오메가 3지방산 Omega-3 Fatty Acids에 대한 최신 논문 - 번역해야....

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Beyond reason

미량원소 치유의학의 세계

오메가 3 지방산의 효과

1) 심혈관 염증방지 보호

2) 항염증효과

3) 혈전방지

4) 중성지방 수치 내림

5) 상피세포 기능 개선

6) 동맥경화 방지

7) 항부정맥 효과

8) 사망율 감소

오메가3지방산이 좋은 이유

우리 몸의 세포막 구성
오메가3지방산은 우리 몸에 꼭 필요하지만 자체적으로 생산되지 않는 필수지방산으로서 불포화지방산의 한 종류다. 세포막을 구성하는 주요 성분이며, 염증을 억제하는 기능과 세포에 산소를 원활하게 해주는 역할도 한다. 또한 ‘피떡’(혈전)을 예방하는 효과가 크다. 오메가3지방산의 효능이 부각된 것은 1970년대 북극에 사는 에스키모를 연구하면서부터다. 에스키모들은 생선을 주로 먹는데 심장질환이 없었다. 생선기름의 오메가3 지방산이 혈액의 중성지방을 낮추고 혈액순환을 개선시키는 효능이 있음을 알아낸 것이다. 미국(FDA)와 캐나다 정부가 오메가3지방산의 효능을 인정했다.

에스키모인들에게 심장병이 없는 이유는?
에스키모에게서 확인됐듯, 오메가3지방산은 주로 고등어·참치·연어 같은 생선과 해조류에 많다. 호두, 들기름, 아마씨유 같은 식품에도 풍부하다. 생선, 즉 동물성 오메가3지방산은 DHA, EPA가 많다. 들기름, 호두, 아마씨유 같은 식물성 기름에는 알파리놀렌산이 많이 포함되어 있다. DHA, EPA는 두뇌 기능을 발달시키고 혈중 콜레스테롤을 저하시키는 반면, 알파리놀렌산은 우리 몸의 세포막을 이루는 필수 지방산 중 대부분을 차지해 세포 건강에 중요한 역할을 한다.

오메가3지방산의 효능은 각종 연구결과로 발표됐다. 심혈관질환을 예방할 뿐만 아니라 염증 감소에 효과적이라 천식이나 만성염증 완화에 좋다. 또한 우울증이나 치매 예방에 도움이 된다는 연구 결과가 있다. 최근엔 사망률까지 낮춘다는 연구결과가 발표됐다. 스페인의 비만·영양·생리학연구소 알렉스 박사팀은 6년간 7000명을 대상으로 오메가3지방산 섭취와 사망률 간의 연관성을 조사해 <미국심장학회저널>에 게재했다. 조사결과, 하루 에너지의 0.7%를 호두 같은 식물성 오메가3 지방산으로 섭취한 집단이 비교적 적은 양의 식물성 오메가3지방산을 섭취한 대조군보다 사망률이 더 낮다는 사실을 발견했다.

오메가3 건강기능식품, 이럴 때 복용
1 심장에 좋은 고밀도 콜레스테롤의 수치가 낮은 경우
2 등푸른생선에 알레르기가 있어 식품으로 섭취하지 못하는 경우
3 혈관질환자. 흡연자 중에서 아스피린 복용이 어려운 경우
4 생선 속 수은을 피해야 하는 임산부와 어린이
5 중성지방 수치가 높은 경우
6 혈당 수치가 높은 경우

혈전 생성 막고 항염 효과 커
대장암 환자의 사망률도 낮췄다. 영국 의학저널 <거트(GUT)>는 미국인 17만 명 중 대장암이 발병한 1659명을 상대로 역학 조사를 실시한 결과, 오메가3지방산 섭취와 낮은 사망률 사이에 높은 상관관계가 있음을 밝혔다. 조사결과, 매일 0.1g에 못 미치는 오메가3지방산을 먹던 사람에 비교해 매일 최소 0.3g의 오메가3지방산을 먹던 사람의 사망률이 41% 더 낮은 것. 고대안암병원 가정의학과 윤진희 교수는 “심장박동수를 낮추고, 심근효율을 증가시키며, 자율신경계 기능을 향상시킨다”며 “하루 4g 이상을 먹으면 혈전 생성을 낮추며, 7g 이상일 땐 중성지방 형성을 감소하고, 2g 이상 먹으면 항염 효과도 볼 수 있다”고 말했다.

오메가3지방산, 이것을 주의하라

과도하게 먹으면 뇌졸중 위험 증가
오메가3지방산의 과다한 섭취는 다른 불포화지방산인 오메가6의 대사를 방해할 수 있으므로 적정량을 지켜야 한다. 또 오메가3지방산은 혈전을 녹여 혈액순환을 원활하게 하는 효과가 있기 때문에 뇌졸중이나 수술 환자는 먹지 않는 편이 좋다. 특히 혈압약을 복용한다면 혈압 저하가 심하게 일어날 수 있으므로 주의한다. 오메가3를 과다하게 섭취할 경우 세포막의 지질이 산화 스트레스에 취약해질 수 있어, 항산화 비타민인 비타민E를 함께 먹는 것이 좋다. 현재 오메가3지방산의 일일 권장량은 500~2000mg이다. 이는 생선을 일주일에 2번 이상 먹어야 충족되는 수치이다 보니 대부분 건강기능식품을 통해 섭취한다.

산패된 오메가3지방산은 독이다
문제는 건강기능식품 속의 오메가3지방산은 기름이기 때문에 쉽게 산패되는 점이다. 산패는 기름이 공기나 물 같은 외부 물질과 접촉하면서 맛과 성분이 변하는 걸 말한다. 산패된 오메가3지방산은 유효 성분이 줄어드는 게 아니라 아예 다른 성분이 되면서 인체 내에서 활성산소를 증가시켜 DNA와 세포 변형을 일으키는 발암물질로 작용한다.

동물실험을 통해 산패된 기름이 생체기관의 손상, 염증, 발암성, 죽종동맥경화증의 악화를 유발한다는 사실도 입증됐다. 쥐에게 산화된 오메가3지방산을 지속적으로 투여 했더니, 성장 지연과 장 과민 증상, 간 비대, 신장 비대, 용혈성 빈혈, 체내 비타민E 감소, 간내 지방 산화 및 염증 증가, 심근증, 대장 악성종양세포 증식 등이 관찰됐다. 따라서 산패된 오메가3지방산은 섭취하지 말아야 한다.

산패된 오메가3지방산 건강기능식품은 역할 정도의 비린내가 나고, 캡슐이 말랑거리면서 캡슐끼리 붙어 있는 특징을 보인다. 헬스조선 약사자문위원인 압구정스타약국 이보현 약사는 “우리는 오메가3지방산 제품에 대해서 오염원에 대한 검사분석까지만 확인해 왔다”며 “전 세계적으로 오메가3를 포함한 어유제품군의 산패도 검사 및 관리의 중요성에 대한 주장이 점점 더 커지고 있다”고 말했다.

이보현 약사는 “액상 어유는 향미로 마스킹되어 있고, 연질 캡슐이나 장용성 캡슐로 제형화되어 있는 것이 산패도를 확인할 수 있는 냄새나 맛을 인지할 수 없게 하여 전문적 과학적인 산패도 검사의 도입이 필요하다”고 했다. 따라서 제품 살 때 빛이 쉽게 투과할 수 있는 투명 용기로 되어 있거나, 포장을 뜯은 후 빨리 먹지 못하는 대용량은 구입하지 않는다.

