Rebuttal to Aung et al, "Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals".

No Abstract Available.

Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder.

BACKGROUND: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. METHODS: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. RESULTS: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1ß (IL-1ß) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. CONCLUSIONS: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention.

Trans-fatty acid levels in erythrocytes in Europe.

PURPOSE: High, but not low levels of trans-fatty acids (TFA) in erythrocytes are associated with increased mortality. Current erythrocyte TFA levels in Europe are not known. METHODS: TFA levels in samples submitted by physicians for erythrocyte omega-3 fatty acid analyses are reported, as analysed with a method (HS-Omega-3 Index®) previously used in pertinent prospective epidemiologic studies. From Germany, 6754 samples were included from 2008 through 2015, and 496 samples from 10 other European countries. RESULTS: In Germany, mean levels of C16:1n-7t, a marker for dairy and meat intake, decreased, as did mean levels of industrially produced (IP)-TFA, as did the percentage of individuals with IP-TFA > 1.04 %. Mean levels of IP-TFA in Austria and Switzerland were low before and after measures were taken to reduce them. Average levels of C16:1n-7t were low, and at levels associated with increased risk of death in previous studies. A limitation of our study is that samples were not obtained in a specific or representative manner. CONCLUSIONS: Levels of IP-TFA appear to be decreasing, as are those of ruminant-derived C16:1n-7t, a marker for dairy and meat intake. Few individuals had high levels of IP-TFA above a safe range, while many had low levels of C16:1n-7t. Our data argue against further action against TFA in the countries studied. More systematic biomarker-based studies are needed.

Public health relevance of drug-nutrition interactions.

The public health relevance of drug-nutrition interactions is currently highly undervalued and overlooked. This is particularly the case for elderly persons where multi-morbidity and consequently polypharmacy is very common. Vitamins and other micronutrients have central functions in metabolism, and their interactions with drugs may result in clinically relevant physiological impairments but possibly also in positive effects. On 12 April 2016, the University Medical Center Groningen (The Netherlands), as part of its Healthy Ageing program, organized a workshop on the public health relevance of drug-nutrient interactions. In this meeting, experts in the field presented results from recent studies on interactions between pharmaceuticals and nutrients, and discussed the role of nutrition for elderly, focusing on those persons receiving pharmaceutical treatment. This paper summarizes the proceedings of the symposium and provides an outlook for future research needs and public health measures. Since food, pharma and health are closely interconnected domains, awareness is needed in the medical community about the potential relevance of drug-nutrition interactions. Experts and stakeholders should advocate for the integration of drug-nutrition evaluations in the drug development process. Strategies for the individual patients should be developed, by installing drug review protocols, screening for malnutrition and integrating this topic into the general medical advice.

International Society for the Study of Fatty Acids and Lipids 2016 Debate: For Science-Based Dietary Guidelines on Fats, Meta-Analysis and Systematic Reviews Are Decisive.

This paper summarizes a debate on whether meta-analyses and systematic reviews are decisive in formulating guidelines for dietary fat. Held during the 12th congress of the International Society for the Study of Fatty Acids and Lipids in Stellenbosch, South Africa, September 7, 2016, the debate was hosted by the International Union of Nutritional Sciences and the International Expert Movement to Improve Dietary Fat Quality (IEM, www.theiem.org). Clemens von Schacky, Ludwig Maximilians-University, Munich, Germany, supported the statement, describing the types of weaknesses in individual studies and clinical trials. With examples of how to overcome such limitations, he concluded that nutritional guidelines on fat need a proper scientific basis in which randomized controlled trials (RCTs) with clinical endpoints and their meta-analyses are essential and decisive. In contention, Ingeborg Brouwer, Vrije Universiteit, Amsterdam, declared that recommendations on dietary fat intake should always be based on the totality of the evidence, including physiologic and biochemical knowledge and associations from observational epidemiology. RCTs and meta-analyses have their shortcomings, but well-conducted systematic reviews and meta-analyses support a transparent process for developing dietary fat guidelines. Participants agreed that evidence-based decision-making for dietary guidance should consider all the best available evidence using a transparent, systematic review.

Trans-fatty acids and mortality in patients referred for coronary angiography: the Ludwigshafen Risk and Cardiovascular Health Study.

