Omega-3
Most of this intro info has been cut and pasted from Wikepedia
The 'essential' fatty acids were given their name when researchers found that they were essential to normal growth in young children and animals. (Note that the modern definition of 'essential' is more strict.) A small amount of n−3 in the diet (~1% of total calories) enabled normal growth, and increasing the amount had little to no additional benefit.
Likewise, researchers found that n−6 fatty acids (such as γ-linolenic acid and arachidonic acid) play a similar role in normal growth. However, they also found that n−6 was "better" at supporting dermal integrity, renal function, and parturition. These preliminary findings led researchers to concentrate their studies on n−6, and it was only in recent decades that n−3 has become of interest.
In 1963 it was discovered that the n−6 arachidonic acid was converted by the body into pro-inflammatory agents called prostaglandins. By 1979 more of what are now known as eicosanoids were discovered: thromboxanes, prostacyclins and the leukotrienes. The eicosanoids, which have important biological functions, typically have a short active lifetime in the body, starting with synthesis from fatty acids and ending with metabolism by enzymes. However, if the rate of synthesis exceeds the rate of metabolism, the excess eicosanoids may have deleterious effects. Researchers found that n−3 is also converted into eicosanoids, but at a much slower rate. Eicosanoids made from n−3 fats often have opposing functions to those made from n−6 fats (ie, anti-inflammatory rather than inflammatory). If both n−3 and n−6 are present, they will "compete" to be transformed, so the ratio of n−3:n−6 directly affects the type of eicosanoids that are produced.
In biochemistry, eicosanoids are signaling molecules made by oxygenation of twenty-carbon essential fatty acids, (EFAs). They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system. The networks of controls that depend upon eicosanoids are among the most complex in the human body.
This competition was recognized as important when it was found that thromboxane is a factor in the clumping of platelets, which leads to thrombosis. The leukotrienes were similarly found to be important in immune/inflammatory-system response, and therefore relevant to arthritis, lupus, and asthma. These discoveries led to greater interest in finding ways to control the synthesis of n−6 eicosanoids. The simplest way would be by consuming more n−3 and fewer n−6 fatty acids.
Health benefits
On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) n−3 fatty acids, stating that "supportive but not conclusive research shows that consumption of EPA and DHA [n−3] fatty acids may reduce the risk of coronary heart disease."[2] This updated and modified their health risk advice letter of 2001 (see below).
People with certain circulatory problems, such as varicose veins, benefit from fish oil. Fish oil stimulates blood circulation, increases the breakdown of fibrin, a compound involved in clot and scar formation, and additionally has been shown to reduce blood pressure.[3][4] There is strong scientific evidence that n−3 fatty acids significantly reduce blood triglyceride levels[5][6][7][8] and regular intake reduces the risk of secondary and primary heart attack.[9][10][11][12]
Some benefits have been reported in conditions such as rheumatoid arthritis[13][14] and cardiac arrhythmias.[15][16][17]
There is a promising preliminary evidence that n-3 fatty acids supplementation might be helpful in cases of depression[18][19] and anxiety.[20][21] Studies report highly significant improvement from n-3 fatty acids supplementation alone and in conjunction with medication.[22]
A 2006 report in the Journal of the American Medical Association concluded that their review of literature covering cohorts from many countries with a wide variety of demographic characteristics demonstrating a link between n−3 fatty acids and cancer prevention gave mixed results.[28] This is similar to the findings of a review by the British Medical Journal of studies up to February 2002 that failed to find clear effects of long and shorter chain n−3 fats on total mortality, combined cardiovascular events and cancer.[29]
In 1999, the GISSI-Prevenzione Investigators reported in the Lancet, the results of major clinical study in 11,324 patients with a recent myocardial infarction. Treatment 1 gram per day of n−3 fatty acids reduced the occurrence of death, cardiovascular death and sudden cardiac death by 20%, 30% and 45% respectively.[30] These beneficial effects were seen already from three months onwards.[31]
Mechanisms of ω-3 action
EFA sources: Essential fatty acid production and metabolism to form eicosanoids. At each step, the ω-3 and ω-6 cascades compete for the enzymes.
The eicosanoids from AA generally promote inflammation. Those from EPA and from GLA (via DGLA) are generally less inflammatory, or inactive, or even anti-inflammatory. The figure shows the ω-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA.
Dietary ω-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways, along the eicosanoid pathways:
New supportive Research:
Release Date: September 3, 2008;
http://www.medscape.com/viewarticle/579983
Omega-3 Fatty Acids, but Not Statin Therapy, Cuts Mortality and Hospitalizations in Heart Failure CME
News Author: Michael O'Riordan
CME Author: Laurie Barclay, MD
Complete author affiliations and disclosures, and other CME information, are available at the end of this activity.
