Lovaza

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Jump to: navigation, search Lovaza is a brand name prescription drug. The capsule developed by GlaxoSmithKline contains esterified fish oils and is approved by the U.S. Food and Drug Administration to lower very high triglyceride levels. It is metabolized into Omega-3 fatty acids. It is a dietary supplement that has been purified, chemically altered, branded, and been put through the FDA's approval process; in these respects it is considered a pharmaceutical: unlike unregulated extracts, there is no risk of contamination by methyl mercury, arsenic [1], or other pollutants that are often seen in the world's oceans. Each 1-gram capsule is 38% DHA, 47% EPA, and 17% other fish oils in the form of the ethyl ester. Lovaza is named Omacor in Europe (and this name was once used in the US).[2]

[edit] Effectiveness
Lovaza is approved in the U.S. for treatment of patients with very high triglycerides (hypertriglyceridemia).[3] In the European markets and other major markets outside the US Lovaza is known as Omacor, and is indicated for:
1. Hypertriglyceridemia. Used as monotherapy, or in combination with a statin for patients

with mixed dyslipidemia.[citation needed] 2. Secondary prevention after myocardial infarction (heart attack)[citation needed] Lovaza has been demonstrated to reduce triglycerides in patients with high or very high triglycerides. [3] Lovaza has also been demonstrated to reduce VLDL-cholesterol and non-HDL-cholesterol, and increase HDL-cholesterol. In some patients LDL-cholesterol is moderately increased.[citation needed] The LDL raising activity correlates with a reduction in ApoB levels. Lovaza, through the stimulation of Lipoprotein Lipase, seems to stimulate the production of less atherogenic LDL species. Effects on significant patient outcomes such as acute myocardial infarction, stroke, cardiovascular and all-cause mortality have been studied in patients who have suffered a myocardial infarction. Lovaza has not been shown to lower the rates of all cause mortality and cardiovascular mortality, or the combination of mortality and non-fatal cardiovascular events.[3] GlaxoSmithKline's patent expires in September 2012, when generic versions may be made available. Other DHA/EPA products containing similar amounts of Omega-3 fatty acids are currently sold over the counter in the United States as dietary supplements. Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), precursors of certain eicosanoids that are known to reduce inflammation throughout the body,[1][2] and are thought to have many health benefits.

Fish do not actually produce omega-3 fatty acids, but instead accumulate them by consuming either microalgae or prey fish that have accumulated omega-3 fatty acids, together with a high quantity of antioxidants as iodide and selenium, from microalgae, where these antioxidants are able to protect the fragile polyunsaturated lipids from peroxidation [3] [3][4][5]. Fatty predatory fish like sharks, sword fish, tilefish, and albacore tuna may be high in omega-3 fatty acids, but due to their position at the top of the food chain, these species can also accumulate toxic substances (see biomagnification). For this reason, the U.S. Food and Drug Administration recommends limiting consumption of certain (predatory) fish species (e.g. albacore tuna, shark, king mackerel, tilefish and swordfish) due to high levels of toxic contaminants such as mercury, dioxin, PCBs and chlordane.[6] Fish oil is used as a component in aquaculture feed. More than 50 percent of the world's fish oil used in aquaculture feed is fed to farmed salmon.[7] The omega-3 fatty acids in fish oil are thought to be beneficial in treating hypertriglyceridemia, and possibly beneficial in preventing heart disease.[8] Fish oil and omega-3 fatty acids have been studied in a wide variety of other conditions, such as clinical depression,[9][10] anxiety,[11][12][13] cancer, and macular degeneration, although benefit in these conditions remains to be proven

Production
In 2005, fish oil production declined in all main producing countries with the exception of Iceland. The 2005 production estimate is about 570,000 tonnes in the five main exporting countries (Peru, Denmark, Chile, Iceland and Norway), a 12% decline from the 650,000 tonnes produced in 2004.[citation needed]. Peru continues to be the main fish oil producer worldwide, with about one fourth of total fish oil production. Grams of omega-3 fatty acids per 3oz (85g) serving of popular fish.[14] Common name Tuna Tuna (canned, light) Pollock Salmon Cod Catfish Flounder Grouper Halibut Mahi mahi Orange roughy Red snapper Shark Swordfish Tilefish King mackerel grams 0.211.1 0.17-0.24 0.45 1.11.9 0.150.24 0.220.3 0.48 0.23 0.601.12 0.13 0.028 0.29 0.83 0.97 0.90 0.36

Health benefits
See also: Coronary heart disease, Health benefits, and health risks of Omega 3 fatty acids Cancer

Several studies report possible anti-cancer effects of n3 fatty acids found in fish oil (particularly breast, colon and prostate cancer).[15][16][17] Omega-3 fatty acids reduced prostate cancer growth, slowed histopathological progression, and increased survival in genetically engineered mice.[18] Among n-3 fatty acids (omega-3), neither long-chain nor short-chain forms were consistently associated with reduced breast cancer risk. High levels of docosahexaenoic acid, however, the most abundant n-3 polyunsaturated fatty acid (omega-3) in erythrocyte membranes, were associated with a reduced risk of breast cancer.[19] A recent study of 35,000 middle-aged women found that the women who took fish oil supplements had a 32% lower risk of breast cancer, although the authors stress the result is preliminary and falls short of establishing a causal relationship.[20]
Cardiovascular

A 2008 meta-study by the Canadian Medical Association Journal found fish oil supplementation did not demonstrate any preventative benefit to cardiac patients with ventricular arrhythmias.[21] The American Heart Association recommends the consumption of 1g of fish oil daily, preferably by eating fish, for patients with coronary heart disease although pregnant and nursing women are advised to avoiding eating fish with high potential for mercury contaminants including mackerel, shark, or swordfish.[22] Note that optimal dosage relates to body weight. The US National Institutes of Health lists three conditions for which fish oil and other omega-3 sources are most highly recommended: hypertriglyceridemia, secondary cardiovascular disease prevention and high blood pressure. It then lists 27 other conditions for which there is less evidence. It also lists possible safety concerns: "Intake of 3 grams per day or greater of omega-3 fatty acids may increase the risk of bleeding, although there is little evidence of significant bleeding risk at lower doses. Very large intakes of fish oil/omega-3 fatty acids may increase the risk of hemorrhagic (bleeding) stroke."[8] There is also some evidence that fish oil may have a beneficial effect on some forms of cardiac dysrhythmia.[23] [24]
[edit] Mental health