AIMS: Trans-fatty acids (TFAs) are generated by the food industry and also occur naturally in trace amounts in dairy products. For the latter, beneficial health effects have been claimed, while there are numerous reports about TFA of industrial origin being hazardous to human health. Therefore, we aimed to investigate the association of TFA with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. METHODS AND RESULTS: The fatty acid composition of erythrocyte membranes was analysed using the HS-Omega-3 Index(®) methodology in 3259 participants of the LURIC study at baseline. During a median of 10.0 years of follow-up, a total of 975 (29.9%) study participants died, 614 (18.8%) from cardiovascular causes including 254 (7.8%) sudden cardiac deaths (SCDs). Association of TFA with clinical outcome was investigated with Cox proportional hazards regression. Total TFAs were inversely associated with mortality due to cardiovascular causes or SCD. This was mainly driven by the naturally occurring TFA C16:1n-7t (trans-palmitoleic acid). The reduced risk of SCD associated with C16:1n-7t persisted after multivariate adjustment with a hazard ratio of 0.63 (0.46-0.86) for the third tertile compared with the first tertile. There was no association of any TFA subgroup with an increased risk of adverse outcomes. CONCLUSIONS: In contrast to previous findings, the low concentrations of total TFAs found in LURIC were inversely associated with adverse cardiac outcomes. While the naturally occurring TFA C16:1n-7t was associated with reduced risk, no increased risk was found for industrially produced TFAs.

Cognitive Impairment Is Associated with a Low Omega-3 Index in the Elderly: Results from the KORA-Age Study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFA) may affect the risk of cognitive decline in older adults. METHODS: Cross-sectional analysis was conducted among 720 (50.4% women) participants aged 68-92 years (mean age: 77.6, SD ±6.2) of the population-based KORA-Age study. Eicosapentaenoic acid and docosahexaenoic acid (omega-3 index) were measured in erythrocytes as a percentage of total fatty acids. The categories low (<5.7), intermediate (5.7-6.8), and high (>6.8) levels of the omega-3 index were built using tertiles. The association between cognitive status and omega-3 levels was assessed by logistic regression analyses with adjustments for important concurrent risk factors of cognitive decline. RESULTS: In the sex- and age-adjusted model (model 1), subjects with a low omega-3 index were at a significantly higher risk for cognitive impairment (OR: 1.77, 95% CI: 1.15-2.73, p = 0.009). This association remained stable after further adjusting for educational level (model 2; OR: 1.75, 95% CI: 1.13-2.71, p = 0.01) and metabolic risk factors (model 3; OR: 1.77, 95% CI: 1.14-2.75, p = 0.01). After further controlling for affective disorders (model 4), the association did not attenuate (OR: 1.77, 95% CI: 1.14-2.76, p = 0.01). CONCLUSION: A robust association was found between low omega-3 levels and cognitive impairment in an elderly population. Further research is needed to understand the link between omega-3 PUFA and cognitive functioning.

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway.

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) contribute to the regulation of cardiovascular function. CYP enzymes also accept EPA and DHA to yield more potent vasodilatory and potentially anti-arrhythmic metabolites, suggesting that the endogenous CYP-eicosanoid profile can be favorably shifted by dietary omega-3 fatty acids. To test this hypothesis, 20 healthy volunteers were treated with an EPA/DHA supplement and analyzed for concomitant changes in the circulatory and urinary levels of AA-, EPA-, and DHA-derived metabolites produced by the cyclooxygenase-, lipoxygenase (LOX)-, and CYP-dependent pathways. Raising the Omega-3 Index from about four to eight primarily resulted in a large increase of EPA-derived CYP-dependent epoxy-metabolites followed by increases of EPA- and DHA-derived LOX-dependent monohydroxy-metabolites including the precursors of the resolvin E and D families; resolvins themselves were not detected. The metabolite/precursor fatty acid ratios indicated that CYP epoxygenases metabolized EPA with an 8.6-fold higher efficiency and DHA with a 2.2-fold higher efficiency than AA. Effects on leukotriene, prostaglandin E, prostacyclin, and thromboxane formation remained rather weak. We propose that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA supplementation.

Low Omega-3 Index in 106 German elite winter endurance athletes: a pilot study.