Learning Objectives
Upon completion of this activity, participants will be able to:
1. Inform clinicians of the latest medical information concerning the effect of omega-3 fatty-acid supplementation on mortality and morbidity in symptomatic heart-failure patients, as presented at the European Society of Cardiology Congress 2008.
2. Describe the relevance of the findings about the efficacy of statins to clinicians in the care of their patients with symptomatic heart failure.
Authors and Disclosures
Michael O'Riordan
Disclosure: Michael O'Riordan has disclosed no relevant financial relationships.
Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.
September 3, 2008 — Omega-3 fatty-acid supplementation improves morbidity and mortality in symptomatic heart-failure patients, while statins failed to have any beneficial effect in the same group of patients, two new studies have shown [1,2]. The long-term administration of omega-3 fatty acids reduced all-cause mortality and admission to the hospital for cardiovascular (CV) reasons, while there was no effect on these end points with 10-mg rosuvastatin (Crestor, AstraZeneca).
The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Heart Failure (GISSI-HF) trial — which includes two nested studies designed to test the two hypotheses — was presented here at the European Society of Cardiology (ESC) 2008 Congress and published online in The Lancet.
Speaking to the 9% reduction in all-cause mortality with omega-3 fatty acids in The Lancet, the GISSI-HF investigators write: "Although this moderate benefit was smaller than was expected, we should note that it was obtained in a population already treated with recommended therapies, was consistent across all the predefined subgroups, and was further supported by the findings of the per-protocol analysis."
Chair of the GISSI-HF steering committee, Dr Luigi Tavazzi (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy), who presented the omega-3 fatty-acid data to the media during an ESC press conference, said the treatment is an "effective, safe, simple, and cheap" option for patients with chronic heart failure. In an editorial accompanying the published studies [3], Dr Gregg Fonarow (University of California, Los Angeles) echoed the sentiment, writing that while "questions remain about the mechanism of action, optimum dosing, and formulation, supplementation with n-3 polyunsaturated fatty acids [PUFA] should join the short list of evidence-based life-prolonging therapies for heart failure."
GISSI-HF, polyunsaturated fatty acids, and statins
The GISSI-HF project is a large-scale, randomized, double-blind study designed to investigate the effects of omega-3 fatty acids and statin therapy on mortality and morbidity in patients with symptomatic heart failure. In the PUFA study, investigators enrolled patients with chronic heart failure — NYHA class 2 - 4 regardless of cause and left ventricular ejection fraction — and randomized them to treatment with n-3 PUFA 1 g daily or placebo. Patients were followed for nearly four years, with the co-primary end points being death and death or admission to the hospital for cardiovascular reasons.
After 3.9 years of follow-up, treatment with the omega-3 fatty acids reduced the risk of mortality by 9% and mortality and admission to the hospital for cardiovascular causes by 8%. The absolute reduction in risk was small, just 1.8%, but investigators report that 56 patients would need to be treated to avoid one death and 44 patients would need to be treated to avoid one death or admission for cardiovascular reasons. A per-protocol analysis that included only patients who remained on treatment for the study duration confirmed the overall findings, showing that treatment cut the absolute risk by 3.3% compared with placebo, or a 14% relative risk reduction.
GISSI-HF omega-3 fatty acid study: Primary and secondary outcomes
End point
Omega-3 fatty acids, n=3494 (%)
Placebo, n=3481 (%)
Adjusted hazard ratio (95% CI)
Primary end points
Mortality
27.3
29.1
0.91 (0.833-0.998)
All-cause mortality or hospitalization for cardiovascular causes
56.7
59.0
0.92 (0.849-0.999)
Secondary end points
Death from cardiovascular causes
20.4
22.0
0.90 (0.81-0.99)
Sudden cardiac death
8.8
9.3
0.93 (0.79-1.08)
Patients admitted for cardiovascular causes
46.8
48.5
0.93 (0.87-0.99)
Patients with fatal and nonfatal MI
3.1
3.7
0.82 (0.63-1.06)
Patients with fatal and nonfatal stroke
3.5
3.0
1.16 (0.91-1.53)
Speaking to the media, Tavazzi said the advantage of n-3 PUFA, as documented by the primary end points, is that they appear to have a beneficial effect on the mechanisms leading to the progression of heart failure. Although the exact reasons are unknown, omega-3 fatty acids could possibly exert favorable effects on inflammatory processes, such as reductions in endothelial activation and cytokine production, as well as influence platelet aggregation, blood pressure, heart rate, ventricular function, and autonomic tone.
Asked about the differences in outcomes in the GISSI Prevenzione trial, a study where there was a favorable effect of omega-3 fatty acids in patients with myocardial infarction (MI), with n-3 PUFA supplementation reducing the risk of mortality 21%, Tavazzi told heartwire that fatty acids mainly influenced the risk of sudden death in the post-MI patients. In GISSI-HF, on the other hand, the risk of sudden death was not significantly different between the treated and untreated patients, suggesting the "mechanisms of action in heart-failure patients are broader than post-MI patients."