Studies published in 2004 and 2009 have suggested that the n-3 EPA may reduce the risk of depression and suicide. One study[25] compared blood samples of 100 suicide-attempt patients and to those of controls and found that levels of Eicosapentaenoic acid were significantly lower in the washed red blood cells of the suicide-attempt patients. A small American trial in 2009 suggested that E-EPA, as monotherapy, might treat major depressive disorder but failed to achieve statistical significance.[26] Studies[27][28] were conducted on prisoners in England where the inmates were fed seafood which contains omega-3 fatty acids. The higher consumption of these fatty acids corresponded with a drop in the assault rates. Another Finnish study found that prisoners who were convicted of

violence had lower levels of omega3 fatty acids than prisoners convicted of nonviolent offenses. It was suggested that these kinds of fatty acids are responsible for the neuronal growth of the frontal cortex of the brain which, it is further alleged, is the seat of personal behavior.[citation
needed]

A study from the Orygen Research Centre in Melbourne suggests that omega-3 fatty acids could also help delay or prevent the onset of schizophrenia. The researchers enlisted 81 'high risk' young people aged 13 to 24 who had previously suffered brief hallucinations or delusions and gave half of them capsules of fish oil while the other half received placebo. One year on, only three percent of those on fish oil had developed schizophrenia compared to 28 percent from those on placebo.[29] A study conducted at Sheffield University in England reported positive results with fish oil on patients suffering from schizophrenia. Participants of the study had previously taken anti-psychotic prescription drugs that were no longer effective. After taking fish oil supplements, participants in the study experienced progress compared to others who were given a placebo.[30][31] The largest controlled study to date found no cognitive benefit after two years in the elderly.[32][33]
[edit] Alzheimer's disease

According to a study from Louisiana State University in September 2005, Docosahexaenoic acid, an omega-3 fatty acid often found in fish oil, may help protect the brain from cognitive problems associated with Alzheimer's disease.[34]
[edit] Lupus

In a Northern Ireland study, lupus disease activity, especially in the skin and joints, was significantly reduced in patients who received fish oil supplements at both 12-week and 24-week follow-up periods versus patients who received placebo. There were also changes in the blood platelets of the patients who took the fish oil supplements, with an increase in proteins that are considered anti-inflammatory and a decrease in proteins that promote inflammation; these changes were not evident in the group that took placebo. The fish oil group showed an increase in FMD, which the researchers took as a sign that the omega-3 oils were helping the cells in the blood vessel walls to remain healthy.[citation needed]
[edit] Parkinson's disease

A study[35] examining whether omega-3 exerts neuroprotective action in Parkinson's disease found that it did exhibit a protective effect in mice. The scientists exposed mice to either a control or a high omega-3 diet from two to twelve months of age and then treated them with a neurotoxin commonly used as an experimental model for Parkinson's. The scientists found that high doses of omega-3 given to the experimental group prevented the neurotoxin-induced decrease of dopamine that ordinarily occurs. Since Parkinson's is a disease caused by disruption of the dopamine system, this protective effect exhibited could show promise for future research in the prevention of Parkinson's disease.[35]
[edit] Depression

Evidence regarding the efficacy of fish oil supplements as a treatment for depression is inconclusive. Whereas several methodologically rigorous studies have reported statistically

significant positive effects in the treatment of depressed patients, other studies have found effects to be insignificant. An August 2003 double-blind placebo-controlled study published in the journal European Neuropsychopharmacology found that among 28 patients with major depressive disorder, "patients in the omega-3 PUFA group had a significantly decreased score on the 21-item Hamilton Rating Scale for Depression than those in the placebo group."[9] Another study in the American Journal of Psychiatry reported that the addition of fish oil supplements to regular maintenance anti-depression therapy conferred "highly significant" benefits by the third week of the trial.[13] A 2005 randomized double-blind placebo-controlled study conducted under the auspices of the New Zealand Institute for Crop & Food Research found "no evidence that fish oil improved mood when compared to placebo, despite an increase in circulating -3 polyunsaturated fatty acids."[36] Another study published in October 2007 found that fish oil supplements conferred no additional benefits beyond those conferred by standard treatment.[37] However, both of these studies used omega-3 primary consisting of DHA, not EPA. Dr. Andrew Stoll of Harvard, published a book and double blind study on Omega 3's that showed lifting of depression and manic depression within huge study populations, in days, not weeks or months. A 2009 metastudy found that patients taking omega-3 supplements with a higher EPA:DHA ratio experienced less depressive symptoms. The studies provided evidence that EPA may be more efficacious than DHA in treating depression. However, this metastudy concluded that due to the identified limitations of the included studies, larger, randomized trials are needed to confirm these findings.[38]
[edit] Psoriasis

Diets supplemented with cod liver oil have shown beneficial effects on psoriasis.[39]
[edit] Pregnancy

Omega-3 polyunsaturated fatty acids (commonly found in fish oil) protect against fetal brain injury and promotes fetal and infant brain health.[40] Some studies reported better psycho motor development at 30 months of age in infants whose mothers received fish oil supplements for the first four months of lactation.[41] In addition, five-year-old children whose mothers received modest algae based docosahexaenoic acid supplementation for the first 4 months of breastfeeding performed better on a test of sustained attention. This suggests that docosahexaenoic acid intake during early infancy confers long-term benefits on specific aspects of neurodevelopment.[41] Docosahexaenoic acid supplementation has also been found to be essential for early visual development of the baby.[42] However, the standard western diet is severely deficient in these critical nutrients. This omega-3 dietary deficiency, a nutrient found in fish oil, is compounded by the fact that pregnant women become depleted in omega-3s, since the fetus uses omega-3s for its nervous system development. Omega-3s are also used after birth if they are provided in breast milk.[43] In addition, provision of fish oil during pregnancy may reduce an infants sensitization to common food allergens and reduce the prevalence and severity of certain skin diseases in the

first year of life. This effect may persist until adolescence with a reduction in prevalence and/or severity of eczema, hay fever and asthma.[44] Omega-3 fatty acid supplementation is also beneficial to the mother.[40] It has been shown to prevent pre-term labor and delivery.[43] It is recommended that women who are breastfeeding consume fish oil at least twice a week, although the American Heart Association recommends pregnant and nursing women are to avoiding eating fish with high potential for mercury contaminants including mackerel, shark, or swordfish.[44]

[edit] Dangers
[edit] Maximum intake

The FDA says it is safe to take up to 3000 mg of omega-3 per day.[45] (This is not the same as 3000 mg of fish oil. A 1000 mg pill typically has only 300 mg of omega-3; 10 such pills would equal 3000 mg of omega-3.) Dyerberg studied healthy Greenland Eskimos and found an average intake of 5700 mg of omega-3 EPA per day.[46]
[edit] Vitamins