오메가3지방산을 더 잘 먹는 법
건강기능식품, EPA와 DHA 함유량 500mg 이상 선택
오메가3지방산이 든 건강기능식품을 구입할 때, 산패 여부도 중요하지만 용량이 얼마나 들었는지 꼼꼼히 봐야 한다. 특히 EPA와 DHA 함유량을 봐야 하는데, 단순히 100mg 용량을 볼 것이 아니라 EPA와 DHA가 500mg 이상인 제품을 골라야 우리나라에서 권고하는 최소 권장량을 섭취할 수 있다.

큰 생선보다 작은 생선이 중금속 오염 덜해
오메가3지방산의 재료가 되는 생선 중에는 중금속 오염의 위험이 있는 것들이 많다. 특히 큰 생선으로 만들 경우 중금속 위험이 높아, 가능하면 작은 생선으로 만든 제품을 선택하는 게 좋다. 연어나 하프물범 등 큰 어종은 먹이사슬의 윗단계에 있기 때문에 중 금속 위험이 높은 반면, 멸치·정어리 등 작은 어종에 중금속 오염이 덜하기 때문에 좀 더 안전하다.

오메가3지방산 건강기능식품 구매요령
① 제품의 안전성 체크
중금속 함량 및 캡슐 규격시험, PCBs 오염도 분석 등에서 안전성에 문제가 없는지 여부 확인한다.
③자신에게 적합한 제품 선택
오메가3는 가공 방법, 주원료 등에 따라 세분화되어 있고, 용량과 일일 섭취량도 각각 다르다. 표시사항과 설명서를 잘 확인하고 자신의 건강상태를 꼼꼼히 따져 적합한 제품을 고른다.
③ 건강기능식품 마크 확인은 필수
건강기능식품을 구매할 때에는 식약처에서 승인받은 건강기능식품인지 구별하기 위해 건강기능식품 마크를 반드시 확인한다. 또 유통기한 등의 제품정보를 잘 살펴봐야 한다.

Eur Heart J. 2012 Feb; 33(4): 436–443. 

Published online 2011 Sep 19. doi: 10.1093/eurheartj/ehr362

PMCID: PMC3279313

PMID: 21933782

Fish oil and omega-3 fatty acids in cardiovascular disease: do they really work?

Daan Kromhout,1,* Satoshi Yasuda,2 Johanna M. Geleijnse,1 and  Hiroaki Shimokawa2,*

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Abstract

Omega-3 fatty acids, which are found abundantly in fish oil, exert pleiotropic cardiometabolic effects with a diverse range of actions. The results of previous studies raised a lot of interest in the role of fish oil and omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases. The present review will focus on the current clinical uses of omega-3 fatty acids and provide an update on their effects. Since recently published trials in patients with coronary artery diseases or post-myocardial infarction did not show an effect of omega-3 fatty acids on major cardiovascular endpoints, this review will examine the limitations of those data and suggest recommendations for the use of omega-3 fatty acids.

Keywords: Fish oils, Cardiovascular disease

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Introduction

In 1929, the essential fatty acids were discovered by the biochemists Evans and Burr.1 They showed that mammals do not possess enzymes able to synthesize double bonds at the n-3 and n-6 positions of the carbon chain of a fatty acid. Therefore, humans must obtain the essential fatty acids linoleic acid (C18:2n-6) and alpha linolenic acid (ALA, C18:3n-3) from dietary sources. Alpha linolenic acid can be extended to eicosapentaenoic acid (EPA C20:5n-3) and docosahexaenoic acid (DHA C22:6n-3) through elongation and desaturation. Fish oil is a rich source of these omega-3 fatty acids.

In 1937, the British physiologist Hugh Sinclair visited Evans and became interested in the possibility that deficiencies in polyunsaturated fatty acids could cause coronary artery diseases (CAD). In 1944, he undertook his first visit to the Inuit and became convinced that their diet protects against atherosclerosis and Western diseases.2 In a letter to the Lancet, he hypothesized in 1956 that omega-3 fatty acids may be responsible for the protective effect of their diet.3 This view was contrary to the dogma of that time that all animal fats are harmful. In the 1970s, he joined the Danish investigators Bang and Dyerberg4,5 during one of their expeditions to Greenland. They found that the Inuit consumed ∼400 g of seafood per day and their average intake of omega-3 fatty acids was 14 g per day compared with 3 g per day among Danes. An epidemiological study showed that the incidence of myocardial infarction (MI) was 10 times lower among the Inuit compared with the Danes.6

The difference between the Inuit and the Danes in the intake of omega-3 fatty acids was reflected in their fatty acid composition of platelets. Differences were also observed in haemostatic factors, bleeding time, serum triglycerides, and high-density lipoprotein (HDL)—cholesterol levels. To show that these associations are causal, Sinclair put himself in 1977 on an Inuit diet for 100 days.7 His bleeding time rose from 3–5 to 50 min and substantial decreases were observed in blood platelets, erythrocytes, packed cell volume, and haemoglobin. The triglyceride-rich very low-density lipoprotein (VLDL) fell and the HDL fraction increased considerably. A substantial increase in the EPA concentration and a marked decrease in the linoleic acid concentration of cholesteryl esters were noted. Sinclair concluded from this experiment that it is necessary to have the right balance of omega-3 and omega-6 fatty acids to prevent thrombotic disorders.

In 1985, Kromhout et al.8 showed in the Zutphen Study, a prospective cohort study in the Netherlands, that eating fish once or twice per week was associated with a lower risk of fatal CAD compared with men who did not eat fish. Four years later in 1989, Burr et al.9 showed in the Diet and Reinfarction Trial (DART) that cardiac patients who received an advice to add two fatty fish meals per week to their diet reduced CAD mortality significantly, compared with those who did not get a fish advice. The results of these studies raised a lot of interest in the role of fish oil and omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases (CVD). In this article, we summarize the mechanisms of the action of omega-3 fatty acids and the results of cohort studies and clinical trials on omega-3 fatty acids and CVD. Finally, we draw conclusions on whether omega-3 fatty acids reduce the incidence of these diseases.

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Mechanisms of action of omega-3 fatty acids

The cardiometabolic effects of omega-3 fatty acids continue to be extensively investigated and remain an active area of research. Omega-3 fatty acids can ultimately increase arrhythmic thresholds, reduce blood pressure, improve arterial and endothelial function, reduce platelet aggregation, and favourably affect autonomic tone (Figure 1). In this section, we briefly review recent studies that extend our knowledge on the cardioprotective effects of omega-3 fatty acids.10

Figure 1

Beneficial effects of omega-3 fatty acids. TG, triglycerides; RLP, remnant lipoproteins; RBC, red blood cells.