Dr Michel Komajda (Université Pierre et Marie Curie, Paris, France), who commented on the study during the late-breaking clinical trials sessions, said there "is still a bit of a mystery" regarding the observed benefit, especially as it relates to the mechanism of action. Moreover, the study included few patients with preserved ejection fractions, so further study will be needed to determine whether the benefit extends to them as well.
GISSI-HF and statin therapy
Cochair of the GISSI-HF steering committee, Dr Gianni Tognoni (Istituto di Ricerche Farmacologiche Mario Negri, Milan), presented the data on chronic heart-failure patients treated with rosuvastatin 10 mg. Patients were also followed for nearly four years, with the co-primary end points also being time to death and time to death or admission to the hospital for cardiovascular reasons.
After 3.9 years, there was no significant difference between arms in either of the two co-primary end points. The findings were consistent across all secondary end points as well as consistent across every subgroup analyzed, including older patients, those with left ventricular ejection >40%, and those with and without diabetes. Treatment with rosuvastatin decreased low-density lipoprotein (LDL) cholesterol 27% at three years—down from 123 mg/dL at baseline to 90 mg/dL—and an exploratory analysis revealed no treatment effect based on achieved LDL-cholesterol reductions.
GISSI-HF statin study: Primary outcomes
End point
Rosuvastatin 10 mg, n=2285 (%)
Placebo, n=2289 (%)
Adjusted hazard ratio (95% CI)
Mortality
29.0
28.0
1.00 (0.898-1.122)
All-cause mortality or hospitalization for cardiovascular causes
57.0
56.0
1.01 (0.908-1.112)
Speaking to the media, Tognoni said that the prescription of rosuvastatin or any statin to patients with heart failure should not be considered because the use of the cholesterol-lowering drugs does not translate into any clinically meaningful benefit for heart-failure patients. In his editorial, Fonarow comments that the findings from GISSI-HF, alongside the Controlled Rosuvastatin in Multinational Trial in Heart Failure (CORONA), "establish that, although statin therapy lowers concentrations of LDL cholesterol, is well tolerated, and seems reasonably safe, it does not produce meaningful improvements in survival in patients with chronic heart failure."
Govern by science, not strongly held opinion
In CORONA, presented and published in November 2007, treatment with rosuvastatin had no significant effect on cardiovascular outcomes, as measured by the primary-end-point composite of CV death, nonfatal MI, or stroke. It did, however, significantly reduce the number of hospitalizations from CV causes and from heart failure. Commenting on the findings during the late-breaking clinical-trials session, Dr Philip Poole-Wilson (Imperial College London, UK) said GISSI-HF is an important study in light of the CORONA findings.
"What this study has done is extend what we knew from CORONA, a study where more patients had severe heart failure, to those with less severe heart failure," he said. "To that extent, the two trials are really complementary."
Poole-Wilson said that GISSI-HF is likely to generate disappointment among clinicians, as the results of the study, in light of observational and meta-analyses data, were expected to be positive. When the trial was designed, some even expressed concern that it was unethical to randomize heart-failure patients to placebo because they were so confident of the benefit of statin therapy in this patient population. The results, he said, ultimately should humble researchers, especially as they serve as reminder that medical decisions should be guided "science, and not strongly held opinion."
In terms of why the study failed to show a beneficial effect on clinical outcomes, the GISSI-HF investigators note that treatment with rosuvastatin reduced LDL cholesterol as well as high-sensitivity C-reactive protein (CRP) levels. "These effects might no longer affect the progression of coronary artery disease in patients with ischemic heart failure, perhaps because their effect is attenuated by a biological milieu not favoring the progression of coronary artery disease," they write in The Lancet. In his editorial, Fonarow states that once heart failure is established, statins may not allow patients to escape the underlying heart-disease process.
The GISSI studies are a collaboration of the Mario Negri Institute and the Associazione Nazionale dei Medici Cardiologi Ospedalieri. The GISSI-HF studies are sponsored by the Societa Prodotti Antibiotici, Pfizer, Sigma Tau, and AstraZeneca.
Sources
1. GISSI-HF investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet 2008; DOI: 10.1016/S0140-6736(08)61241-6. Available at: http://www.thelancet.com.
2. GISSI-HF investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet 2008; DOI: 10.1016/S0140-6736(08)61241-6. Available at: http://www.thelancet.com.
3. Fonarow GC. Statins and n-3 fatty acid supplementation in heart failure. Lancet 2008; DOI: 10.1016/S0140-6736(08)61239-8. Available at: http://www.thelancet.com.
European Society of Cardiology 2008 Congress. Presented August 31, 2008.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
1. Inform clinicians of the latest medical information concerning the effect of omega-3 fatty-acid supplementation on mortality and morbidity in symptomatic heart-failure patients, as presented at the European Society of Cardiology Congress 2008.
