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Update on the omega-3 fatty acid trial landscape: A narrative review with implications for primary prevention.
Kapoor, K, Alfaddagh, A, Stone, NJ, Blumenthal, RS
Journal of clinical lipidology. 2021;(4):545-555
Abstract
Residual risk mediated by hypertriglyceridemia among statin-treated individuals is an important clinical and public health challenge. Niacin, fibrates and omega-3 FA are three classes of non-statin agents with demonstrated TG-lowering effects. Randomized controlled trials of niacin and fibrates have been consistently negative, but the trial landscape for two key sources of omega-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is more complex. Clinical trials evaluating omega-3 FA can be differentiated into those that studied mixed formulations (EPA + DHA) and those that studied EPA alone. Those assessing the impact of mixed formulations have not consistently demonstrated CVD risk reduction, whereas trials of EPA alone have been successful. Two recent trials of mixed formulations - STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) and OMEMI (Omega-3 fatty acids in Elderly patients with Myocardial Infarction) - studied contemporarily treated patients with mixed EPA + DHA formulations at higher doses than before and showed no benefit, thus adding valuable information to our overall understanding of this evolving therapeutic class. In this review, we contextualize the findings of STRENGTH and OMEMI within the existing omega-3 FA clinical trial landscape and look ahead to how future trials can inform existing knowledge gaps, particularly with regards to the applicability of these agents within the primary prevention realm.
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2.
Docosahexaenoic and Arachidonic Acids as Neuroprotective Nutrients throughout the Life Cycle.
Sambra, V, Echeverria, F, Valenzuela, A, Chouinard-Watkins, R, Valenzuela, R
Nutrients. 2021;(3)
Abstract
The role of docosahexaenoic acid (DHA) and arachidonic acid (AA) in neurogenesis and brain development throughout the life cycle is fundamental. DHA and AA are long-chain polyunsaturated fatty acids (LCPUFA) vital for many human physiological processes, such as signaling pathways, gene expression, structure and function of membranes, among others. DHA and AA are deposited into the lipids of cell membranes that form the gray matter representing approximately 25% of the total content of brain fatty acids. Both fatty acids have effects on neuronal growth and differentiation through the modulation of the physical properties of neuronal membranes, signal transduction associated with G proteins, and gene expression. DHA and AA have a relevant role in neuroprotection against neurodegenerative pathologies such as Alzheimer's disease and Parkinson's disease, which are associated with characteristic pathological expressions as mitochondrial dysfunction, neuroinflammation, and oxidative stress. The present review analyzes the neuroprotective role of DHA and AA in the extreme stages of life, emphasizing the importance of these LCPUFA during the first year of life and in the developing/prevention of neurodegenerative diseases associated with aging.
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3.
Human milk fatty acid profile across lactational stages after term and preterm delivery: A pooled data analysis.
Floris, LM, Stahl, B, Abrahamse-Berkeveld, M, Teller, IC
Prostaglandins, leukotrienes, and essential fatty acids. 2020;:102023
Abstract
BACKGROUND Lipids in human milk (HM) provide the majority of energy for developing infants, as well as crucial essential fatty acids (FA). The FA composition of HM is highly variable and influenced by multiple factors. We sought to increase understanding of the variation in HMFA profiles and their development over the course of lactation, and after term and preterm delivery, using a pooled data analysis. OBJECTIVE To review the literature and perform a pooled data analysis to qualitatively describe an extensive FA profile (36 FAs) in term and preterm colostrum, transitional - and mature milk up to 60 days postpartum. DESIGN A Medline search was conducted for HMFA profile data following term or preterm delivery. The search was confined to English language papers published between January 1980 and August 2018. Studies reporting original data, extensive FA profiles in HM from healthy mothers were included. Weighted least squares (WLS) means were calculated from the pooled data using random or fixed effect models. RESULTS Our pooled data analysis included data from 55 studies worldwide, for a total of 4374 term milk samples and 1017 preterm milk samples, providing WLS means for 36 FAs. Patterns in both term and preterm milk were apparent throughout lactation for some FAs: The most abundant FAs (palmitic, linoleic and oleic acid) remained stable over time, whereas several long-chain polyunsaturated FAs (including ARA and DHA) seemed to decrease and short- and medium-chain FAs increased over time. CONCLUSIONS High heterogeneity between individual studies was observed for the reported levels of some FAs, whereas other FAs were remarkably consistent between studies. Our pooled data suggests that specific FA categories fluctuate according to distinct patterns over the course of lactation; many of these patterns are comparable between term and preterm milk.
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Oxidative Stress in Chronic Liver Disease and Portal Hypertension: Potential of DHA as Nutraceutical.