Anti-inflammatory effects

Recently, the anti-inflammatory effects of omega-3 fatty acids have attracted much attention. Omega-3 fatty acids reduce the content of arachidonic acid (AA) in membrane phospholipids in platelets, endothelial cells, and inflammatory cells with a resultant reduced production of AA-derived pro-inflammatory mediators, including prostaglandin (PG)-E2, thromboxane (TX)-B2, leucotriene (LT)-B4, hydroxyeicosatetraenoic acid (5-HETE), and LT-E4. Importantly, EPA also acts as a substrate for cyclo-oxygenase and lipoxygenase enzymes, which could increase a different family of eicosanoids—the three-series PGs and TXs.11 In addition to these anti-inflammatory effects, omega-3 fatty acids have a number of other effects that may occur either downstream of altered eicosanoid production or independent of this activity.12 For example, the effects of omega-3 fatty acids on inflammatory cytokine expression‎ could be at least in part through modulating intra-cellular signalling pathways that inactivates transcriptional factors.12Recent studies demonstrated that omega-3 fatty acids could down-regulate the activity of the nuclear factor (NF)-κB,12 which plays a key role in the regulation of gene expression‎ in inflammatory responses and has been implicated in the pathogenesis of CVD.13 The inhibition of NF-κB activation can be mediated by the mechanism that is related to the activation of peroxisome proliferator-activated receptor (PPAR) or the inhibition of toll-like receptors.13

Rho-kinase is a downstream effector of the small GTPase Rho and mediates diverse cellular functions, such as smooth muscle cell contraction, cell migration, and proliferation.14 Rho-kinase also up-regulates pro-inflammatory molecules and down-regulates endothelial nitric oxide (NO) synthase (eNOS).15,16 It has been recently demonstrated that long-term treatment with EPA significantly inhibits Rho-kinase activation in the myocardium subjected to ischaemia–reperfusion in vivo (Figure 2).17

Figure 2

Long-term eicosapentaenoic acid treatment inhibits myocardial Rho-kinase activation induced by ischaemia/reperfusion. Male pigs were treated with either a control chow or eicosapentaenoic acid (600 mg/kg/day) for 3 weeks and were subjected to myocardial ischaemia by 90 min occlusion of the left circumflex coronary artery and subsequent 60 min reperfusion. The eicosapentaenoic acid group had increased eicosapentaenoic acid level in red blood cells (eicosapentaenoic acid 4.30 ± 0.63 mol%). The eicosapentaenoic acid treatment significantly ameliorated myocardial ischaemia/reperfusion injury and significantly inhibited myocardial Rho-kinase activity, assessed by the extent of myosin-binding subunit (MBS) phosphorylation. Top panel (A) shows representative western blots of myocardial expression‎ of phosphorylated (p)- and total (t)-MBS. Bottom panel (B) shows quantitative results of the ratio of p-MBS to t-MBS, indicating Rho-kinase activity. Results are expressed as mean ± SD. (Reproduced from Gao et al.17 with permission.)

In addition, supplementation with EPA and DHA could exert a protective effect on the heart through improvement in mitochondrial function and the efficiency of ATP generation.18 This effect may be due to changes in mitochondrial membrane phospholipids composition and improved efficiency of ATP generation.18

Inhibition of platelet aggregation

Omega-3 fatty acids decrease the risk of thrombosis by inhibiting platelet aggregation. Importantly, omega-3 fatty acids inhibit platelet TXA2 synthesis and acts as antagonists of the pro-aggregatory TXA2/PG H2receptor in human platelets in vitro.19 Supplementing a diet with omega-3 fatty acids down-regulate mRNA expression‎ of platelet-derived growth factor-A and -B in mononuclear blood cells in humans.20

Triglyceride-lowering effects

Omega-3 fatty acids play an important role to regulate genes that are critical for controlling lipid homeostasis. Omega-3 fatty acids decrease VLDL assembly and secretion, resulting in diminished triacylglycerol production, through a decreased activity of sterol receptor element-binding protein-1c, which is the key switch in controlling lipogenesis.21 In addition, omega-3 fatty acids could promote β-oxidation simultaneously in mitochondria and/or peroxisomes, possibly through the activation of peroxisome PPAR-α, leading to the reduction of fatty acids substrate for triglyceride synthesis.21,22 The remnant lipoprotein (RLP), produced from the triacylglycerol-rich chylomicrons and VLDL, exerts potent pro-atherogenic effects and is thus regarded as an important risk factor of CVD.22,23 The involvement of RLP has been suggested in the pathogenesis of sudden cardiac death22 and restenosis after coronary angioplasty.23 Although omega-3 fatty acids do not have a major effect on fasting total cholesterol and LDL cholesterol levels, EPA effectively reduces RLP in hyperlipidaemic patients.24

Improvement of endothelial function

Long-term treatment with fish oils augments endothelium-dependent relaxation of normal porcine coronary arteries,25 for which EPA, a major omega-3 fatty acids of fish oils, is responsible for the augmentation.26This augmenting effect of EPA was also noted in porcine coronary microvessels.27 Long-term treatment with fish oils improves endothelium-dependent relaxation of hypercholesterolaemic and atherosclerotic porcine coronary arteries28 and femoral veins.29 Eicosapentaenoic acid augments endothelium-dependent relaxation by NO as well as that by endothelium-derived hyperpolarizing factor.30 Docosahexaenoic acid alters caveolae microenvironment not only by modifying membrane lipid composition, but also by changing distribution of major structural proteins, eventually increasing eNOS activity in human umbilical vein endothelial cells.31 Nitric oxide also inhibits platelet aggregation and adhesion, leucocytes adhesion, and smooth muscle cell proliferation. In addition, in endothelial cells, co-incubation with DHA following challenge with interleukin (IL)-1, IL-4, tumour necrosis-α, or lipopolysaccharide decreases expression‎ of vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin, and secretion of IL-6 and IL-8.32

Plaque stabilization

As mentioned above, through their anti-inflammatory effects, omega-3 fatty acids could not only prevent the plaque development but also contribute to the plaque stabilization.33 The randomized clinical trial demonstrated that omega-3 fatty acids supplementation substantially increases tissue levels of EPA and DHA and decreases macrophage infiltration and thickened fibrous cap in human carotid arteries.34Exacerbated release of matrix metalloproteinase (MMP) by the activated endothelium and macrophages plays a pathological role in plaque progression and instabilization.35 Eicosapentaenoic acid significantly suppresses the development of atherosclerotic lesions in ApoE−/− and LDL-receptor−/− mice with reduced production of MMPs by macrophages in a PPARα-dependent manner.36

Anti-arrhythmic effects

The omega-3 fatty acids are incorporated into cell membranes and affect the ion-channel function of myocytes. There are several mechanisms by which omega-3 fatty acids could exert anti-arrhythmic effects. Omega-3 fatty acids inhibit voltage-gated Na channels, prolonging relative refractory period and increased voltage that are required for membrane depolarization.37 Omega-3 fatty acids also exhibit a modulatory action on L-type calcium Ca channels, resulting in lowered cytosolic free Ca and Ca influx rate and in preventing cytosolic Ca overload during ischaemic insult.38 Long-term treatment with EPA reduces ischaemia-induced ventricular fibrillation in pigs in vivo, for which attenuation of shortening of monophasic action potential duration through suppression of cardiac KATP channels may be involved.39Anti-arrhythmic effect of omega-3 fatty acids may be mediated in part by their effects on autonomic control, especially by an increased vagal tone.40 Through these mechanisms, omega-3 fatty acids may prevent ventricular tachyarrhythmias and hence decrease sudden cardiac death.41

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Fish, omega-3 fatty acids, and coronary artery disease in cohort studies

Based on the ecological studies among the Inuit and those comparing farmers and fishermen in Japan, Kromhout et al.8 hypothesized that a low level of fish consumption may reduce CAD mortality. They investigated this association in 852 middle-aged men free from CAD who were followed for 20 years. The average fish consumption in these men was 20 g per day, including those who did not eat fish (20%). About two-thirds of the fish was lean (e.g. cod and plaice) and one-third consisted of fatty fish (e.g. herring and mackerel). An inverse dose–response relationship was observed and CAD mortality was >50% lower among those who consumed at least 30 g of fish per day. Kromhout42 deduced from the studies among the Inuit, Japanese fishermen and farmers, and the Zutphen men that two different mechanisms could be responsible for the association between fish consumption and CAD. He hypothesized an acute effect on fatal CAD in cultures with a low level of fish consumption and a chronic effect in cultures with a high level of fish consumption (Figure 3).