2. Describe the relevance of the findings about the efficacy of statins to clinicians in the care of their patients with symptomatic heart failure.
Study Highlights
• The GISSI-HF was a randomized, double-blind, placebo-controlled trial conducted at 326 cardiology and 31 internal medicine centers in Italy.
• The goal of GISSI-HF was to assess whether omega-3 PUFA could improve morbidity and mortality in a large population of patients with symptomatic heart failure of any cause.
• Enrollment criteria were chronic heart failure of New York Heart Association class II to IV, irrespective of cause and left ventricular ejection fraction.
• A concealed, computerized telephone randomization system was used to randomly assign participants to receive omega-3 PUFA 1 g (n = 3494) or placebo (n = 3481) daily.
• Median follow-up was 3.9 years (interquartile range 3.0 - 4.5).
• Main outcome measures were time to death and time to death or to hospitalization for CV cause.
• Analysis was by intent-to-treat.
• Death from any cause occurred in 955 (27%) patients in the omega-3 PUFA group and 1014 (29%) in the placebo group (adjusted hazard ratio [HR], 0.91; 95.5% confidence interval [CI], 0.833 - 0.998; P = .041).
• Death or admission to hospital for CV reasons occurred in 1981 (57%) patients in the omega-3 PUFA group and 2053 (59%) in the placebo group (adjusted HR, 0.92; 99% CI, 0.849 - 0.999; P = .009).
• To avoid 1 death, 56 patients needed to be treated for a median duration of 3.9 years.
• To avoid 1 death or admission to hospital for cardiovascular reasons, 44 patients needed to be treated for a median duration of 3.9 years.
• Gastrointestinal symptoms were the most frequent adverse effect in both groups.
• The investigators concluded that treatment with omega-3 PUFA was simple, safe, and provided a small benefit in terms of mortality and admission to hospital for CV reasons in patients with heart failure in usual care.
• GISSI-HF data on chronic heart-failure patients treated with rosuvastatin 10 mg were also presented at the ESC.
• After 3.9 years, there was no significant difference between rosuvastatin vs placebo in either time to death or time to death or admission to the hospital for CV reasons.
• Secondary end points also did not differ significantly between rosuvastatin vs placebo groups.
• These findings were consistent in all subgroups analyzed, including older patients, those with left ventricular ejection more than 40%, and those with and without diabetes.
• Treatment with rosuvastatin was associated with a 27% decrease in LDL cholesterol at 3 years, from 123 mg/dL at baseline to 90 mg/dL.
• Exploratory analysis showed no treatment effect based on achieved LDL-cholesterol reductions.
Pearls for Practice
• Omega-3 PUFA supplementation was associated with reduction in death from any cause and in death or admission to hospital for CV reasons in a large population of patients with symptomatic heart failure of any cause.
• After 3.9 years, there was no significant difference between rosuvastatin 10 mg vs placebo in either time to death or time to death or admission to the hospital for CV reasons in all subgroups analyzed, including older patients, those with left ventricular ejection more than 40%, and those with and without diabetes.
According to the GISSI-HF study, which of the following statements about the effects of omega-3 PUFA supplementation on mortality and morbidity in a large population of patients with symptomatic heart failure of any cause is not correct?
Death from any cause occurred in 27% of patients in the omega-3 PUFA group and in 29% in the placebo group
Death or admission to hospital for CV reasons occurred in 57% of patients in the omega-3 PUFA group and in 59% in the placebo group
To avoid 1 death, 56 patients needed to be treated for a median duration of 3.9 years
The difference in mortality between groups was not statistically significant
According to the findings in the GISSI-HF study, which of the following statements about the effect of treatment with rosuvastatin 10 mg vs placebo is correct?
After 3.9 years, all-cause mortality was significantly lower with rosuvastatin
Time to death or admission to the hospital for CV reasons was significantly lower with rosuvastatin
Secondary end points did not differ significantly between rosuvastatin vs placebo groups
The CV treatment effect of rosuvastatin was based on achieved LDL-cholesterol reductions
Target Audience
This article is intended for clinicians who want to maintain a current understanding of recent research and evidence regarding the effect of omega-3 fatty-acid supplementation on morbidity and mortality in symptomatic heart-failure patients.
This is from Consumer Labs:
What It Is:
EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are the two principal fatty acids found in fish. They belong to a family of essential nutrients known as omega-3 fatty acids. DHA can also be obtained from other marine sources, such as algae (algal oil). EPA and DHA are polyunsaturated fats ("good" fats, as opposed to saturated fats which are thought to increase the risk of heart disease). The body can manufacture both EPA and DHA from another essential fatty acid, alpha-linolenic acid (ALA) -- found in flaxseed oil, canola oil, soy oil and walnut oil -- but only to a limited extent. For more information about ALA see the separate review covering ALA and GLA products.