The liver and liver products (such as cod liver oil) of fish and many animals (such as seals and whales) contain omega-3, but also the active form of vitamin A. At high levels, this form of the vitamin can be dangerous (Hypervitaminosis A).[47]
[edit] Toxic pollutants

Fish oil supplements came under scrutiny in 2006, when the Food Standards Agency in the UK and the Food Safety Authority of Ireland reported PCB levels that exceeded the European maximum limits in several fish oil brands,[48][49] which required temporary withdrawal of these brands. To address the concern over contaminated fish oil supplements, the International Fish Oil Standards program, a voluntary review process, was created at University of Guelph.[50] A March 2010 lawsuit filed by a California environmental group claimed that eight brands of fish oil supplements contained excessive levels of PCB's, including CVS/pharmacy, Nature Made, Rite Aid, GNC, Solgar, Twinlab, Now Health, Omega Protein and Pharmavite.[51][52] The majority of these products were either cod liver or shark liver oils. Because the liver is the major filtering and detoxifying organ, PCB content is much higher in liver-based oils than in fish oil produced from the processing of whole fish.[citation needed] An analysis based on data from the Norwegian Women and Cancer Study (NOWAC) with regards to the dangers of persistent organic pollutants (POPs) in cod liver came to the conclusion that "in Norwegian women, fish liver consumption was not associated with an increased cancer risk in breast, uterus, or colon. In contrast, a decreased risk for total cancer was found."[53] However, a report by the Harvard Medical School studied five popular brands of fish oil, including Nordic Ultimate, Kirkland and CVS. They found that the brands had negligible amounts of mercury, suggesting either that mercury is removed during the manufacturing of purified fish oil or that the fish sources used in these commercial preparations are relatively mercury-free. [54]

Pharmaceutical Grade Fish Oil?

There is no such thing as Pharmaceutical Grade Fish Oil. It is a term dreamt up initially by an aggressive marketer and adopted by others. The US Pharmacopeia does not yet have a monograph to regulate the specifications and purity of fish oil. In the absence of any strict guidelines the US Council for Responsible Nutrition (CRN) has developed a voluntary monograph. The CRN monograph was developed taking into account various European and World Health Organization (WHO) standards. A number of responsible fish oil manufacturers worldwide are now working to this monograph by either equaling it or in some cases, even exceeding it.

Xtend-Life exceeds ALL minimum specifications

It is important to be aware that there is an official sounding organization called International Fish Oil Standards (IFOS) which a number of fish oil marketers use for testing. It is actually a private organization. IFOS will issue star ratings for various manufacturers who are prepared to submit their products to them in order to get tested for a fee. Some manufacturers feel that if they meet the specifications of IFOS then they can call their products pharmaceutical grade fish oil because the IFOS standards are tougher for some components of the oil. This is true for some parameters but not all. Even though they are stricter in some areas, they still do not meet Xtend-Lifes specifications.

What about the US FDA? Do they have minimum purity levels?

Yes. But their levels for mercury and oxidation are so lenient (high) that they are insignificant within the context of this discussion.

What is the level of purity for Xtend-Life Omega 3 / DHA Fish Oil?
If you go to our page on Fish Oil Purity, you will see a table of values.

Can Xtend-Lifes Omega 3 / DHA Fish Oil purity claims be proven? Fish can be reduced to meal and oil in a number of ways. Common to all methods of practical importance are the following processing steps:

heating, which coagulates the protein, ruptures the fat depots and liberates oil and physico-chemically bound water; pressing (or occasional centrifugation), which removes a large fraction of the liquids from the mass; separation of the liquid into oil and water (stickwater). This step may be omitted if the oil content of the fish is less than 3%; evaporation of the stickwater into a concentrate (fish solubles); drying of the solid material (presscake) plus added solubles, which removes sufficient water from the wet material to form a stable meal, grinding the dried material to the desired particle size.

What is purity?
Fish oil purity is assessed by measuring the levels of heavy metals, PCBs and dioxins in the fish oil-

polychlorinated biphenyls

(PCBs)
At the moment there are four standards of fish oil purity that are used internationally. These are indicated in the below table. You will note that we at Xtend-Life have set our own specification standards which are much more stringent than anyone elses. They are all set at the lowest limits of detection for most laboratory analytical equipment. You will also notice that most of them are significantly lower than the normal international standard. If you check our COA (Certificate of Analysis) you will see that the levels of purity are so good with our Omega 3 / DHA Fish Oil that even at these lower levels, NO contaminants are detected.

Component

Xtend-Life Specifications

International Fish Oil Standards (IFOS)

Council for Responsible Nutrition (CRN)

European Pharmacopoeia

Norwegian Medicinal Standard

Arsenic (ppb)

<90

100

100

100

100

Cadmium (ppb)

<10

100

100

100

100

Mercury (ppb)

<10

100

100

100

100

Lead (ppb)

<50

100

100

100

100

Total PCBs (ppb)

<5

45

90

N/A

N/A

Total Dioxins & Furans (ppt)

<0.5

1*

Notes: * N/A means Not Available * < means less than the indicated Xtend-Life Specifications which are the minimal levels of detection for standard testing equipment. * ppb means part per billion / ppt means part per trillion * IFOS although included in the table is not a recognized entity. It is a private organization and it is claimed by some observers that it was established for the benefit of a few marketers of fish oil.

Tips for Taking Fish Oil Once again we borrow from the wisdom of Dr. Barry Sears who devoted most of his career to researching lipids as an NIH Postdoctoral Fellow at the University of Virginia which, at the time, was the center of lipid research in the United States . Here are his tips on taking fish oil: 1. Never take fish oil capsules on an empty stomach. 2. Take your fish oil capsule at night before bedtime, preferably with a snack. 3. Divide up your capsules throughout the day. Unlike vitamins and minerals that last only a few hours in the blood, fatty acids from fish oil last several days in the blood. So if you cant take them at all once, split them up. Either way, he says, youll still maintain stable blood levels. 4. If you need to take more than four capsules a day, consider switching to a liquid version. This is a good way to save money, given that you no longer have to pay for the expensive gel capsules. 5. Freeze the liquid fish oil this prevents oxidation, and makes the liquid taste better. 6. Whether in gel or liquid form, it is still fish and many people dislike its taste. A trick would be to mix the liquid fish oil with two ounces of orange juice. Or you can add tablespoons of fish oil into your morning shake.

