derived omega-3 fatty acids in improving IFALD; however, no biomarker has been developed as yet. The authors report the case of a preterm infant with IFALD complicated by extensive short bowel syndrome. Intravenous administration of omega-3 fatty acids were introduced using Omegaven®at the age of 4 mo for IFALD. The IFALD improved with an increase in Eicosapentaenoic acid (EPA)/ Arachidonic acid (AA) ratio (from 0.08 to 1.99) 7 d after the intravenous treatment. It is important to administer omega-3 fatty acids intravenously at an early stage for IFALD associated with extensive short bowel syndrome. A low EPA/AA ratio may be a serum marker of disease activity in IFALD.