Figure 3

The association between seafood consumption and fatal coronary heart disease. (Reproduced from Kromhout42with permission.)

Since 1985, results of many prospective cohort studies on fish consumption and CAD have been published, with several studies showing a protective effect although others did not. The first quantitative review was published in 1999 by Marckmann and Gronbaek43 and included 11 studies with 116 764 individuals. Four studies were judged to be of high quality, of which the two were performed in populations at high risk and the two in populations at low risk. In the high-risk populations, a protective association was found but not in the low-risk populations. The authors drew the conclusion that only in high-risk populations, a fish consumption of 40–60 g per day is associated with a markedly lower CAD mortality.

In 2004, two meta-analyses were published on fish consumption and fatal CAD.44,45 The study of Whelton et al.44 included both prospective cohort studies and case–control studies and the study by He et al.45 only cohort studies. Case–control studies are more prone to selection and information bias and it is particularly difficult to obtain accurate data on fish consumption in patients before the occurrence of a CAD event. Therefore, only the results of the cohort studies are summarized here. The meta-analyses by Whelton et al.44 and He et al.45 were based on 14 and 13 cohort studies, respectively. Both had approximately 220 000 participants who were followed for ∼12 years.

Whelton et al.44 found a 17% lower incidence of fatal CAD (RR = 0.83, 95% CI 0.75–0.92) among those who consumed fish less than twice a week compared with those who ate little or no fish. A similar result was found by He et al.45 for fish consumed once a week (RR = 0.85, 95% CI 0.76–0.96). He et al. observed a dose–response relationship between fish consumption and CAD death and individuals who consumed fish five or more times per week had a 38% lower risk of fatal CAD (RR = 0.62, 95% CI 0.46–0.82). These associations were confirmed in cohort studies in which, besides fish consumption, information about the intake of the omega-3 fatty acids EPA and DHA was also obtained.46–49

There is less evidence for a relationship between fish consumption and non-fatal MI. Based on the results of their meta-analysis, He et al.45 concluded that the evidence for an inverse association between fish consumption and non-fatal MI was weak, even though there was a significant association for those eating fish five times per week or more. This conclusion was confirmed by De Goede et al.,49 who found that consuming fish less than once per month up to once per week was not associated with non-fatal MI in a population-based study in the Netherlands. However, a Japanese cohort study showed that a high level of fish consumption may be protective against non-fatal CAD. In the Japan Public Health Center-based Study, the relative risk (RR) of non-fatal MI was 0.43 (95% CI 0.23–0.81) in participants with a median fish consumption of 180 g per day compared with participants with a daily consumption of 23 g per day.48These results support the outcome of the meta-analysis of He et al.45 that only a high level of fish consumption may reduce the risk of non-fatal MI.

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Fish, omega-3 fatty acids, and sudden death in observational studies

The hypothesis that fish consumption may be protective against sudden cardiac death is derived from the DART trial. This secondary prevention trial showed a significant 33% reduction in CAD mortality in cardiac patients who consumed at least two portions of fatty fish per week and were followed for 2 years. The authors suggested that the protective effect of fatty fish may be due to preventing ventricular fibrillation during acute ischaemia. This hypothesis was tested in two population-based case–control studies.50,51

Siscovick et al.50 identified 334 patients with primary cardiac arrest and 493 population-based controls. An average intake of 185 mg per day of EPA–DHA corresponding to eating fatty fish once a week was associated with a 50% lower risk of primary cardiac arrest (OR = 0.5, 95% CI 0.4–0.8). An even stronger association was observed for the corresponding quartile of red blood cell membrane omega-3 fatty acids (OR = 0.3, 95% CI 0.2–0.6). Similarly, a strong inverse relation was found between baseline blood levels of long-chain omega-3 fatty acids and sudden death in the Physicians' Health Study.51 The RR value was 90% lower in those in the highest compared with the lowest quartile of omega-3 fatty acids (RR = 0.10, 95% CI 0.02–0.48).

The evidence from prospective cohort studies on fish, omega-3 fatty acids, and sudden cardiac death is less convincing than that from population-based case–control studies.52–54 Albert et al.53 showed, using again data from the Physicians' Health Study, that men who consumed one fish meal per week had a 52% lower risk of sudden cardiac death (RR = 0.48, 95% CI 0.24–0.96) compared with those who consumed fish less than once a month. A significant inverse dose–response relationship with sudden cardiac death was not observed for the intake of omega-3 fatty acids, although the data suggested that an intake of ∼200 mg omega-3 fatty acids per day compared with ∼10 mg per day was associated with a lower risk of sudden cardiac death.

In contrast to these findings, sudden cardiac death was not significantly inversely associated with fish consumption in the Western Electric Study.52 In this study, information on causes of death was obtained only from death certificates. Sudden cardiac death was defined as death occurring no more than 12 h after the onset of the terminal acute illness. In the Physicians' Health Study, detailed information was available from next of kin, medical records, and autopsy reports; and sudden death was defined as death within 1h of the onset of symptoms. This definition of sudden cardiac death is superior to the one used in the Western Electric Study.

The association between long-term fish consumption, omega-3 fatty acids, and sudden cardiac death was also investigated in the Zutphen Study.54 Long-term fatty fish consumption was inversely associated with sudden coronary death, and men who consumed fatty fish had a 54% lower risk (RR = 0.46, 95% CI 0.27–0.78) than those who did not eat fatty fish. Lean fish consumption was not associated with sudden coronary death. The intake of omega-3 fatty acids was also inversely related to sudden coronary death but this association was not statistically significant.

In summary, the results of the population-based case–control and prospective cohort studies suggest a protective effect of fish consumption on cardiac arrest and sudden death. The two case–control studies showed the strongest effect for the omega-3 fatty acids measured in blood.

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Fish oils and cardiovascular diseases in randomized trials

Several trials tested the hypothesis that omega-3 fatty acids reduce fatal CAD and sudden death. The first meta-analysis of these trials was published in 2002,55 followed by others.56–59 However, several meta-analyses included not only trials in which the effect of omega-3 fatty acids in fish oils was investigated but also trials in which a fish advice or margarines enriched with ALA were given.55,56,58 One meta-analysis on fish oils included besides patients with MI, CAD, and heart failure also patients with peripheral vascular diseases, hypercholesterolaemia, and implanted cardioverter defibrillators (ICDs).58 Only the meta-analysis by León et al.57 eval‎uated the effect of EPA–DHA in a homogeneous group of patients with CAD or had had an MI. They used fatal CAD, sudden cardiac death, and severe arrhythmias as endpoints.