Boyer-Diaz, Z, Morata, P, Aristu-Zabalza, P, Gibert-Ramos, A, Bosch, J, Gracia-Sancho, J
Nutrients. 2020;(9)
Abstract
Chronic liver disease constitutes a growing public health issue worldwide, with no safe and effective enough treatment clinical scenarios. The present review provides an overview of the current knowledge regarding advanced chronic liver disease (ACLD), focusing on the major contributors of its pathophysiology: inflammation, oxidative stress, fibrosis and portal hypertension. We present the benefits of supplementation with docosahexaenoic acid triglycerides (TG-DHA) in other health areas as demonstrated experimentally, and explore its potential as a novel nutraceutical approach for the treatment of ACLD and portal hypertension based on published pre-clinical data.
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Docosahexaenoic Acid, a Potential Treatment for Sarcopenia, Modulates the Ubiquitin-Proteasome and the Autophagy-Lysosome Systems.
Lee, JH, Jeon, JH, Lee, MJ
Nutrients. 2020;(9)
Abstract
One of the characteristic features of aging is the progressive loss of muscle mass, a nosological syndrome called sarcopenia. It is also a pathologic risk factor for many clinically adverse outcomes in older adults. Therefore, delaying the loss of muscle mass, through either boosting muscle protein synthesis or slowing down muscle protein degradation using nutritional supplements could be a compelling strategy to address the needs of the world's aging population. Here, we review the recently identified properties of docosahexaenoic acid (DHA). It was shown to delay muscle wasting by stimulating intermediate oxidative stress and inhibiting proteasomal degradation of muscle proteins. Both the ubiquitin-proteasome and the autophagy-lysosome systems are modulated by DHA. Collectively, growing evidence indicates that DHA is a potent pharmacological agent that could improve muscle homeostasis. Better understanding of cellular proteolytic systems associated with sarcopenia will allow us to identify novel therapeutic interventions, such as omega-3 polyunsaturated fatty acids, to treat this disease.
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Abnormal n-6 fatty acid metabolism in cystic fibrosis contributes to pulmonary symptoms.
Wheelock, CE, Strandvik, B
Prostaglandins, leukotrienes, and essential fatty acids. 2020;:102156
Abstract
Cystic fibrosis (CF) is a recessively inherited fatal disease that is the subject of extensive research and ongoing development of therapeutics targeting the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). Despite progress, the link between CFTR and clinical symptoms is incomplete. The severe CF phenotypes are associated with a deficiency of linoleic acid, which is the precursor of arachidonic acid. The release of arachidonic acid from membranes via phospholipase A2 is the rate-limiting step for eicosanoid synthesis and is increased in CF, which contributes to the observed inflammation. A potential deficiency of docosahexaenoic acid may lead to decreased levels of specialized pro-resolving mediators. This pathophysiology may contribute to an early and sterile inflammation, mucus production, and to bacterial colonization, which further increases inflammation and potentiates the clinical symptoms. Advances in lipid technology will assist in elucidating the role of lipid metabolism in CF, and stimulate therapeutic modulations of inflammation.
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Expert Opinion on Benefits of Long-Chain Omega-3 Fatty Acids (DHA and EPA) in Aging and Clinical Nutrition.
Troesch, B, Eggersdorfer, M, Laviano, A, Rolland, Y, Smith, AD, Warnke, I, Weimann, A, Calder, PC
Nutrients. 2020;(9)
Abstract
Life expectancy is increasing and so is the prevalence of age-related non-communicable diseases (NCDs). Consequently, older people and patients present with multi-morbidities and more complex needs, putting significant pressure on healthcare systems. Effective nutrition interventions could be an important tool to address patient needs, improve clinical outcomes and reduce healthcare costs. Inflammation plays a central role in NCDs, so targeting it is relevant to disease prevention and treatment. The long-chain omega-3 polyunsaturated fatty acids (omega-3 LCPUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to reduce inflammation and promote its resolution, suggesting a beneficial role in various therapeutic areas. An expert group reviewed the data on omega-3 LCPUFAs in specific patient populations and medical conditions. Evidence for benefits in cognitive health, age- and disease-related decline in muscle mass, cancer treatment, surgical patients and critical illness was identified. Use of DHA and EPA in some conditions is already included in some relevant guidelines. However, it is important to note that data on the effects of omega-3 LCPUFAs are still inconsistent in many areas (e.g., cognitive decline) due to a range of factors that vary amongst the trials performed to date; these factors include dose, timing and duration; baseline omega-3 LCPUFA status; and intake of other nutrients. Well-designed intervention studies are required to optimize the effects of DHA and EPA in specific patient populations and to develop more personalized strategies for their use.