What It Does:
Cardiovascular Disease:
Omega-3 fatty acids have been most widely studied regarding their effects on cardiovascular health. Increased consumption of fish oil may help slow the progression of atherosclerosis, thereby preventing heart attacks, and reduce the risk of sudden death due to cardiac arrhythmias. The omega-3 fatty acids EPA and DHA have a number of heart-healthy effects, including reducing triglyceride levels, raising levels of HDL ("good") cholesterol and, possibly, "thinning" the blood, reducing levels of homocysteine and reducing blood pressure. Fish oils also appear to enhance the effectiveness of statin drugs used to improve cholesterol profile. The U.S. Food and Drug Administration (FDA) permits supplements containing omega-3 fatty acids to state: "Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease."
Arthritis and Other Inflammatory Diseases:
Increased intake of the omega-3 fatty acids in fish oil alter the body's production of substances known as prostaglandins, and, consequently, reduce some forms of inflammation. On the basis of this, EPA and DHA have been tried in the treatment of symptoms of rheumatoid arthritis with considerable success (especially in early stages of the disease). Unlike "disease modifying" drugs, however, fish oil probably doesn't slow the progression of the disease.
The anti-inflammatory effects of EPA and DHA have also caused researchers to investigate possible benefits of fish oil for the treatment of menstrual cramps, inflammatory bowel disease (ulcerative colitis and Crohn's disease), lupus, and IgA nephropathy. For each of these conditions, at least one double-blind study has found positive results. However, in Crohn's disease, a trial of four grams per day of omega-3 fatty acids (50-60% EPA and 15-25% DHA) was ineffective at preventing relapses.
Range of EPA + DHA Concentrations and Pill Sizes:
The concentrations of EPA and DHA in the pills and liquids were found to vary by as much as ten fold -- from just 8% to as high as 79% of the liquid content. Concentration depends on the source of the omega-3's, how the oil is processed, and the amounts of other ingredients included in the supplement. If you are trying to get as much EPA or DHA from the smallest serving size (i.e., fewer or smaller pills or smaller liquid amounts), look for supplements with higher concentrations of EPA and DHA. A more concentrated product will generally allow you to ingest less total fish oil -- although this may mean saving less than a gram (9 calories) of oil per daily serving. Higher concentrations are not necessarily better for you. You can get the same amount of EPA and DHA from both high and low concentration products as long as you adjust the dose accordingly. To help you compare the concentrations of products, refer to the fifth column in the results table below. The products are grouped based on the total amount of EPA and DHA per gram of liquid content:
Relative Concentrations of EPA + DHA in Tested Products:
Very high: 65% to 79%
High: 45% to 55%
Moderate: 26% to 34%
Low: 17% to 23%
Very low: 8%
Most of the supplements were softgels and ranged in length from just under one-half inch to over one inch in length. These are fairly large sizes compared to capsules of other types of supplements. If you have trouble swallowing large softgels, the fifth column of the results table also includes descriptions of the pill size, shape and amount of EPA and DHA per pill or unit. The tested softgels are grouped by length as follows:
Softgel Sizes by Length: (Oblong shape unless noted otherwise)
Very large: over 1 inch
Large: up to 1 inch
Medium/Large: up to 3/4 inch
Medium: approx. 1/2 inch
Test Results by Product:
Listed alphabetically below are the test results for 50 supplements, foods or beverages containing omega-3 fatty acids. Twenty-three were selected by ConsumerLab.com and twenty-seven others (each indicated with an asterisk) were tested at the request of their manufacturers/distributors through CL's Voluntary Certification Program. Also listed are seven products similar to ones that passed testing but sold under different brand names.
The full list of ingredients is available for each product by clicking on the word "Ingredients" in the first column. All "Approved" products met their label claims for omega-3's, lacked contamination by mercury, lead and PCBs, and, if labeled as "enteric coated," passed the relevant USP disintegration testing. Several of the products (each indicated with a "D" in the second to last column) also passed optional dioxin testing undertaken at the request of their manufacturer/distributor.
There's little doubt remaining that omega-3 fatty acids from fish oil reduce dangerous events from heart disease (heart attack and sudden death), abnormal heart rhythms (particularly atrial fibrillation), stroke, and are an effective therapeutic agent to reduce triglycerides. In fact, fish oil is so effective that a prescription form is now available, in addition to the over-the-counter nutritional supplements that have been available for several years.
A typical fish oil capsule obtainable at most health food stores, pharmacies, or even department stores contains 180 mg of the omega-3 EPA, 120 mg of the omega-3 DHA, for a total of 300 mg per capsule. Many bottles will suggest a dosage of 2-3 capsules per day.
Is that enough? Is more desirable? Is less sufficient?