Understanding omega-3s

Andrew P. DeFilippis, MD, a and Laurence S. Sperling, MD, FACC, FACP b Atlanta, GA Omega-3 fatty acids are a subset of polyunsaturated fatty acids found in marine sources as eicosapentaenoic acid anddocosahexaenoic acid and in some leafy vegetables, nuts, and oils as a -linolenic acid (ALA). The metabolism of omega-3smay explain the cardioprotective effects observed in epidemiologic and experimental studies. Although most data forcardioprotective effects come from studies of marine sources, vegetable sources of omega-3 fatty acids ( a -linolenic acid) mayhave similar effects through in vivo conversion to eicosapentaenoic acid and docosahexaenoic acid. This document willprovide an overview of omega-3 fatty acids with a focus on specific sources, metabolism, safety issues, and their potentialindication for cardiovascular prevention. (Am Heart J 2006;151:564-70.) Interest in omega-3 fatty acids has grown steadily since the observation that Greenlands Eskimos have alow incidence of cardiovascular diseas e ( C V D ) i n t h e s e t t i n g o f a d i e t r i c h i n f a t t y f i s h. 1 Importantly, both epidemiologic and experimental data have providedevidence for a beneficial effect of omega-3 fatty acids inthe prevention of CVD. In 2002, the American Heart Association released a scientific statement endorsing t h e u s e o f o m e g a - 3 f atty acids in both primary andsecondary prevention. 2 What are omega-3s? There are 3 types of naturally occurring fats classified b y t h e n u m b e r o f d o u b l e b o n d s p r e s e n t i n t h e i r f a t t y acid side chains:saturated, monounsaturated, andpolyunsaturated( Figure 1 ). The food industry created afourth class, trans fats, by adding hydrogen ions topolyunsaturatedfats through a process called hydroge-nation ( Figure 1 ). Polyunsaturated fats can be further c l a s s i f i e d i n t o 2 g r o u p s b a s e d o n t h e p o s i t i o n o f t h e first double bond site: omega-3 fatty acids and omega-6fatty acids ( Fi g u r e 1 ).The most prominent omega-6fatty acids in the human diet are arachidonic acid(found in animal meat) and linoleic acid (found in vegetable oils, seeds, and nuts), which can be con- v erted into arachidonic acid by a desaturase enzyme ( Figure 2 ). Major dietary sources of omega-3s are fish containing eicosapentaenoic acid (EPA) and docosa-hexaenoic acid (DHA) and nuts, seeds, and vegetableoils containing a -linolenic acid (ALA), which can beconverted to EPA and then DHA by the same desaturaseenzyme that converts linoleic acid to arachidonic acid ( Figure 2 ).T h e c o n v e r s i o n o f A L A t o E P A i s o f i n t e r e s t b e c a u s e the cardioprotective effects of omega3s have beenmost rigorously studied and closely associated with E P A . T h i s c o n v e r s i o n m a y e x p l a i n , i n p a r t o r i n whole, ALAs potential benefit. Isotope-labeled ALA f e e d i n g t r i a l s h a v e s h o w n t h e c o n v e r s i o n o f A L A t o EPA to vary between 0.2% and 21 % an d t h a t of ALA toD H A t o v a r y b e t w e e n 0 % a n d 9 % . 3 Most feedingstudies that measure interval changes in membranefatty acid composition show that ALA feeding will lead t o a n i n c r e a s e i n E P A buth a s a n u l l e f f e c t o r s l i g h t decrease in DHA levels. 3 These studies, however, ares o m e w h a t l i m i t e d b e c a u s e t h e c o n v e r s i o n o f A L A t o E P A + D H A i s l i k e l y i n f l u e n c e d b y m u l t i p l e f a c t o r s including, sex, competitive inhibition of desaturase by linoleic acid( Figure 2 ), negative feedback inhibition of d e s a t u r a s e b y E P A + D H A ( F i g u r e 2 ) , a n d t i m i n g o f the sample collection. Analysis of the Health Professional Follow-up Study cohort found that ALAs CVD protective properties wereinversely related to EPA + DHA intake. The authorsconcluded that ALAs cardioprotective properties werecontingent on conversion to EPA + DHA and that thisc o n v e r s i o n w a s i n h i b i t e d b y E P A + D H A i n t a ke 4 ( Fi g u r e 2 ). Where are omega-3s? Dietary intake of omega-3 and omega-6 fatty acids varies within and between different populations.NHANES III, the largest database of nutrient consump- tion of Americans, reportsa median intake of EPA + DHA of 0 and b 1 g/d of AL A. 5 The ratio of omega-6 to omega-3intake is estimated to be 20 to 1 in a modern Westerndiet, compared with that of our Paleolithic ancestors who ate a diet much richer in omega-3s

(estimated From the Division of a General Medicine, and b Cardiology, Emory University School of Medicine, Atlanta, GA.Submitted December 15, 2004; accepted March 26, 2005.Reprint requests: Andrew P. DeFilippis, MD, Division of General Medicine, Emory University School of Medicine, 49 Jessie Hill Jr Dr, Atlanta, GA 30303. E-mail: APDeF@yahoo.com0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.03.051 Curriculum in Cardiology

omega-3/omega-6 ratio of 1-2:1) ( Figure3 ). 6,7 Thisdramatic dietary shift is thought to be related to anabsolute reduction in fish consumption as well as aproportionate increased consumption of domestically raised fish. Meat and fish presently contain less omega-3 and more omega-6 fatty acids than in the past, secondary t o u s e o f c o m m ercialfeeds high in omega-6 and low inomega-3 content. 8,9 E ven cultivated vegetables ar e p o o r in omega-3 when compared with wild plant s. 10 The metabolism of omega-3s A dietary shift toward less omega-3s and moreomega-6s may significantly impact ones health be-cause of their different metabolic pathways. Eicosa-noids are a class of bioactive molecules derived fromomega-3s and omega-6s that include leuko trienes,prostaglandins, and thromboxanes ( Figure 2 ). Eicosa-noids derived from omega-6s are generally proinflam-matory and proaggretory, whereas those derived fromomega-3s are predominantly anti-inflammatory andinhibit platelet aggregation. 6 This fundamental differ-ence may account for the cardioprotective effects of omega3s.Inflammation is a central component in atheromaformation and plaque ruptur e, 11 and studieshavelinkedsystemic markers of inflammation to CVD risk. 12 A cross-sectional study of 727 women in the Nurses Health Study I found dietary intake of omega-3s to be inversely related to inflammatory markers C-reactive protein, IL-6, Figure 1 Classification of fats. Figure 2 Metabolic pathway of omega-6 and omega-3 fatty acids. Figure 3 Historical schematic of relative percentages of fat and intake of different fatty acids in human beings. Reproduced with permission by the American Journal of Clinical Nutrition . n A m J C l i n N u t r . American Society for Clinical Nutrition. American Heart JournalVolume 151, Number 3 DeFilippis and Sperling 565