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Omega n-3 Supplementation: Exploring the Cardiovascular Benefits Beyond Lipoprotein Reduction.
Zambon, A, Pirillo, A, Zambon, S, Norata, GD, Catapano, AL
Current atherosclerosis reports. 2020;(12):74
Abstract
PURPOSE OF REVIEW Hypertriglyceridaemia is a highly prevalent disorder worldwide. Genetic and Mendelian randomization studies have suggested that triglyceride (TG)-rich lipoproteins are causal risk factors for coronary heart disease and contribute to the residual cardiovascular risk observed in patients optimally treated with statins. However, clinical trials failed to show cardiovascular benefits of TG-lowering; in this context, trials with omega-3 fatty acids provided contrasting results. Few trials have tested the supplementation of EPA alone rather than the combination of EPA + DHA. The JELIS study showed that EPA 1.8 g/day significantly reduced CV events in hypercholesterolaemic patients given statins, an effect that was independent on lipid reduction. RECENT FINDINGS The REDUCE-IT trial showed that high-dose (4 g/day) EPA significantly reduces the incidence of major cardiovascular events compared with placebo in patients with elevated TG levels. The clinical benefit was higher than expected by the reduction of TG-rich lipoprotein levels. Recent data support the efficacy of high-dose EPA supplementation on a background of optimal LDL-C-lowering therapy as a key approach to achieve a further and significant reduction of CV events in very-high CV risk patients with persistent hypertriglyceridaemia. The effect on lipids does not appear to fully explain the CV benefit, and additional mechanisms of action of EPA likely contribute to the cardiovascular protection, including the reduction of inflammation and platelet aggregation. Current guidelines recommend using high-dose EPA in combination with a statin in high/very-high CV risk patients with mild-to-moderate elevation of plasma TG to reduce the residual CV risk.
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Omega-3 PUFA Responders and Non-Responders and the Prevention of Lipid Dysmetabolism and Related Diseases.
Serini, S, Calviello, G
Nutrients. 2020;(5)
Abstract
The long-chain omega-3 polyunsaturated fatty acids (LC-omega-3 PUFAs) eicosapentaenoic acid and docosahexaenoic acid are the most popular dietary supplements recommended for the prevention/management of lipid dysmetabolisms and related diseases. However, remarkable inconsistencies exist among the outcomes of the human intervention studies in this field, which contrast with the impressive homogeneity of positive results of most of the preclinical studies. In the present review, we will firstly examine a series of factors-such as background diet composition, gut microbiota and genetic/epigenetic variants, which may lie beneath these inconsistencies. Moreover, we will discuss the recent advance in the knowledge of possible specific biomarkers (genetic-, epigenetic- and microbiota-related) that are being investigated with the goal to apply them in a personalized supplementation with omega-3 PUFAs. We will also consider the possibility of using already available parameters (Omega-3 index, Omega-6 PUFA/Omega-3 PUFA ratio) able to predict the individual responsiveness to these fatty acids and will discuss the optimal timing for their use. Finally, we will critically examine the results of those human studies that have already adopted the distinction of the subjects into omega-3 PUFA responders and non-responders and will discuss the advantage of using such an approach.
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Sports-related concussions and subconcussive impacts in athletes: incidence, diagnosis, and the emerging role of EPA and DHA.
Lust, CAC, Mountjoy, M, Robinson, LE, Oliver, JM, Ma, DWL
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2020;(8):886-892
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Abstract
Sports-related concussions (SRC) are traumatic brain injuries induced as the result of a biomechanical force to the body that temporarily impair neurological functions. Not all traumatic impacts reach the threshold necessary to produce concussive symptoms; however, the culmination of these events is known as a subconcussive impact (SCI). Athletes who have been diagnosed with a SRC or those who accumulate multiple SCI have exhibited structural damage to the brain, impairments to learning and memory, and an increase in depressive symptoms. This area is rapidly evolving, and current clinical definitions of injury, diagnosis, and treatment of SRC and SCI are reviewed. In tandem, there is also growing research examining the role of nutrition in brain injuries, focusing primarily on n-3 polyunsaturated fatty acids (PUFA). The potential role of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in reducing inflammation and promoting recovery following brain injury are also reviewed. Overall, advancements in the evaluation of SRC and SCI coupled with n-3 PUFA supplementation show promise in the management of brain injuries, leading to better long-term health outcomes for athletes. Novelty SRC have garnered widespread attention due to the growing body of reported prevalence in youth and professional sports. Current definitions and protocol(s) for diagnosing SRC and SCI have improved, but still require further evaluation. n-3, EPA and DHA, reduce inflammation and promote recovery following brain injuries in experimental models.