The dose of omega-3 fatty acids depends on what you are using it for. For instance, if you are 30 years old and are just looking to reduce the likelihood heart disease in your lifetime, then the suggested dosage on the label of 2-3 capsules per day is reasonable advice. This daily dosage approximates the two servings of fish per week that has been shown in several large studies to be enough to impact on dangerous heart events.
What if you are trying to reduce triglycerides? (The National Cholesterol Panel Adult Treatment Panel-III guidelines suggest triglycerides ≤150 mg/dl; in our heart disease reversal program, we aim for <60 mg/dl.) Then higher doses may be required. Four standard fish oil capsules, providing 1200 mg EPA and DHA, reduces triglycerides around 20%. Higher doses reduce triglycerides an even greater amount. A solid dose for high triglycerides is 1800 mg per day or more (six capsules of the standard supplement). When doses get this high, it may be time to consider a more concentrated form of fish oil. Some over-the-counter nutritional supplements contain 500, 600, and all the way up to 850 mg omega-3 fatty acids per capsule. Prescription Lovaza® contains 850 mg omega-3s per capsule. (Of course, you should be working with your health care provider when high triglycerides are being treated).
Fish oil is very safe even at high doses with virtually no side-effects beyond stomach upset or belching (which can be minimized by taking with meals, refrigerating the capsules, or taking enteric-coated fish oil tablets). Occasionally doses of omega-3s as high as 5000 mg or more are required for unusual disorders like "familial hypertriglyceridemia," in which triglycerides can reach into the thousands, and lipoprotein(a), a high-risk marker for heart disease. Dosages this high should only be prescribed by your doctor.
Incidentally, along with reducing triglycerides, fish oil raises HDL a few points, reduces the important triglyceride-containing particle, very low-density lipoprotein (VLDL), and dramatically accelerates the clearance of after-eating by-products of food, all of which translate in to reduced risk for heart attack and stroke.
How about the dose of fish oil for confident reduction of heart attack and sudden death? According to the now-classic GISSI-Prevenzione Trial of 11,000 participants, a dosage of 850 mg EPA and DHA per day provided substantial benefit: 28% reduction in heart attack, 45% reduction in sudden death. Benefits began as soon as three months after the starting of supplementation. (Interestingly, omega-3s exert no cholesterol-reducing benefit at all and, in fact, may increase LDL cholesterol modestly).
For reduction of heart rhythm disorders, the dosage of omega-3 is not well sorted out. However, omega-3 doses of 1000-4500 mg per day have been studied, with most studies suggesting significant reduction in the occurrence of abnormal heart rhythms. Benefits may take many weeks or months to develop and so the omega-3s from fish oil are most effective as a preventive strategy, not an acute treatment once rhythms occur.
Fish oil is truly powerful and so effective and well-grounded in clinical research that it straddles a role between nutritional supplement and prescription agent. Regardless of what you call it, the omega-3 fatty acids from fish oil are an important component of an overall program of heart health and one of the great bargains in overall health.
Research indicates that omega-3s may be better absorbed from food than supplements. Norwegian researchers compared 71 volunteers' absorption of omega-3s (EPA and DHA) from salmon, smoked salmon, cod (14 ounces of fish per week) or cod liver oil (3 teaspoons per day). Cooked salmon provided 1.2 grams of omega-3s daily, while cod liver oil provided more than twice as much: 3 grams of omega-3s per day.
Despite the fact that the salmon group got less than half the amount of omega-3s as the cod liver oil group, blood levels of omega-3s increased quite a bit more in those eating salmon than those taking cod liver oil. After 8 weeks, EPA levels had risen 129% and DHA rose 45% in those eating cooked salmon compared to 106% and 25%, respectively, in those taking cod liver oil.
In the group eating smoked salmon, blood levels of omega-3s rose about one-third less than in the salmon group. In those eating cod, the rise in omega-3s was very small.
Concurrent with the rise in omega-3s in those eating salmon, a drop was seen in blood levels of a number of pro-inflammatory chemicals (TNFalpha, IL-8, leukotriene B4, and thromboxane B2). Researchers think omega-3s may be better absorbed from fish because fish contains these fats in the form of triglycerides, while the omega-3s in almost all refined fish oils are in the ethyl ester form. Once absorbed, omega-3s are converted by the body from their triglyceride to ester forms as needed. Lipids. 2006 Dec;41(12):1109-14.
Description
What are omega 3 fatty acids?
You've probably been hearing about omega 3 fatty acids in recent years. The reason? A growing body of scientific research indicates that these healthy fats help prevent a wide range of medical problems, including cardiovascular disease, depression, asthma, and rheumatoid arthritis.
Unlike the saturated fats found in butter and lard, omega 3 fatty acids are polyunsaturated. In chemistry class, the terms "saturated" and "polyunsaturated" refer to the number of hydrogen atoms that are attached to the carbon chain of the fatty acid. In the kitchen, these terms take on a far more practical meaning.