The Omega-3 Index is defined as erythrocyte eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and represents an individual's status in these two marine omega-3 fatty acids. A target range of 8 to 11% has been suggested, because values below predispose to cardiovascular events, especially sudden cardiac death, as well as to suboptimal brain function, like prolonged reaction times or even depression. Compared with the general population, elite athletes have an increased incidence of sudden death. The Omega-3 Index has not yet been investigated in elite athletes. In an exploratory approach, we determined the Omega-3 Index in 106 consecutive German national elite winter endurance athletes presenting for preparticipation screening, using a well-established analytical procedure (HS-Omega-3 Index). Surprisingly, only one athlete had a value within the target range, but all others had values <8%. We conclude that we have identified a deficiency of EPA and DHA in these elite athletes. This deficiency presents a potential option for prevention of cardiovascular events such as sudden cardiac death, and improving aspects of brain function. It will be important to scrutinize our finding by more thorough epidemiologic studies and appropriate intervention trials.

Krill oil supplementation's effect on school grades in typically developing adolescents.

Long-chain polyunsaturated fatty acids (LCPUFA) are important for brain development and functioning and with that, possibly school performance. Several cross-sectional studies have shown significant positive associations between fish consumption, an important source of LCPUFA and school grades in adolescents. The effect of LCPUFA supplementation on school grades in adolescents has not been investigated yet. The goal of the current study was to investigate (I) the associations between the Omega-3 Index (O3I) at baseline and after 12 months respectively and school grades and (II) the effect of one year krill oil supplementation (source of LCPUFA) on school grades in adolescents with a low O3I at baseline. A double-blind randomised placebo-controlled trial with repeated measurements was executed. Participants received either 400 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day for the first three months in Cohort 1 and the nine months thereafter 800 mg EPA + DHA per day, Cohort 2 started immediately with 800 mg EPA + DHA per day,or a placebo. The O3I was monitored with a finger prick at baseline, three, six and twelve months. Subject grades for English, Dutch and math were collected, a standardised mathematics test was executed at baseline and at 12 months. Data was analysed with (I) explorative linear regressions to investigate associations at baseline and follow-up and (II) mixed model analyses separately for each of the subject grades and the standardised mathematics test to investigate the effect of supplementation after 12 months. The krill oil group had a small significant increase in the mean O3I at all time points. However, very few participants achieved the intended target O3I range of 8-11%. At baseline a significant association between baseline O3I and English grade was show, additionally a trend for an association with Dutch grade was shown. After 12 months no significant associations were found. Additionally, there was no significant effect of krill oil supplementation on subject grades or standardised mathematics test score. In this study, no significant effect of krill oil supplementation on subject grades or standardised mathematics test performance was found. However, as many participants dropped out and/or were non-adherent, results should be interpreted with caution.

De Novo Lipogenesis-Related Monounsaturated Fatty Acids in the Blood Are Associated with Cardiovascular Risk Factors in HFpEF Patients.

De novo lipogenesis (DNL)-related monounsaturated fatty acids (MUFAs) in the blood are associated with incident heart failure (HF). This observation's biological plausibility may be due to the potential of these MUFAs to induce proinflammatory pathways, endoplasmic reticulum stress, and insulin resistance, which are pathophysiologically relevant in HF. The associations of circulating MUFAs with cardiometabolic phenotypes in patients with heart failure with a preserved ejection fraction (HFpEF) are unknown. In this secondary analysis of the Aldosterone in Diastolic Heart Failure trial, circulating MUFAs were analysed in 404 patients using the HS-Omega-3-Index® methodology. Patients were 67 ± 8 years old, 53% female, NYHA II/III (87/13%). The ejection fraction was ≥50%, E/e' 7.1 ± 1.5, and the median NT-proBNP 158 ng/L (IQR 82-298). Associations of MUFAs with metabolic, functional, and echocardiographic patient characteristics at baseline/12 months follow-up (12 mFU) were analysed using Spearman's correlation coefficients and linear regression analyses, using sex/age as covariates. Circulating levels of C16:1n7 and C18:1n9 were positively associated with BMI/truncal adiposity and associated traits (dysglycemia, atherogenic dyslipidemia, and biomarkers suggestive of non-alcoholic-fatty liver disease). They were furthermore inversely associated with functional capacity at baseline/12 mFU. In contrast, higher levels of C20:1n9 and C24:1n9 were associated with lower cardiometabolic risk and higher exercise capacity at baseline/12 mFU. In patients with HFpEF, circulating levels of individual MUFAs were differentially associated with cardiovascular risk factors. Our findings speak against categorizing FA based on physicochemical properties. Circulating MUFAs may warrant further investigation as prognostic markers in HFpEF.

Trans-fatty acid blood levels of industrial but not natural origin are associated with cardiovascular risk factors in patients with HFpEF: a secondary analysis of the Aldo-DHF trial.