E-selectin, soluble intercellular cell adhesionmolecule 1,and soluble vascular cell adhesion molecule1. 13 Thisrelationship was consistent for ALA , EPA, and DHA independently and in aggregate. 13 A n inverse relation-ship between EPA + DHA intake and soluble tumor necrosis factor receptors was demonstrated in a cohortof 405 healthy men in the Health Professionals Follow-up Study and 454 healthy women in the Nurses Health Study II. 14 L evels of tumor necrosis factor receptors were lowest in subjects with a high ratio of EPA + DHA to omega-6 intake and highest in subjects with a low ratio of EPA + DHA to omega-6. In this study, ALA intakedid not influence the levels of any of the inflammatory markers measured.In addition to markers of vascular inflammation,omega-3s may beneficially influence other factorsrelated to CVD risk: ventricular arrhythmias, thrombo-sis, triglycerides, apolipoprotein B, high-density lipo-protein, adhesion molecule expression in plaque,platelet-derived growth factor, nitric oxide

inducedendothelial relaxation, and blood pressure. 2,6,15-17 Ingeneral, these studies have been performed largely w i t h E P A + D H A; f e w s tu d i e s e x am i n e t h e i mp ac t o f ALA on these intermediate markers of CVD. Impor-tantly, vascular inflammation may be the commonpathologic mechanism in which omega-3s impact all of these factors. Epidemiologic data Several important observational studies have con-cluded that omega-3 consumption i s i nversely relatedto CVD, especially cardiac death. 1 8- 2 2 I n a s tu d y of 22071 male American physicians, those who consumedfish once a week had a 52% reduction of sudden cardiac death comparedwith those who ate fish less than once amonth ( P = . 04 ). 20 There was no additional protectiveeffect for men eating fish in amounts greater than once a week. Although a reduction in sudden cardiac death andtotal mortality was observed, there was no relationshipbetween omega-3 consumption and myocardial infarc-tion, nonsudden cardiac death, or CVD mortality. TheNurses Health Study of 84688 women showed aninverse relationship between consumption of EPA +DHA and both fatal and nonfatal CVD events, whereas ALA intake was onl y s i gnificantly related to a reductionin fatal CVD events. 21 In the MRFIT trial of 12866 men,dietary intake of both EPA + DHA and ALA was inversely related to coronary heart disease, all CVD events, and all-cause mortality.In the Honolulu Heart Program study of 8006 men, low fish intake was defined as consumption of fish less thantwice a w eek and high fish intake as that z 2 times a week . 23 There was no difference in the incidence of coronary heart disease between the cohorts, but this lack of association may have been secondary to a thresholdeffect. Maximal reduction of sudden cardiac death in thePhysicians Health Study was seen at a fish intake of oncea week. A threshold effect may also explain the lack of association between fish consumption and coronary heartdisease in the Health Professionals Follow-upStudy . 24 A lthough a 4-fold difference in fish consumptionexisted between the highest and lowest quintile of participants in this study, the mean fish intake in the lowest quintile was still 1.2 servings/wk.In addition todietary intake studies, omega-3 f atty acid whole blood 25 and platelet phospholipid content 16 h avebeen shown to be inversely related to CVD death. Prospective randomized trials The impact of omega-3s on cardiovascular end pointshas been evaluated in 4 well-designed secondary prevention trials. These trials evaluated omega-3s either as part of a comprehensive diet plan or as a capsulesupplement, and although these trials differed in many respects, their findings were consistent and compel-lingomega-3s are effective for secondary preventionof cardiovascular events.The DAR T 26

randomized 2033 postmyocardial in-farction Welsh men to one of the following groups:(1) sensible eating (placebo); (2) low fat with an increased polyunsaturated-to-saturated ratio; (3) fatty fish consumption twice a week or 1.5 g fish oilcapsules/d; (4) increased dietary fiber; or (5) a combi-nation of the above. At 2 years, there was a 4-foldincrease in EPA intake in the fish advice group (22% were taking fish oil capsules instead of eating fish). Allcause mortality and ischemic heart disease events were not reduced in the high-fiber and low-fat groups.The group advised to consume fatty fish twice a week or take fish oil capsules had a 29% (3.5% absolute risk, P b .05) reduction in all-cause mortality attributable to areduction in ischemic deaths, whereas nonfatal ische-mic heart disease events were not reduced. A survey of 47% of DART participants still living 10 years after thetrials conclusion showed no long-ter m survival benefitin any of the intervention group s. 27 This lack of sustained benefit may be caused by the substantialreduction in the difference in fish and fish oil intakebetween the in terv ention and placebo groups observedduring the trial. 27 The Indian Experiment of Infarct Survival 4 tri al 28 randomized 360 patients with acute coronary syndrometo 1 of 3 interventions: (1) placebo; (2) fish oil capsules( 1 . 8 g /d E P A + D H A) ; an d ( 3 ) 20 g /d of m u s ta rd o i l ( 2. 9 g /d of AL A) .A f t e r 1y e a r, t ot a l c a rd i a c e v e n ts ( s u d d e n cardiac death, nonfatal reinfarction, cardiac death) werereduced from 34.7% in the placebo group to 28% in themustard oil group ( P b .01) and to 24.5% in the fish oilgroup ( P b .01). Statistically significant reductions wereseen in patients in both the fish oil and the mustard oil American Heart JournalMarch 2006 566 DeFilippis and Sperling g ro u p sf or n o n f at al i n f a rc ti on s, an g i n a , a r rh yt h m i a s, h e a rt failure, and left ventricular hypertrophy. Only patients inth e f i s h o i l g ro u p h a d a st at i s ti c al l y si g n i f i ca n t re d u ct i o n i n all cardiac deaths when compared with those in theplacebo group.The Lyon Heart Study 29 compared a Mediterranean ALA-rich diet with a prudent diet in 608 post myocardialinfarction patients. After an average follow-up of 27 months, the Mediterranean ALA-rich diet groupachieved a 70% reduction in all deaths ( P = .02), 76%re d u c ti on i n c ar d i ac d e a th ( P = . 0 2 ) , a n d a 7 3 % r e d u c t i o n in the primary end point of cardiac death and nonfatalmyocardial infarction ( P = .001) after multivariantadjustment. A follow-up assessment at 46 monthsrevealed continued good compliance with the Mediter-ranean ALA-rich diet and similar reductions in totalmortality and cardiovascular events. 30