Polyunsaturated fats, unlike saturated fats, are liquid at room temperature and remain liquid when refrigerated or frozen. Monounsaturated fats, found in olive oil, are liquid at room temperature, but harden when refrigerated. When eaten in appropriate amounts, each type of fat can contribute to health. However, the importance of omega 3 fatty acids in health promotion and disease prevention cannot be overstated.
The three most nutritionally important omega 3 fatty acids are alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Alpha-linolenic acid is one of two fatty acids traditionally classified as "essential." The other fatty acid traditionally viewed as essential is an omega 6 fat called linoleic acid. These fatty acids have traditionally been classified as "essential" because the body is unable to manufacture them on its own and because they play a fundamental role in several physiological functions. As a result, we must be sure our diet contains sufficient amounts of both alpha-linolenic acid and linoleic acid.
Dietary sources of alpha-linolenic acid include flaxseeds, walnuts, hemp seeds, soybeans and some dark green leafy vegetables. Linoleic acid is found in high concentrations in corn oil, safflower oil, sunflower oil, and canola oil. Most people consume a much higher amount of linoleic acid than alpha-linolenic acid, which has important health consequences. For more information on the proper ratio of these fatty acids in the diet, see our FAQ entitled, A New Way of Looking at Proteins, Fats, and Carbohydrates
The body converts alpha-linolenic acid into two important omega 3 fats, eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA). These fats can also be derived directly from certain foods, most notably cold-water fish including salmon, tuna, halibut, and herring. In addition, certain types of algae contain DHA. EPA is believed to play a role in the prevention of cardiovascular disease, while DHA is the necessary for proper brain and nerve development.
How it Functions
What are the functions of omega 3 fatty acids?
Every cell in our body is surrounded by a cell membrane composed mainly of fatty acids. The cell membrane allows the proper amounts of necessary nutrients to enter the cell, and ensures that waste products are quickly removed from the cell.
Promoting Healthy Cell Membranes
To perform these functions optimally, however, the cell membrane must maintain its integrity and fluidity. Cells without a healthy membrane lose their ability to hold water and vital nutrients. They also lose their ability to communicate with other cells. Researchers believe that loss of cell to cell communication is one of the physiological events that leads to growth of cancerous tumors.
Because cell membranes are made up of fat, the integrity and fluidity of our cell membranes is determined in large part by the type of fat we eat. Remember that saturated fats are solid at room temperature, while omega 3 fats are liquid at room temperature. Researchers believe that diets containing large amounts of saturated or hydrogenated fats produce cell membranes that are hard and lack fluidity. On the other hand, diets rich in omega 3 fats produce cell membranes with a high degree of fluidity.
In addition, recent in vitro (test tube) evidence suggests when omega 3 fatty acids are incorporated into cell membranes they may help to protect against cancer, notably of the breast. They are suggested to promote breast cancer cell apoptosis via several mechanisms including: inhibiting a pro-inflammatory enzyme called cyclooxygenase 2 (COX 2), which promotes breast cancer; activating a type of receptor in cell membranes called peroxisome proliferator-activated receptor (PPAR)-ã, which can shut down proliferative activity in a variety of cells including breast cells; and, increasing the expression of BRCA1 and BRCA2, tumor suppressor genes that, when functioning normally, help repair damage to DNA, thus helping to prevent cancer development.
Animal and test tube studies published in the November 2005 issue of the International Journal of Cancer suggest yet another way in which the omega-3 fatty acids found in cold water fish-docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)-help protect against breast cancer development.
All dietary fatty acids are incorporated into cell membranes, and the type of fatty acids dictates how a cell responds and grows. Researchers found that omega-3 fatty acids affect cell growth by activating an enzyme called sphingomyelinase, which then generates the release of ceramide, a compound that induces the expression of the human tumor suppressor gene p21, which ultimately causes cancer cell death.
In the animal experiments, mice were fed diets rich in either omega-3 (fish oil) or omega-6 (corn oil) fatty acids after which breast cancer cells were implanted. Three weeks later, tumor volume and weight was significantly lower in mice on the omega-3 rich diet. In the lab culture experiments, when cells were treated with DHA or EPA, sphingomyelinase activity increased by 30-40%, and breast cancer cell growth dropped 20-25%.
Prostaglandin Production
Omega 3 fats also play an important role in the production of powerful hormone-like substances called prostaglandins. Prostaglandins help regulate many important physiological functions including blood pressure, blood clotting, nerve transmission, the inflammatory and allergic responses, the functions of the kidneys and gastrointestinal tract, and the production of other hormones.
In essence, all prostaglandins perform essential physiological functions. However, depending on the type of fat in the diet, certain types of prostaglandins may be produced in large quantities, while others may not be produced at all. This can set up an imbalance throughout the body that can lead to disease.