In three trials, patients with an ICD were included. In these trials, fish oil capsules containing an additional amount of 0.9–2.8 g omega-3 fatty acids per day reduced the risk of severe arrhythmias by 10% (OR = 0.90, 95% CI 0.55–1.46).57 A similar result was found in a meta-analysis by Brouwer et al.60 based on the same studies. Eight trials using fish oil capsules containing 0.9–2.8 g of EPA–DHA showed a significant 20% reduction of cardiac death (OR = 0.80, 95% CI 0.69–0.93).57 In four trials, an additional amount of 0.9–2.4 g of EPA–DHA per day reduced the incidence of sudden cardiac death by 26% (OR = 0.74, 95% CI 0.59–0.92).57 The results for fatal CAD and sudden death were dominated by those of the GISSI-Prevenzione trial41 that contributed >85% to both endpoints.57

In 2010, the results of the Alpha Omega, OMEGA, and SU.FOL.OM3 trials were published.61–63 The results of these trials and those of the large trials published before 2010—the GISSI-Prevenzione trial, the secondary prevention component of the JELIS trial, and the GISSI Heart Failure trial—will be discussed in detail64,65 (Table 1). The GISSI-HF published in 200865 and the three trials published in 201061–63 were not included in the meta-analysis of León et al.57

Table 1

Effects of fish oil on cardiovascular diseases in trials with patients with heart disease

	GISSI-P 1999 (41)	JELIS 2007 (64)	GISSI-HF 2008 (65)	Alpha Omega 2010 (61)	OMEGA 2010 (62)	SU.FOL.OM3 2010 (63)
Number	11 324	3664	7046	4837	3851	2501
Patients	Post-MI	CAD	HF	Post-MI	Post-MI	CAD
Post-event	<3 months			<10 years	3–14 days	<12 months
Design	Open label	Open label	Double-blind	Double-blind	Double-blind	Double-blind
Inclusion period	1993–95	1996–99	2002–05	2002–06	2003–07	2003–07
Follow-up (months)	42	55	47	41	12	56
Person-years	38 505			15 531		10 656
Dose EPA (mg)	289	1800	394	226	460	400
Dose DHA (mg)	577	0	472	150	380	200
Medication use (%)
Antiplatelets	88		87	98	95	94
Antihypertensives				90
Beta-blockers	41		65	69	94	68
ACE-I/ARBs	41		94	56	91	66
Statins	29	97	23	85	94	87
Number of events
MCE	1115	355	4359	671	331
Fatal CVD	639		1447	162		157a
Fatal CAD	479	39	236a	138
Sudden death	286	26	632	57	57
Relative risk
MCE	0.80*	0.81*	0.92*	1.01	1.21
Fatal CVD	0.70*		0.90*	0.98		1.08a
Fatal CAD	0.65*	0.87a	0.82a	0.95
Sudden death	0.55*	1.02	0.93	0.90	0.95

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MI, myocardial infarction; CAD, coronary artery diseases; HF, heart failure; MCE, major cardiovascular event; CVD, cardiovascular diseases.

aFatal and non-fatal events.

*P < 0.05.

The number of patients included in these trials ranged from 2501 to 11 324 with 15–26% females. Three trials included post-MI patients,41,61,62 two trials CAD patients,63,64 and one trial heart failure patients.65The average age of the patients varied between 59 and 69 years. Two trials recruited patients in the 1990s and used an open-label design.41,64 The remaining trials were initiated between 2002 and 2007 and were double-blind.61–63,65 The OMEGA trial had a 12-month follow-up and in the other trials the average follow-up period varied between 41 and 56 months. In four trials, the patients received fish oil capsules containing 600–900 mg of EPA–DHA per day and in the JELIS trial 1800 mg of EPA per day. In the Alpha Omega Trial, margarine spreads provided an average additional intake of EPA–DHA of ∼400 mg per day.61

The most important commonly used endpoints in these trials were major cardiovascular events, fatal CVD, fatal CAD, and sudden death. The strongest effects were observed in the GISSI-P trial for patients surviving a recent MI. In this trial, an additional amount of EPA–DHA of 900 mg per day reduced significantly fatal CVD by 30%, fatal CAD by 35%, and sudden death by 45%.41 In the GISSI-HF trial, in which heart failure patients were included, fatal CVD was significantly reduced by 10%, sudden death non-significantly by 7%, and first hospital admissions for ventricular arrhythmias significantly by 28%.65The JELIS trial showed that an additional intake of 1800 mg of EPA per day reduced only major coronary events (fatal and non-fatal CAD, unstable angina, percutaneous coronary intervention, and coronary artery bypass grafting).64 The three trials published in 2010 included either post-MI or CAD patients.61–63Additional amounts of EPA–DHA varying from 400–800 mg/day did not reduce cardiovascular events.

The strongest reductions in cardiovascular endpoints were obtained in the oldest trials. An explanation could be differences in study design. The GISSI-P and the JELIS trial used an open label design.41,64 This may have confounded the results of these trials, because placebo capsules were lacking. Another explanation could be that the patients in the more recent trials were very well treated not only by antithrombotics but also by antihypertensives and statins. Compared with the recent trials, the treatment level with statins was low in the GISSI-P trial (29%).41 This could be the reason for the high risk of fatal CAD and sudden death in the GISSI-P trial compared with the Alpha Omega Trial. The absolute risk for fatal CAD in the control group was 15.8/1000 person-years in the GISSI-P and 8.9/1000 person-years in the Alpha Omega Trial. For sudden death, the rates were 10.4/1000 person-years in the GISSI-P and 3.7/1000 person-years in the Alpha Omega Trial. A likely explanation is that these differences in absolute risk between the trials were responsible for the absence of an effect of EPA–DHA on fatal CAD and sudden death in the recent trials.

Those differences in absolute risk of fatal CAD and sudden death could play an important role in explaining the different results in the GISSI-P and the Alpha Omega Trial. This is supported by the results of the subgroup analysis of patients in the Alpha Omega Trial who also had diabetes.61 The absolute risk of fatal CAD in the control group of diabetes patients in the Alpha Omega Trial was 17.1/1000 person-years. This is in the same order of magnitude as the absolute risk in the control group of the GISSI-P trial.41 In the diabetes patients who received an additional amount of 400 mg of EPA–DHA per day, a significant reduction in fatal CAD was obtained comparable with the GISSI-P trial (Figure 4). Similar results were found in the Alpha Omega Trial for sudden death and ventricular arrhythmia-related events, although these effects were not statistically significant.

Figure 4

Effect of eicosapentaenoic acid–docosahexaenoic acid on cardiovascular diseases in the Alpha Omega Trial (AOT) and the GISSI-Prevenzione trial (GISSI-P). CVD, cardiovascular diseases; CAD, coronary artery diseases.

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Emerging issues on the effects of fish oils/omega-3 fatty acids

Results of observational prospective cohort studies and randomized trials in subjects with or without CVD published before 2000 demonstrated that diets with higher amounts of omega-3 fatty acids or supplements with omega-3 fatty acids reduced cardiovascular mortality. These results formed the basis for recommendations, including the American Heart Association Guidelines, that patients with documented CAD should be advised to take 900–1000 mg of omega-3 fatty acids (EPA–DHA combined) per day.66However, this recommendation was challenged in a review and meta-analysis published by Hooper et al.56in 2006. They concluded that there was no clear benefit of additional amount of omega-3 fatty acids on cardiovascular events. In addition, the three recently published double-blind trials—the Alpha Omega, the OMEGA, and the SU.FOL.OM3—did not show an effect of an additional amount of EPA–DHA on major cardiovascular endpoints.61–63 These negative results with omega-3 fatty acids supplementation were disappointing but were obtained in the current practice where other optimal conventional drug therapy was performed. It should be pointed out, however, that the OMEGA and the SU.FOL.OM3 trial were also underpowered.62,63