BACKGROUND: Industrially processed trans-fatty acids (IP-TFA) have been linked to altered lipoprotein metabolism, inflammation and increased NT-proBNP. In patients with heart failure with preserved ejection fraction (HFpEF), associations of TFA blood levels with patient characteristics are unknown. METHODS: This is a secondary analysis of the Aldo-DHF-RCT. From 422 patients, individual blood TFA were analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were: 67 ± 8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥ 50%, E/e' 7.1 ± 1.5; NT-proBNP 158 ng/L (IQR 82-298). A principal component analysis was conducted but not used for further analysis as cumulative variance for the first two PCs was low. Spearman's correlation coefficients as well as linear regression analyses, using sex and age as covariates, were used to describe associations of whole blood TFA with metabolic phenotype, functional capacity, echocardiographic markers for LVDF and neurohumoral activation at baseline and after 12 months. RESULTS: Blood levels of the naturally occurring TFA C16:1n-7t were inversely associated with dyslipidemia, body mass index/truncal adiposity, surrogate markers for non-alcoholic fatty liver disease and inflammation at baseline/12 months. Conversely, IP-TFA C18:1n9t, C18:2n6tt and C18:2n6tc were positively associated with dyslipidemia and isomer C18:2n6ct with dysglycemia. C18:2n6tt and C18:2n6ct were inversely associated with submaximal aerobic capacity at baseline/12 months. No significant association was found between TFA and cardiac function. CONCLUSIONS: In HFpEF patients, higher blood levels of IP-TFA, but not naturally occurring TFA, were associated with dyslipidemia, dysglycemia and lower functional capacity. Blood TFAs, in particular C16:1n-7t, warrant further investigation as prognostic markers in HFpEF. Higher blood levels of industrially processed TFA, but not of the naturally occurring TFA C16:1n-7t, are associated with a higher risk cardiometabolic phenotype and prognostic of lower aerobic capacity in patients with HFpEF.

Impact of intravenous fish oil on omega-3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition.

BACKGROUND: Long-term parenteral nutrition (PN) can lead to intestinal failure-associated liver disease (IFALD). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were shown to prevent IFALD. EPA-derived and DHA-derived oxylipins could contribute to this protective effect. METHODS: We analyzed the effect of parenteral fish oil on oxylipins in patients with chronic intestinal failure receiving PN (n = 8). Patients first received no fish oil for 8 weeks and then switched to PN with 25% of fat as fish oil for another 8 weeks. Fatty acid profiles of red blood cells, PUFA-derived oxylipins generated by cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 (CYP) pathways, inflammatory markers, and liver function were assessed before and during fish-oil PN. RESULTS: EPA plus DHA in erythrocytes (the Omega-3 Index) was high with a median of 11.96% at baseline and decreased to 9.57% without fish oil in PN. Addition of fish oil in PN increased the median Omega-3-Index to 12.75%. EPA-derived and DHA-derived CYP-dependent and LOX-dependent metabolites increased significantly with fish oil in PN, with less pronounced changes in arachidonic acid and its oxylipins. There were no significant changes of inflammation and liver function parameters. CONCLUSIONS: This study shows that fish oil-containing PN leads to primarily CYP- and LOX-dependent n-3 PUFA-derived inflammation-dampening oxylipins arising from EPA and DHA. Within this short (16-week) study, there were no significant changes in inflammation and clinical readout parameters.

Omega-3 fatty acids in bipolar patients with a low omega-3 index and reduced heart rate variability: the "BIPO-3" trial.