For example, EPA and DHA serve as direct precursors for series 3 prostaglandins, which have been called "good" or "beneficial" because they reduce platelet aggregation, reduce inflammation and improve blood flow. The role of EPA and DHA in the prevention of cardiovascular disease can be explained in large part by the ability of these fats to increase the production of favorable prostaglandins.
The omega 6 fats serve as precursors for series 1 and series 2 prostaglandins. Like the series 3 prostaglandins produced from omega 3 fats, series 1 prostaglandins are believed to be beneficial. On the other hand, series 2 prostaglandins are usually considered to be "bad" or "unhealthy," since these prostaglandins promote an inflammatory response and increase platelet aggregation. As a result, it is important to ensure proper balance of omega 3 and omega 6 fats in the diet.
EPA Directly Anti-Inflammatory
A recently identified lipid (fat) product our bodies make from EPA, called resolvins, helps explain how this omega-3 fat provides anti-inflammatory effects on our joints and improves blood flow.
Resolvins, which have been shown to reduce inflammation in animal studies, are made from EPA by our cellular enzymes, and work by inhibiting the production and regulating the migration of inflammatory cells and chemicals to sites of inflammation. Unlike anti-inflammatory drugs, such as aspirin, ibuprofen and the COX-2 inhibitors, the resolvins our bodies produce from EPA do not have negative side effects on our gastrointestinal or cardiovascular systems.
Deficiency Symptoms
What are deficiency symptoms for omega 3 fatty acids?
Recent statistics indicate that nearly 99% of people in the United States do not eat enough omega 3 fatty acids. However, the symptoms of omega 3 fatty acid deficiency are very vague, and can often be attributed to some other health conditions or nutrient deficiencies.
Consequently, few people (or their physicians, for that matter) realize that they are not consuming enough omega 3 fatty acids. The symptoms of omega 3 fatty acid deficiency include fatigue, dry and/or itchy skin, brittle hair and nails, constipation, frequent colds, depression, poor concentration, lack of physical endurance, and/or joint pain.
Toxicity Symptoms
What are toxicity symptoms for omega 3 fatty acids?
In its 2002 guidelines for omega 3 fatty acid intake, the Institute of Medicine at the National Academy of Sciences declined to establish a Tolerable Upper Intake Level (UL) for omega 3s. However, research was cited showing increased risk of bleeding and hemorrhagic stroke in a few studies following supplementation with omega 3s. Individuals who have disorders involving bleeding, who bruise very easily, or who are taking blood thinners should consult with a medical practitioner before taking supplemental omega 3 fatty acids.
Impact of Cooking, Storage and Processing
How do cooking, storage, or processing affect omega 3 fatty acids?
Polyunsaturated oils, including the omega 3 fats, are extremely susceptible to damage from heat, light, and oxygen. When exposed to these elements for too long, the fatty acids in the oil become oxidized, a scientific term that simply means that the oil becomes rancid.
Rancidity not only alters the flavor and smell of the oil, but it also diminishes the nutritional value. More importantly, the oxidation of fatty acids produces free radicals, which are believed to play a role in the development of cancer and other degenerative diseases.
Under most circumstances, the problem of rancidity only arises when the oils are removed from their natural food package. For example, the hard shell of the flaxseed protects the oil inside the seed from heat, light, and oxygen. Flaxseeds also contain antioxidant compounds, such as vitamin E, that provide additional protection against oxidation. But, when the seed is pressed to isolate the oil, the oil becomes vulnerable to the elements.
As a result, oils rich in polyunsaturated fatty acids should be stored in dark glass, tightly closed containers in the refrigerator or freezer. In addition, these oils should never be heated on the stove. So, instead of sautéing your vegetables in flaxseed or walnut oil, make a salad dressing using these oils.
Factors that Affect Function
What factors might contribute to a deficiency of omega 3 fatty acids?
The conversion of alpha-linolenic acid to EPA and DHA involves a series of chemical reactions. One of the first reactions in this series is catalyzed by the enzyme delta-6 desaturase. Further down the line is a reaction that is catalyzed by the enzyme delta-5 desaturase. Unfortunately, it is now well-known that these enzymes do not function optimally in many people, and, consequently, only a small amount of the alpha-linolenic acid consumed in the diet is converted to EPA, DHA, and ultimately to the anti-inflammatory prostaglandins.
To increase the activity of your desaturase enzymes, be sure that your diet includes a sufficient amount of vitamin B6, vitamin B3, vitamin C, magnesium and zinc. In addition, limit your intake of saturated fat and partially hydrogenated fat, as these fats are known to decrease the activity of delta-6 desaturase. Also, to be on the safe side, consider including a direct source of EPA and DHA if your diet, such as wild-caught salmon, halibut, or tuna.