In addition, there is some evidence for possible pro-arrhythmic effects of omega-3 fatty acids in certain subgroups with CVD. In the three randomized controlled trials of patients with an implantable cardioverter defibrillator (ICD) and a history of ventricular tachyarrhythmias, fish oil of omega-3 fatty acids did not show a significant benefit on the risk of appropriate ICD shocks.57,60 In a trial of patients with stable angina pectoris without previous MI, a detrimental effect of omega-3 fatty acids on sudden death was observed.67 Thus, further studies are needed to determine which patient population may or may not benefit from omega-3 fatty acids supplementation. Evidence is also insufficient regarding the optimal dose, source (oily fish or fish-oil supplements), and formulation of EPA and/or DHA in order to reduce cardiovascular events.68

Recently, a potential new indication of omega-3 fatty acids has been demonstrated, that is heart failure.36In the GISSI-HF trial,65 a placebo-controlled trial of approximately 7000 patients with class II to IV heart failure, the patients were randomized to 1 g of omega-3 fatty acids (containing 850–882 mg of EPA plus DHA), rosuvastatin (10 mg), both of them, or dual placebo. This study was performed in addition to well-established current therapies, and the results showed a significant benefit of omega-3 fatty acids.65However, the optimal dose of omega-3 fatty acids remains to be determined depending on different stages and/or aetiology of heart failure and underlying mechanisms.68 Growing evidence demonstrates anti-inflammatory effects of omega-3 fatty acids, including reduced circulating levels of inflammatory cytokines and AA-derived eicosanoids, and elevated plasma adiponectin.18 In animal studies, fish oil favourably alters cardiac mitochondrial function.18 All of these effects may work together to prevent the development and progression of heart failure.

Several issues remain to be elucidated. First, no evidence has been found for the optimal dosage, ratios of DHA to EPA, and ratios of omega-3 to omega-6. Second, whether dietary intake or therapeutic supplements are the best source of omega-3 fatty acids is yet to be determined. These issues remain to be clarified in future studies.

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Conclusions

Omega-3 fatty acids exert pleiotropic, cardiometabolic effects with a diverse range of actions, most of which are beneficial for the cardiovascular system. Supplementation up to 1 g of omega-3 fatty acids per day is well tolerated except dysgeusia and does not increase the risk of bleeding. Recently published trials in patients with CAD or after MI did not show an effect of omega-3 fatty acids on major cardiovascular endpoints, probably due to state of the art drug treatment. However, as suggested by the current guidelines, the potential value of omega-3 fatty acids supplementation in patients with CAD or after MI and possibly in those with heart failure remains to be encouraged.

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Funding

The work by the authors in this review article was supported in part by the Netherlands Heart Foundation, the Netherlands Prevention Foundation, the National Institutes of Health, USA, and an unrestricted grant of Unilever R&D (to D.K.), and the grants from the Japanese Ministry of Education, Sports, and Culture, Tokyo, Japan, and those from the Japanese Ministry of Health, Labour and Welfare, Tokyo, Japan (to H.S.).

Conflict of interest: none declared.

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출처 : http://health.chosun.com/site/data/html_dir/2016/12/08/2016120802072.html

클릭클릭

Omega-3 Fatty Acids EPA and DHA: Health Benefits Throughout Life1,2 

Danielle Swanson,3 Robert Block,4 and Shaker A. Mousa3,5* 3 The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY; 4 Department of Community and Preventive Medicine, and Division of Cardiology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY; 5 College of Medicine, King Saud University, Riyadh, Saudi Arabia 

ABSTRACT 

Omega-3 [(n-3)] fatty acids have been linked to healthy aging throughout life. Recently, fish-derived omega-3 fatty acids EPA and DHA have been associated with fetal development, cardiovascular function, and Alzheimer’s disease. However, because our bodies do not efficiently produce some omega-3 fatty acids from marine sources, it is necessary to obtain adequate amounts through fish and fish-oil products. 

생선에서 유래된 오메가 3지방산(EPA, DHA)은 최근 태아발달, 심장혈관기능, 알츠하이머 치매에 효과적이라고 연구됨. 

우리 몸은 오메가 3 지방산을 만들지 못하기 대문에 생선과 생선오일 추출물을 복용해야 함. 

Studies have shown that EPA and DHA are important for proper fetal development, including neuronal, retinal, and immune function. EPA and DHA may affect many aspects of cardiovascular function including inflammation, peripheral artery disease, major coronary events, and anticoagulation. EPA and DHA have been linked to promising results in prevention, weight management, and cognitive function in those with very mild Alzheimer’s disease. 

EPA, DHA는 적절한 태아발달(특히 신경, 눈, 면역기능)에 중요한 역할

EPA, DHA는 심혈관기능(염증, 말초혈관, 관상동맥, 항응고) 다양한 분야에 영향을 미침.

EAP, DHA는 가벼운 알츠하이머의 예방, 체중관리, 인지기능에 중요한 역할을 함. 

Adv. Nutr. 3: 1–7, 2012. 

Introduction 

Omega-3 [(n-3)] long-chain PUFA, including EPA and DHA, are dietary fats with an array of health benefits (1). They are incorporated in many parts of the body including cell membranes (2) and play a role in antiinflammatory processes and in the viscosity of cell membranes (3,4). EPA and DHA are essential for proper fetal development and healthy aging (5). DHA is a key component of all cell membranes and is found in abundance in the brain and retina (6). EPA and DHA are also the precursors of several metabolites that are potent lipid mediators, considered by many investigators to be beneficial in the prevention or treatment of several diseases (7). It can be challenging to get the appropriate intake of EPA and DHA through diet alone, even though EPA and DHA are produced by water plants such as algae and are preval‎ent in marine animals. A shorter chain omega-3 fatty acid, a-linolenic acid (ALA),6 is a prominent component of our diet as it is found in many land plants that are commonly eaten, but it does not provide the health benefits seen with EPA and DHA. Although it is possible for the body to convert ALA to EPA and DHA by enlongase and desaturase enzymes, research suggests that only a small amount can be synthesized in the body from this process (8). For example, 1 study suggested that only w2 to 10% of ALA is converted to EPA or DHA (9), and other studies found even less: Goyens et al. (10) found an ALA conversion of w7% for EPA, but only 0.013% for DHA; Hussein et al. (11) found an ALA conversion of only 0.3% for EPA and <0.01% for DHA. The current American diet has changed over time to be high in SFA and low in omega-3 fatty acids (12). This change in eating habits is centered on fast food containing high amounts of saturated fat, which has small amounts of essential omega-3 PUFA compared with food prepared in the home (13). Seafood sources such as fish and fish-oil supplements are the primary contributors of the 2 biologically important dietary omega-3 fatty acids, EPA and DHA (14–16). This low intake of dietary EPA and DHA is thought to be associated with increased inflammatory processes as well as poor fetal development, general cardiovascular health, and risk of the development of Alzheimer’s disease (AD). This review focuses on the many benefits of EPA and DHA supplementation throughout life, including use during pregnancy for proper fetal development and full-term gestation, to reduce many cardiovascular issues, and potential uses in AD.

Omega-3 fatty acids and fetal development Maternal nutrition guidelines have always stressed a diet including sufficient caloric and protein requirements, but recently fatty acids have also been deemed important (17). This is partially due to the fact that EPA and DHA supplementation during pregnancy has been associated with multiple benefits for the infant (Table 1). During pregnancy, the placenta transfers nutrients, including DHA, from the mother to the fetus (18). The amount of omega-3 fatty acid in the fetus is correlated with the amount ingested by the mother, so it is essential that the mother has adequate nutrition (19). The 2010 U.S. Department of Health and Human Services dietary guidelines recommend that women who are pregnant or breastfeeding should “consume 8 to 12 ounces of seafood per week from a variety of seafood types” (12). Ingesting 8–12 oz of seafood per week, depending on the type of fish, is equivalent to w300–900 mg EPA+DHA per day. Unfortunately, this amount is not being met by most mothers in the United States and Canada, which means that infants many not be receiving adequate amounts of these vital nutrients in the womb (20). 