Because subjectsin the Mediterranean diet group made multiple dietary changes, it is not possible to determine if ALA wasspecifically responsible for the positive results; none-th e l e s s, i t i s cl e a r f ro mt h i s s tu d y t h a tA LA ca n b e p ar t o f a cardioprotective Mediterranean diet.The GISSI-Prevenzione trial, 31 an open-label designtrial, randomized 11324 postmyocardial infarctionp at i e n ts to 1 of 4 g ro u p s: ( 1 ) 1 g /d o f f i s h oi l supplement; (2) 300 mg/d of vitamin E supplement;(3) both; or (4) neither in addition to intensive postmyocardial infarction care and good adherence to aMediterranean diet with N 70% of the participants eatingfish at least once a week. This care did not differ between the intervention and control groups and data were collected on 99.9% of participants during the3.5 years of intervention. The fish oil supplement grouphad a 15% reduction in the combined end point of death,nonfatal myocardial infarction, and nonfatal stroke ( P = .023) when compared with the control group (no supplement). Analysis of individual end points showed a20% reduction in death ( P b .05), 30% reduction incardiovascular deaths ( P = .02), and a 45% reduction insudden death ( P = .01). There was no reduction innonfatal cardiovascular events in the fish oil group. Vitamin E did not impact CVD outcomes in the presenceor absence of fish oil. All 4 trials report a reduction in secondary cardiacevents with either 1.0 to 1.8 g/d of fish oil capsules/1serving of fish per day (DART, the Indian Experiment of Infarct Survival 4 trial, GISSI) or ALA supplementation (Indian Experiment of Infarct Survival 4 trial, Lyon HeartStudy). Results are similar with fish/fish oil supple-mented as part of a comprehensive dietary interventionand as a single intervention (DART), fish oil capsulesalone (GISSI), and ALA as a single intervention (IndianExperiment of Infarct Survival 4 trial) or as part of acomprehensive diet plan (Lyon). Of the 4 trials, GISSIprovides the most convincing data because of its large size (11324), randomized intervention with a controlleddose (1 g/d) of fish oil, and 99.9% follow up rate,although it can be criticized for its open-label design. Clinical use In addition to being useful in the secondary preven- tion of CVD events, a prescription formulation of omega-3 fatty acids, Omacor, has gained Food and Drug Administration (FDA) approval as an adjunct to diet toreduce very high ( N 500 mg/dL) triglycerides in adults.Two studies of 4 g/d of Omacor demonstrated a 50%reduction in triglycerides and a 44.5% increase in lowdensity lipoprotein (LDL) ch olesterol in 84 adults with primary hypertriglyceridemia. 32 A review of 10 trialsin 606 subjects with primary hypertriglyceridemia(triglycerides N 150 mg/dL and/or total cholesterol N 200 mg/dL) supplemented with 3.4 to 4 g/d of fish oil f or 4 to 16 w e e k s w as n ot ab l e f or a 16% t o 4 5%reduction in triglycerides in all but one study . 33

Totalcholesterol decreased 0% to 9.3%, high-density lipopro-tein increased 0% to 13%, and changes in LDL rangedfrom 11.3% to +32%. Although fish oil may increase total LDL (at doses N 1 g/d), the resultant LDL populationmay have an increased particle size th a t i spotentially less atherogenic than small, dense LDL . 34 In normotri-glyceridemic diabetics, fish oil supplementation mod- estly lowers triglycerides without any clinically significant effect on glycemic control. In hypertrigly-ceridemic diabetics, fish oil supplementation r educestriglycerides; however, it may increase LDL . 35 In threesm al l st u d i e s (n = 41 , n = 48 , n = 55 ) , f i sh oi l supplementation has been used as a safe adjunct tostatin therapy to further reduce trigl ycerides, whilemaintaining a reduction in LDL. 3 6- 3 8 The impact of ALA on triglycerides remains uncertain given that a singlestudy of 30 adults supplemented with 4.5 g/d of ALA demonstrated no significant change in a baselinetriglyceride level of 147 mg/dL . 39 Fish oil supplementation at 1 to 2 g/d titratable to 4 g/din single or divided doses can be considered for patients with modest hypertriglyceridemia (200-499 mg/dL) who do not have a reversible secondary cause of hypertriglyceridemia and have failed dietary interven-tion. Periodic monitoring of LDL and triglycerides levelsis prudent until a safe, steady, therapeutic dose isachieved. Treatment recommendations for severehypertriglyceridemia ( N 500 mg/dL) are beyond thescope of this article. Safety The US Department of Health and Human Services Agency for Healthcare Research and Quality identified148 omega-3 fatty acid stu diesthat reported on adverseevents in N 20000 subjects. 5 In summary, gastrointesti-nal complaints were reported in 6.6% of the subjects American Heart JournalVolume 151, Number 3 DeFilippis and Sperling 567 taking omega-3s versus 4.3% in the placebo groups. Anincreased incidence of bleeding was not observed, andonly 1 of the 148 studies reviewed reported such anassociation in patients randomized to 6 g/d of omega-3.There are no reported deaths or life-threatening illnessas a consequence of omega-3 consumption, and 77 of the studies reported no adverse events at all. Theagency concluded that adverse events related toco n s u m p t i o n o f f i s h oi l o r A LA s u p p l e me n t s a p p e ar t o b e m i n o r . I n a d d i t i o n , t h e F DA h a s r u l e d t h a t u p t o 3 g / d o f E P A + D H A i s s a f e, 40 although mostdata are limited to b 6 months. Importantly, cautionshould be exercised when applying safety datagenerated in a clinical research setting to patients in the general

population.Concerns have been raised regarding potential mer-cury exposure from fish and fish oil consumption.However, there have been no cases of mercury poison-ing related to fish consumption reported in the UnitedStates over the last 35 years. Subclinical neural damage from chronic exposureto low levels of mercury found infish is controversial. 41 One observational study reportedsubtle neuropsychological changes in children whohad been exposed to high levels of mercury through frequent maternal consumption of w hales(1.6 A gmethyl-mercury/g) during pregnancy. 41,42 A similar study found no adverse effects in children whosemothers consumed an average of 12 servings of fish per week that conta ined average levels of methylmercury (0.3 A g/g). 41,42 Although the risk posed by mercury exposure through fish consumption is speculative, the FDA recommendslimiting consumption of fish that are high in mercury ( N 1 ppmor approximately 1 A g/g) to one serving (7 oz)per week . 43 Because the fetal brain is more susceptiblethan the adult brain to mercuryinduced damage, theFDA and the Environmental Protection Agency recommend that pregnant women, nursing mothers, and young children avoid eating fish with high mercury content. The FDA maintains a web page ( http://www.cfsan.fda.gov ) that currently lists shark, swordfish,king mackerel, and tilefish as having a high mercury content. With the exception of Omacor, available by prescription, the FDA does not regulate fish oil supplements, and, at the time of this review, we were able toidentify only one peer-reviewed English language study that had evaluated fish oil supplements for mercury content. This study examined 5 popular fish oil supple-ments: 3 were found to have undetectable levels of mercury ( b 6 A g/L) and 2 had levels between 10 and12 A g /L o f me r cury by coldvapor atomic absorptionspectroscopy ( Table I ). 44 Th is level of mercury isconsidered negligible. Table II. Omega-3 fatty acid content of select food Food itemE P A D H A A L A FishCatfishT r a c e 0 . 2 0 . 1 CodT r a c e 0 . 1 T r a c e Mackerel0 . 9 1 . 4 0 . 2 SalmonFarmed0 . 6 1 . 3 T r a c e Wild0 . 3 1 . 1 0 . 3 Canned0 . 9 0 . 8 T r a c e Salmon, Chinook 1 . 0 0 . 9 T r a c e Swordfish0 . 1 0 . 5 0 . 2 Tuna, Bluefin0 . 3 0 . 9