BACKGROUND: Research suggests that a low omega-3 index may contribute to the low heart rate variability and the increased risk of cardiovascular morbidity and mortality in bipolar disorders. However, so far, no intervention trial with EPA and DHA has been conducted in bipolar patients attempting to increase their heart rate variability. METHODS: 119 patients with bipolar disorder according to DSM-IV were screened, with 55 euthymic bipolar patients-owing to inclusion criteria (e.g. low omega-3 index (< 6%), SDNN < 60 ms.)-being enrolled in a randomized, double-blind, 12-week parallel study design with omega-3 fatty acids (4 capsules of 530 mg EPA, 150 mg DHA) or corn oil as a placebo, in addition to usual treatment. Heart rate variability as well as the omega-3 index were measured at baseline and at the endpoint of the study. RESULTS: A total of 42 patients (omega-3: n = 23, corn oil: n = 19) successfully completed the study after 12 weeks. There was a significant increase in the omega-3 index (value at endpoint minus value at baseline) in the omega-3 group compared to the corn oil group (p < 0.0001). However, there was no significant difference in the change of the SDNN (value at endpoint minus value at baseline) between the treatment groups (p = 0.22). In addition, no correlation between changes in SDNN and change in the omega-3 index could be detected in the omega-3 group (correlation coefficient = 0.02, p = 0.94) or the corn oil group (correlation coefficient = - 0.11, p = 0.91). Similarly, no significant differences between corn oil and omega-3 group regarding the change of LF (p = 0.19), HF (p = 0.34) and LF/HF ratio (p = 0.84) could be demonstrated. CONCLUSIONS: In our randomized, controlled intervention trial in euthymic bipolar patients with a low omega-3 index and reduced heart rate variability no significant effect of omega-3 fatty acids on SDNN or frequency-domain measures HF, LF and LF/HF ratio could be detected. Possible reasons include, among others, the effect of psychotropic medication present in our trial and/or the genetics of bipolar disorder itself. Further research is needed to test these hypotheses. Trial registration ClinicalTrials.gov, NCT00891826. Registered 01 May 2009-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT00891826.

Long-term fasting: Multi-system adaptations in humans (GENESIS) study-A single-arm interventional trial.

Fasting provokes fundamental changes in the activation of metabolic and signaling pathways leading to longer and healthier lifespans in animal models. Although the involvement of different metabolites in fueling human fasting metabolism is well known, the contribution of tissues and organs to their supply remains partly unclear. Also, changes in organ volume and composition remain relatively unexplored. Thus, processes involved in remodeling tissues during fasting and food reintroduction need to be better understood. Therefore, this study will apply state-of-the-art techniques to investigate the effects of long-term fasting (LF) and food reintroduction in humans by a multi-systemic approach focusing on changes in body composition, organ and tissue volume, lipid transport and storage, sources of protein utilization, blood metabolites, and gut microbiome profiles in a single cohort. This is a prospective, single-arm, monocentric trial. One hundred subjects will be recruited and undergo 9 ± 3 day-long fasting periods (250 kcal/day). We will assess changes in the composition of organs, bones and blood lipid profiles before and after fasting, as well as high-density lipoprotein (HDL) transport and storage, untargeted metabolomics of peripheral blood mononuclear cells (PBMCs), protein persulfidation and shotgun metagenomics of the gut microbiome. The first 32 subjects, fasting for 12 days, will be examined in more detail by magnetic resonance imaging (MRI) and spectroscopy to provide quantitative information on changes in organ volume and function, followed by an additional follow-up examination after 1 and 4 months. The study protocol was approved by the ethics board of the State Medical Chamber of Baden-Württemberg on 26.07.2021 and registered at ClinicalTrials.gov (NCT05031598). The results will be disseminated through peer-reviewed publications, international conferences and social media. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05031598].

Saturated Fatty Acid Blood Levels and Cardiometabolic Phenotype in Patients with HFpEF: A Secondary Analysis of the Aldo-DHF Trial.

BACKGROUND: Circulating long-chain (LCSFAs) and very long-chain saturated fatty acids (VLSFAs) have been differentially linked to risk of incident heart failure (HF). In patients with heart failure with preserved ejection fraction (HFpEF), associations of blood SFA levels with patient characteristics are unknown. METHODS: From the Aldo-DHF-RCT, whole blood SFAs were analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were 67 ± 8 years, 53% female, NYHA II/III (87%/13%), ejection fraction ≥50%, E/e' 7.1 ± 1.5; and median NT-proBNP 158 ng/L (IQR 82-298). Spearman´s correlation coefficients and linear regression analyses, using sex and age as covariates, were used to describe associations of blood SFAs with metabolic phenotype, functional capacity, cardiac function, and neurohumoral activation at baseline and after 12-month follow-up (12 mFU). RESULTS: In line with prior data supporting a potential role of de novo lipogenesis-related LCSFAs in the development of HF, we showed that baseline blood levels of C14:0 and C16:0 were associated with cardiovascular risk factors and/or lower exercise capacity in patients with HFpEF at baseline/12 mFU. Contrarily, the three major circulating VLSFAs, lignoceric acid (C24:0), behenic acid (C22:0), and arachidic acid (C20:0), as well as the LCSFA C18:0, were broadly associated with a lower risk phenotype, particularly a lower risk lipid profile. No associations were found between cardiac function and blood SFAs. CONCLUSIONS: Blood SFAs were differentially linked to biomarkers and anthropometric markers indicative of a higher-/lower-risk cardiometabolic phenotype in HFpEF patients. Blood SFA warrant further investigation as prognostic markers in HFpEF. One Sentence Summary: In patients with HFpEF, individual circulating blood SFAs were differentially associated with cardiometabolic phenotype and aerobic capacity.