Several studies confirmed the benefit of omega-3 supplementation during pregnancy in terms of proper development of the brain and retina. Of the 2 most important long-chain omega-3 fatty acids, EPA and DHA, DHA is the more important for proper cell membrane function and is vital to the development of the fetal brain and retina (17). During the third trimester, vast amounts of DHA accumulate in fetal tissue (20). The 2 most infiltrated fetal areas include the retina and brain, which may correlate with normal eyesight and brain function (19). A study by Judge et al. (20) found that children whose mothers had taken DHA supplementation during pregnancy (n = 29) had significantly better problem-solving skills at 9 mo old (P = 0.017) than those whose mothers had not taken DHA supplementation during pregnancy (n = 15). Another study provided a cognitive assessment of children 2.5 y after maternal EPA+DHA supplementation during pregnancy from 20 wk of gestation until delivery (n = 33) compared with children in a placebo group (n = 39). Children in the EPA + DHA–supplemented group attained significantly higher scores for eye and hand coordination [mean score, 114 

(SD 10.2] than those in the placebo group [mean score, 108 (SD 11.3)] (P = 0.021, adjusted P = 0.008) (19). Of great clinical importance, EPA and DHA supplementation during pregnancy has been associated with longer gestation and increased concentrations of EPA and DHA in fetal tissues (21). In 2005, preterm births accounted for 12.7% of all births in the United States, increasing the likelihood of health complications (22). Carrying a baby to term is very important because prematurity is the cause of various infant diseases and can lead to death; preterm delivery is an underlying factor for 85% of the deaths of normally formed infants (23). One mechanism by which EPA and DHA may decrease the incidence of preterm birth is by decreasing prostaglandin E2 and prostaglandin F2a production, therefore reducing inflammation within the uterus, which could be associated with preterm labor (21,24). Several studies investigated EPA and DHA intake during pregnancy and its correlation with longer gestation. Conclusions were that EPA+DHA supplementation during pregnancy delayed the onset of delivery to term or closer to term; however, supplementation did not delay delivery to the point of being postterm (20,23,25). This supports the evidence that EPA+DHA ingestion leads to optimal pregnancy length. EPA+DHA supplementation reduced the HR of preterm delivery by 44% (95% CI: 14–64%) in those who consumed relatively low amounts of fish and 39% (95% CI: 16–56%) in those who consumed medium amounts of fish; however, a level of statistical significance was not met (P = 0.10) (23). The Judge et al. (20) study found that women who had DHA supplementation from gestation week 24 until full-term delivery carried their infants significantly (P = 0.019) longer than did the women in the placebo group. One study found that DHA supplementation after gestation week 21 led to fewer preterm births (<34 wk of gestation) in the DHA group compared with the control group (1.09% vs. 2.25%; adjusted RR, 0.49; 95% CI: 0.25–0.94; P = 0.03). Also, mean birth weight was 68 g heavier (95% CI: 23–114 g; P = 0.003) and fewer infants were of low birth weight in the DHA group compared with the control group (3.41% vs. 5.27%; adjusted RR, 0.65; 95% CI: 0.44–0.96; P = 0.03) (25). There is also evidence that mothers who use EPA and DHA supplementation during pregnancy and breastfeeding may protect their children against allergies. This may be due to the fact that fish-oil supplementation has been associated with decreased levels of body cells associated with inflammation and immune response (26). In a study about food allergy and IgE-associated eczema, the period preval‎ence of food allergy was lower in the maternal EPA+DHA supplementation group compared to placebo (P < 0.05), and the incidence of IgE-associated eczema was also lower in the maternal EPA+DHA supplementation group compared to placebo (P < 0.05) (27). Omega-3 fatty acids and cardiovascular disease Cardiovascular disease is the cause of 38% of all deaths in the United States, many of which are preventable (28). Chronic inflammation is thought to be the cause of many chronic diseases, including cardiovascular disease (29). EPA and DHA are thought to have antiinflammatory effects and a role in oxidative stress (30) and to improve cellular function through changes in gene expression‎ (31). In a study that used human blood samples, EPA+DHA intake changed the expression‎ of 1040 genes and resulted in a decreased expression‎ of genes involved in inflammatory and atherogenesis-related pathways, such as nuclear transcription factor kB signaling, eicosanoid synthesis, scavenger receptor activity, adipogenesis, and hypoxia signaling (31). Circulating markers of inflammation, such as C-reactive protein (CRP), TNF a, and some ILs (IL-6, IL-1), correlate with an increased probability of experiencing a cardiovascular event (32). Inflammatory markers such as IL-6 trigger CRP to be synthesized by the liver, and elevated levels of CRP are associated with an increased risk of the development of cardiovascular disease (33). A study of 89 patients showed that those treated with EPA+DHA had a significant reduction in high-sensitivity CRP (66.7%, P < 0.01) (33). The same study also showed a significant reduction in heat shock protein 27 antibody titers (57.69%, P < 0.05), which have been shown to be overexpressed in heart muscle cells after a return of blood flow after a period of ischemia (ischemia-reperfusion injury) and may potentially have a cardioprotective effect (33). There have been conflicting results reported about EPA and DHA and their use with regard to major coronary events and their use after myocardial infarction. EPA+DHA has been associated with a reduced risk of recurrent coronary artery events and sudden cardiac death after an acute myocardial infarction (RR, 0.47; 95% CI: 0.219–0.995) and a reduction in heart failure events (adjusted HR: 0.92; 99% CI: 0.849–0.999) (34–36). A study using EPA supplementation in combination with a statin, compared with statin therapy alone, found that, after 5 y, the patients in the EPA group (n = 262) who had a history of coronary artery disease had a 19% relative reduction in major coronary events (P = 0.011). However, in patients with no history of coronary artery disease (n = 104), major coronary events were reduced by 18%, but this finding was not significant (37). This Japanese population already has a high relative intake of fish compared with other nations, and, thus, these data suggest that supplementation has cardiovascular benefits in those who already have sufficient baseline EPA+DHA levels. Another study compared patients with impaired glucose metabolism (n = 4565) with normoglycemic patients (n = 14,080). Impaired glucose metabolism patients had a significantly higher coronary artery disease HR (1.71 in the non-EPA group and 1.63 in the EPA group). The primary endpoint was any major coronary event including sudden cardiac death, myocardial infarction, and other nonfatal events. Treatment of impaired glucose metabolism patients with EPA showed a significantly lower major coronary event HR of 0.78 compared with the non–EPA-treated impaired glucose metabolism patients (95% CI: 0.60–0.998; P = 0.048), which demonstrates that EPA significantly suppresses major coronary events (38). When looking at the use of EPA+DHA and cardiovascular events after myocardial infarction, of 4837 patients, a major cardiovascular event occurred in 671 patients (13.9%) (39). A post hoc analysis of the data from these diabetic patients showed that rates of fatal coronary heart disease and arrhythmia-related events were lower among patients in the EPA+DHA group than among the placebo group (HR for fatal coronary heart disease: 0.51; 95% CI: 0.27–0.97; HR for arrhythmia-related events: 0.51; 95% CI: 0.24–1.11, not statistically significant) (39). Another study found that there was no significant difference in sudden cardiac death or total mortality between an EPA +DHA supplementation group and a control group in those patients treated after myocardial infarction (40). Although these last 2 studies appear to be negative in their results, it is possible that the more aggressive treatment with medications in these more recent