 Tuna, Light Canned in oilT r a c e 0 . 1 T r a c e Canned in water T r a c e 0 . 2 T r a c e Tuna, WhiteCanned in oilT r a c e 0 . 2 0 . 2 Canned in water 0 . 2 0 . 6 T r a c e ShellfishLobster Mussels0 . 2 0 . 3 T r a c e Shrimp0 . 3 0 . 2 T r a c e Nuts and seedsButternuts 8 . 7 Flaxseed 1 8 . 1 Walnuts 9 . 1 Plant oilsCanola 9 . 3 Flaxseed 5 3 . 3 Measurements are expressed in grams per 100 grams (3.5 oz)of fooditem.Trace = b 0.1; () = 0 or no data. Adapted from the US Department of Health and Human Services. 5 Table III. Summary of American Heart Associationrecommendations for omega-3 fatty acid intake PopulationRecommendation Patients without documented CHDEat a variety of (preferably fatty) fish at least twice a week. Include food and oils rich in ALA in your diet.Patients withdocumented CHDConsume approximately 1 g of EPA + DHA (3 g of fish oil) everyday,preferably from fatty fish. EPA + DHA (fish oil)supplements could beconsidered in consultation with a physician. Data from Kris-Etherton et al. 2 Table I. Mercury level in 5 popular fish oil supplements Supplement brand nameMercury level ( AAAAAAAA g/L) CVS10Kirkland b 6Nordic Ultimate b 6Omega Brite12Sundown b 6 Data from Foran et al. 44 American Heart JournalMarch 2006 568 DeFilippis and Sperling Several cohort and case-control studies evaluating the relationship between omega-3s and prostate cancer have been conducted with varying results. A meta-analysis combining the results of 4 cohort and 5 case-control studies concluded that high intake of ALA isassociated with an increased risk of prostate cancer (relative risk 1.70, 95% CI 1.12-2.58). 45 The authors notethat the studies were quite heterogeneous, with only 1of the 4 prospective cohort trials and 3 of the 5 case-control studies showing a statistically significant positiveassociation to prostate cancer. To date, null and inverseassociations between E PA + DHA and prostate cancer have been reported.

45,46 Conclusion Omega-3s are a unique group of polyunsaturated fats that can be found most abundantly in fatty fish, flaxseed, walnuts, soy, and canola oil( Table II ). The metabolismof omega-3s from fish (EPA + DHA) and vegetables(ALA) results in the production of the same eicosanoids(thromboxane, leukotrienes, prostaglandins); however,it is unclear as to what extent ALA is metabolized intothese eicosanoids and if this metabolism is directly related to its effect on CVD. It does seem clear from the4 prospective randomized trials outlined above thatboth fish and plant sources of omega-3s can favorably impact cardiovascular health. The impact of omega-3s ismost consistently related to the use of fish oil. Although data on reduction in cardiovascular events with plantsources of omega-3s (ALA) exist, the number of subjectsstudied in the Indian Experiment of Infarct Survival4 was small and ALA supplementation was part of multiple dietary interventions in the Lyon Heart Study.Clearly, a prospective randomized controlled trial,similar to GISSI, with ALA would be very valuable.Strong cohort trial data exist for the primary preventionof cardiovascular events with omega-3s (EPA, DHA, ALA), but no prospective randomized controlled trialhas adequately evaluated the effect of omega-3 fatty acids on the primary prevention of CVD. To date, no serious adverse effects of omega-3s have been identifieddespite trial data on 20000 subjects. Potential harmfrom mercury exposure can be avoided with prudentfish and fish oil supplement selection. Data on theassociation between ALA and prostate cancer areinconsistent and limited to case-control and cohort trials. Given this concern, if omega-3 supplementation isgoing to be implemented in men, fish oil may be a moreprudent choice than ALA.It is recommended that patients with know n C VD consume one serving (200-400 g) of fatty fish ( Table II )or 1 g / d of f i sh o i l su p p lementand maintain a healthy diet that is rich in ALA ( Table II ). Patients with a CVDrisk equivalent (diabetes, peripheral vascular disease,etc) should consider consumption of a single serving of fatty fish or 1 g/d of fish oil supplement and eat a healthy diet rich in ALA. Fish oil supplements may be particu-larly helpful in patients with known CVD or CVD risk equivalents and hypertriglyceridemia. For patients without known CVD, a single serving of fatty fish approximately once or twice a week and a diet rich in ALA should be encouraged. It is prudent to avoid fish that contain high levels of mercury as defined by theFDA. These recommendations are in agreement with the American Heart Associations scientific statement( Table III ). References 1. Dyerberg J, Bang HO, Stoffersen E, et al. Eicosapentaenoic acid andprevention of thrombosis and atherosclerosis? Lancet 1978;2:117-9.2. Kris-Etherton PM, Harris WS, Appel LJ, et al. Nutrition C. Fishconsumption, fish oil, omega-3 fatty acids, and cardiovascular disease [erratum appears in Circulation 2003;107:512]. Circulation2002;106:2747-57.3. Burdge G. Alpha-linolenic acid metabolism in men and women:nutritional and biological implications. Curr Opin Clin Nutr MetabCare 2004;7:137-44.4. Mozaffarian DM, Ascherio A, Hu FB, et al. Interplay betweendifferent polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation 2005;111:166-73.5. US Department of Health and Human Services AfHRaQ. Effects of omega-3 fatty acids on cardiovascular disease. Evid Rep Technol Assess (Summ) 2004;1-8.6. Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999;70(3 Suppl):560S-9S.7. Eaton SB, Konner M. Paleolithic nutrition. A consideration of itsnature and current implications. N Engl J Med 1985;312:283-9.8. Crawford MA. Fatty-acid ratios in free-living and domestic animals.Possible implications for atheroma. Lancet 1968;1:1329-33.9. van Vliet T, Katan MB. Lower ratio of n-3 to n-6 fatty acids incultured than in wild fish. Am J Clin Nutr 1990;51:1-2.10. Simopoulos AP, Salem Jr N. Purslane: a terrestrial source of omega-3 fatty acids. N Engl J Med 1986;315:833.11. Ross R.