Red blood cell fatty acid patterns from 7 countries: Focus on the Omega-3 index.

Red blood cell (RBC) fatty acid (FA) patterns are becoming recognized as long-term biomarkers of tissue FA composition, but different analytical methods have complicated inter-study and international comparisons. Here we report RBC FA data, with a focus on the Omega-3 Index (EPA + DHA in% of total FAs in RBC), from samples of seven countries (USA, Canada, Italy, Spain, Germany, South Korea, and Japan) including 167,347 individuals (93% of all samples were from the US). FA data were generated by a uniform methodology from a variety of interventional and observational studies and from clinical laboratories. The cohorts differed in size, demographics, health status, and year of collection. Only the Canadian cohort was a formal, representative population-based survey. The mean Omega-3 Index of each country was categorized as desirable (>8%), moderate (>6% to 8%), low (>4% to 6%), or very low (≤4%). Only cohorts from Alaska (treated separately from the US), South Korea and Japan showed a desirable Omega-3 Index. The Spanish cohort had a moderate Omega-3 Index, while cohorts from the US, Canada, Italy, and Germany were all classified as low. This study is limited by the use of cohorts of convenience and small sample sizes in some countries. Countries undertaking national health status studies should utilize a uniform method to measure Omega-3 FA levels.

Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of {omega}-3 fatty acids.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect against cardiovascular disease by largely unknown mechanisms. We tested the hypothesis that EPA and DHA may compete with arachidonic acid (AA) for the conversion by cytochrome P450 (CYP) enzymes, resulting in the formation of alternative, physiologically active, metabolites. Renal and hepatic microsomes, as well as various CYP isoforms, displayed equal or elevated activities when metabolizing EPA or DHA instead of AA. CYP2C/2J isoforms converting AA to epoxyeicosatrienoic acids (EETs) preferentially epoxidized the ω-3 double bond and thereby produced 17,18-epoxyeicosatetraenoic (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from EPA and DHA. We found that these ω-3 epoxides are highly active as antiarrhythmic agents, suppressing the Ca(2+)-induced increased rate of spontaneous beating of neonatal rat cardiomyocytes, at low nanomolar concentrations. CYP4A/4F isoforms ω-hydroxylating AA were less regioselective toward EPA and DHA, catalyzing predominantly ω- and ω minus 1 hydroxylation. Rats given dietary EPA/DHA supplementation exhibited substantial replacement of AA by EPA and DHA in membrane phospholipids in plasma, heart, kidney, liver, lung, and pancreas, with less pronounced changes in the brain. The changes in fatty acids were accompanied by concomitant changes in endogenous CYP metabolite profiles (e.g. altering the EET/EEQ/EDP ratio from 87:0:13 to 27:18:55 in the heart). These results demonstrate that CYP enzymes efficiently convert EPA and DHA to novel epoxy and hydroxy metabolites that could mediate some of the beneficial cardiovascular effects of dietary ω-3 fatty acids.

The Omega-3 Index as a risk factor for cardiovascular diseases.

The Omega-3 Index has been defined as eicosapentaenoic plus docosahexaenoic acids in erythrocytes. Integral part of the definition is a standardized analytical procedure, which conforms to the standards of Clinical Chemistry. This resulted in more than 90 collaborative research projects, concluded and ongoing, and 64 publications so far. The Omega-3 Index is emerging as a risk factor for fatal and non-fatal cardiovascular events. This standardized analysis of fatty acid patterns adds incremental information to standard risk factor algorithms, and it correctly reclassifies persons from intermediate to high or low risk. Circumstantial evidence indicates that determining the Omega-3 Index has a therapeutic consequence. Thus, the Omega-3 Index fulfils important criteria for novel biomarkers, set forth by the American Heart Association and others, and compares well to other novel biomarkers. Future results will add precision to the value of the Omega-3 Index in cardiology, and probably expand its application to other areas, like psychiatry and pregnancy.