studies could attribute to this. Omega-3 fatty acids have been found to play a role in atherosclerosis and peripheral arterial disease (PAD). It is thought that both EPA and DHA improve plaque stability, decrease endothelial activation, and improve vascular permeability, thereby decreasing the chance of experiencing a cardiovascular event (41). It was found that EPA supplementation is associated with significantly higher amounts of EPA in the carotid plaque than placebo (P < 0.0001), which may lead to decreased plaque inflammation and increased stability (42). PAD, a manifestation of atherosclerosis, is characterized by buildup of plaque in the arteries of the leg and can eventually lead to complete blockage of the arteries. EPA+DHA supplementation has been shown to improve endothelial function in patients with PAD by decreasing plasma levels of soluble thrombomodulin from a median value of 33.0 mg/L to 17.0 mg/L (P = 0.04) and improve brachial artery flow–mediated dilation from 6.7% to 10.0% (P = 0.02) (43). Patients who had PAD and were supplemented with EPA experienced a significantly lower major coronary event HR than those who did not take EPA (HR: 0.44; 95% CI: 0.19–0.97; P = 0.041) (44). Omega-3 fatty acids have been shown to increase platelet responsiveness to subtherapeutic anticoagulation therapies, including aspirin. Recently, it was noted that patient response to aspirin for anticoagulation therapy is widely variable (45), and, thus, the number of patients with a low response to aspirin or aspirin resistance is estimated to range from <1% to 45%, depending on many variables. However, in patients with stable coronary artery disease taking lowdose aspirin, EPA+DHA supplementation has been proven to be as effective as aspirin dose escalation to 325 mg/d for anticoagulation benefits (45). The antiplatelet drug clopidogrel has also been associated with hyporesponsiveness in some patients. This could be attributed to poor patient compliance, differences in genes and platelet reactivity, variability of drug metabolism, and drug interactions. More importantly, in 1 study, patients receiving standard dual antiplatelet therapy (aspirin 75 mg/d and clopidogrel 600-mg loading dose followed by 75 mg/d) were assigned to either EPA+DHA supplementation or placebo. After 1 mo of treatment, the P2Y12 receptor reactivity index (an indicator of clopidogrel resistance) was significantly lower, by 22%, for patients taking EPA+DHA compared with patients taking placebo (P = 0.020) (46). Omega-3 fatty acids and AD AD is a devastating disease for which there are limited treatment options and no cure. Memory loss is an early indicator of the disease, which is progressive, and leads to the inability of the patient to care for him- or herself and eventually to death (47). Currently, the number of individuals with AD is estimated to be 26.6 million and is expected to increase to 106.2 million by 2050 (48). There have been many studies conducted regarding the use of omega-3 fatty acid supplementation and AD (Table 2). DHA is present in large amounts in neuron membrane phospholipids, where it is involved in proper function of the nervous system, which is why it is thought to play a role in AD (49). A case-control study consisting of 148 patients with cognitive impairment [Mini-Mental State Examination (MMSE) score <24] and 45 control patients (MMSE score $24) showed that serum cholesteryl ester-EPA and -DHA levels were significantly lower (P < 0.05 and P < 0.001, respectively) in all MMSE score quartiles of patients with AD compared with control values (49). Another study found that a diet characterized by higher intakes of foods high in omega-3 fatty acids (salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, dark and green leafy vegetables), and a lower intake of foods low in omega-3 fatty acids (high-fat dairy products, red meat, organ meat, butter) was strongly associated with a lower AD risk (50). Image analysis of brain sections of an aged AD mouse model showed that overall plaque burden was significantly reduced by 40.3% in mice with a diet enriched with DHA (P < 0.05) compared with placebo. The largest reductions (40–50%) were seen in brain regions that are thought to be involved with AD, the hippocampus and parietal cortex (51). A central event in AD is thought to be the activation of multiple inflammatory cells in the brain. Release of IL-1B, IL-6, and TNF a from microglia cells may lead to dysfunction of the neurons in the brain (52). In 1 study, AD patients treated with EPA +DHA supplementation increased their plasma concentrations of EPA and DHA, which were associated with reduced release of inflammatory factors IL-1B, IL-6, and granulocyte colony–stimulating factor from peripheral blood mononuclear cells (53). Unintended weight loss is a problem that many patients with AD may face, and EPA+DHA supplementation has had a positive effect on weight gain in patients with AD. In a study using EPA+DHA supplementation, patients’ weight significantly increased by 0.7 kg in the EPA+DHA treatment group at 6 mo (P = 0.02) and by 1.4 kg at 12 mo (P < 0.001) and was observed mainly in patients with a BMI <23 at the study start (54). This means that those patients with a lower BMI preferentially gained weight compared with those patients already with a higher BMI. Although results from studies regarding the disease processes of AD seem to be promising, there are conflicting data regarding the use of omega-3 fatty acids in terms of cognitive function. Neuropsychiatric symptoms accompany AD from early stages and tend to increase with the progression of the disease (55). An analysis of 174 patients randomized to a placebo group or to a group with mild to moderate AD (MMSE score $15) treated with daily DHA (1.7 g) and EPA (0.6 g) found that at 6 mo, the decline in cognitive function did not differ between the groups. Yet, in a subgroup with very mild cognitive dysfunction (n = 32, MMSE score >27), they observed a significant reduction in the MMSE decline rate in the DHA+EPA-supplemented group compared with the placebo group (47). Another study that looked at DHA supplementation in individuals with mild to moderate AD used the Alzheimer’s Disease Assessment Scale–Cognitive subscale, which eval‎uates cognitive function on a 70-point scale in terms of memory, attention, language, orientation, and praxis. This study found that DHA supplementation had no beneficial effect on cognition during the 18-mo trial period for the DHA group vs. placebo (56). Conclusion The omega-3 PUFA EPA and DHA are important throughout life and are a dietary necessity found predominantly in fish and fish-oil supplements. The omega-3 fatty acids EPA and DHA are essential for proper fetal development, and supplementation during pregnancy has also been linked to decreased immune responses in infants including decreased incidence of allergies in infants. Omega-3 fatty acid consumption has been associated with improved cardiovascular function in terms of antiinflammatory properties, PAD, reduced major coronary events, and improved antiplatelet effects in the face of aspirin resistance or clopidogrel hyporesponsiveness. Patients with AD have been shown to be deficient in DHA, and supplementing them with EPA +DHA not only reverses this deficiency, but may also improve cognitive functioning in patients with very mild AD. With increasing rates of pediatric allergies, cardiovascular disease, and AD in the United States, EPA and DHA may be a safe and inexpensive link to a healthier life. Further research should be conducted in humans to assess a variety of clinical outcomes including quality of life and mental status. In addition, because potent lipid mediator metabolites of EPA and DHA are of great interest currently, their influence on these important outcomes should be assessed because current evidence suggests that their antiinflammatory and tissue-protective effects are nearly 1000 times greater than those of EPA and DHA (7). Acknowledgments Thanks to Dr. Kelly A. Keating (Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences) for her outstanding editorial support. All authors have read and approved the final version of this manuscript. Literature Cited 1. Su KP, Huang SY, Chiu TH, Huang KC, Huang CL, Chang HC, Pariante CM. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69:644–51. 2. 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