Atherosclerosisan inflammatory disease. N Engl J Med1999;340:115-26. 12. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein andother markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-43.1 3. L op e z - Ga rc i a E , S c h u l z e M B , M a n s on JE , e t a l . C on su mp ti on of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr 2004;134: 1 80 6- 1 1. 14. Pischon T, Hankinson SE, Hotamisligil GS, et al. Habitual dietary intake of n-3 and n6 fatty acids in relation to inflammatory markersamong US men and women. Circulation 2003;108:155-60.15. Weber PC, Leaf A. Cardiovascular effects of omega 3 fatty acids. Atherosclerosis risk factor modification by omega 3 fatty acids. World Rev Nutr Diet 1991;66:218-32.16. Weber PC. Clinical studies on the effects of n-3 fatty acids on cellsand eicosanoids in the cardiovascular system. J Intern Med Suppl1989;225:61-8.17. Harper CR, Jacobson TA. The fats of life: the role of omega-3 fatty acids in the prevention of coronary heart disease. Arch Intern Med2001;161:2185-92. American Heart JournalVolume 151, Number 3 DeFilippis and Sperling 569 18. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverserelation between fish consumption and 20-year mortality fromcoronary heart disease. N Engl J Med 1985;312:1205-9.19. Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the30-year risk of fatal myocardial infarction. N Engl J Med1997;336:1046-53.20. Albert CM, Hennekens CH, ODonnell CJ, et al. Fish consumptionand risk of sudden cardiac death. JAMA 1998;279:23-8.21. Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287:1815-21.22. Dolecek TA. Epidemiological evidence of relationships betweendietary polyunsaturated fatty acids and mortality in the multiplerisk factor intervention trial. Proc Soc Exp Biol Med 1992;200:1 7 7 - 8 2 . 23. Rodriguez BL, Sharp DS, Abbott RD, et al. Fish intake may limit theincrease in risk of coronary heart disease morbidity and mortality among heavy smokers. The Honolulu Heart Program. Circulation1996;94:952-6.24. Ascherio A, Rimm EB, Stampfer MJ, et al. Dietary intake of marinen-3 fatty acids, fish intake, and the risk of coronary disease amongmen. N Engl J Med 1995;332:977-82.25. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med2002;346:1113-8.26. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish,and fibre intakes on death and myocardial reinfarction: diet andreinfarction trial (DART). Lancet 1989;2:757-61.27. Ness AR, Hughes J, Elwood PC, et al. The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet andReinfarction Trial (DART). Eur J Clin Nutr 2002;56:512-8.28. Singh RB, Niaz MA, Sharma JP, et al. Randomized, doubleblind,placebo-controlled trial of fish oil and mustard oil in patients withsuspected acute myocardial infarction: the Indian experiment of infarct survival4. Cardiovasc Drugs Ther 1997;11:485-91.29. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acidrich diet in secondary prevention of coronary heart disease [erratum appears in Lancet 1995;345:738]. Lancet 1994;3 43 :1 45 4- 9. 30. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet,traditional risk factors, and the rate of cardiovascular complicationsafter myocardial infarction: final report of the Lyon Diet Heart Study.Circulation 1999;99:779-85.31. Anonymous. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvi- venza nellInfarto miocardico [erratum appears in Lancet 2001;357:642]. Lancet 1999;354:447-55.32. Omacor [package insert]. Liberty Corner (NJ): Reliant Pharma-ceuticals, Inc; 2004.33. Lewis A, Lookinland S, Beckstrand RL, et al.

Treatment of hyper-triglyceridemia with omega-3 fatty acids: a systematic review. J Am Acad Nurse Pract 2004;16:384-95.34. Green ML. Management of dyslipidemias in the age of statins. PrimCare Clin Off Pract 2003;30:641-69.35. Farmer A, Montori V, Dinneen S, et al. Fish oil in people withtype 2 diabetes mellitus. Cochrane Database Syst Rev 2001;CD003205.36. Chan DC, Watts GF, Barrett PH, et al. Regulatory effects of HMGCoA reductase inhibitor and fish oils on apolipoprotein B-100kinetics in insulin-resistant obese male subjects with dyslipidemia.Diabetes 2002;51:2377-86.37. Chan DC, Watts GF, Mori TA, et al. Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity. Eur JClin Invest 2002;32:429-36.38. Nordoy A, Bonaa KH, Nilsen H, et al. Effects of simvastatin andomega-3 fatty acids on plasma lipoproteins and lipid peroxidationin patients with combined hyperlipidaemia. J Intern Med1998;243:163-70.39. US Department of Health and Human Services AfHRaQ. Effects of omega-3 fatty acids on cardiovascular risk factors and intermedi-ate markers of cardiovascular disease. Evid Rep Technol Assess2 00 4; 1- 6. 40. Administration USFaD. Safety reporting requirements for humandrug and biological products. 2003:21 CFR Part 310, 312, 314,320, 600, 606.41. Clarkson TW, Magos L, Myers GJ. The toxicology of mercurycurrent exposures and clinical manifestations. N Engl J Med 2003;3 49 :1 73 1- 7. 42. Myers GJ, Davidson PW, Cox C, et al. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles childdevelopment study. Lancet 2003;361:1686-92.43. Administration USFaD. Center for food safety and applied nutrition.2004 [12/1/2004].44. Foran SE, Flood JG, Lewandrowski KB. Measurement of mercury levels in concentrated overthe-counter fish oil preparations: isfish oil healthier than fish? Arch Pathol Lab Med 2003;127:1 6 0 3 - 5 . 45. Brouwer IA, Katan MB, Zock PL. Dietary alphalinolenic acid isassociated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J Nutr 2004;134:9 1 9 - 2 2 . 46. Terry PD, Terry JB, Rohan TE. Long-chain (n-3) fatty acid intake andrisk of cancers of the breast and the prostate: recent epidemiologicalstudies, biological mechanisms, and directions for future research. J Nutr 2004;134(12 Suppl):3412S-20S. American Heart JournalMarch 2006 570 DeFilippis and Sperling

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