Abstract
The protective effects of omega-3 fatty acids found in fish and fish oil supplementats on cardiovascular risks and diseases has been a topic of robust research for the past 30-plus years. This large and growing body of research indicates that the 2 omega-3 fatty acids found in fish oil, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), play an important role in prevention and treatment of cardiovascular diseases, including coronary heart disease, atherosclerosis, stroke, hypertension, arrythmias, heart failure, and dysplipidemia; they also reduce mortality from heart disease. Physiological effects of EPA and DHA as they relate to cardiovascular diseases include enhancing fibrinolysis, increasing vascular reactivity and vasodilation, improving ejection fractions, lowering plasma lipoprotein concentrations, regulating sodium and calcium channels in arrhythmias, lowering blood pressure, and reducing coagulation. These physiological effects and the results of the studies discussed in this article can help the clinician more effectively use specific doses and blends of fish oils based on which cardiovascular endpoints are desired.
Introduction
Omega-3 fatty acids from fish oil continue to show great promise in primary prevention and treatment of cardiovascular diseases. In the past 3 decades, numerous observational and epidemiologic studies have been conducted related to the benefits of omega-3 fatty acids and cardiovascular disease.1-3 A key observational study in the history of fish oil research by Bang and Dyerberg reported on the Greenland Eskimos and the protective “Eskimo factor,” whereby the Greenland Inuits' diet low in fruit, vegetables, and complex carbohydrates but high in saturated fat and cholesterol from a high-fish diet still resulted in serum cholesterol and triglycerides that were lower than age-matched residents of Denmark and a lower risk of myocardial infarction (MI) than the Danes.4-6
As fish oils have become a greater part of clinical practice and more popular amongst consumers, we see a vast array of ranges when it comes to dosing of capsules and EPA/DHA blends and milligrams used. This seemingly random perspective that any amount and any blend of fish oils is a good thing limits the true efficacy of using omega-3 fatty acids from fish oils for prevention and treatment in the spectrum of cardiovascular diseases.
The following summary citing select research will review trials in coronary heart disease, atherosclerosis, arrhythmias, hypertension, heart failure, and dyslipidemia to encourage among clinicians and consumers a more specific utilization of dietary advice and fish oil supplementation.
Coronary Heart Disease
A review of 25 trials that evaluated the risk of coronary heart disease (CHD) related to the body’s omega-3 levels showed that there was an inverse relationship between major cardiovascular (CV) events and tissue levels of EPA and even more so, DHA.7 Three large, randomized trials have documented omega-3 polyunsaturated fatty acids (PUFA) in both primary and secondary prevention of CHD. In the Diet and Reinfarction Trial (DART),8 men with recent MI showed that omega-3 PUFA either in dietary oily fish or fish oil capsules, but far more with the fish oil capsules, reduced 20-year all-cause mortality by 29%, mostly due to reduction in CHD mortality.
The Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico (GISSI) trial9 randomized 11,323 post-MI patients with 1,850 mg capsule of EPA/DHA in a 1.2:1 ratio versus customary care. After 1 year, patients taking the fish oil had a 21% reduction in total mortality and a 30% reduction in CV mortality. In addition, there was a highly significant 45% reduction in sudden cardiac death (SCD) after only 4 months.
The Japan EPA Lipid Intervention Study (JELIS) trial included a total of 18,645 subjects (men aged 40–75 and postmenopausal women aged >75; mean age of 61 years; 31% men).10 Those with a serum total cholesterol of >250 mg/dL were eligible. About 36% were hypertensive, 15% had diabetes, and 20% had coronary artery disease. Subjects were randomized to pravastatin 10 mg/day or simvastatin 5 mg/day or the same statin doses with 1,800 mg/day of EPA. After 5 years, those in the EPA group had a 19% reduction in major cardiac events.
These 3 trials indicated that omega-3 PUFAs lowered the risk of CV disease in both primary and secondary prevention. While not all studies have shown favorable results, the numbers of patients treated, the doses used, and the results of the DART, GISSI, and JELIS study are strong motivations for clinicians to recommend increased dietary fish intake, and especially fish oil supplementation.
Recommended doses for primary and secondary prevention
1,000 mg/day or higher of combined EPA/DHA
Atherosclerosis/Strokes
Japanese men living in Japan have lower grades of atherosclerosis, measured by intima-media thickness and coronary artery cacification, compared with Japanese men and Caucasian men living in the United States, leading some reasearchers to consider a “Japanese” factor in cardiovascular health.11,12 In the 2008 study, 12 Japanese men had substantially less coronary artery calcification (9.3%) than did Caucasian (26.1%) and Japanese-American men (31.4%). The Japanese men also showed less plaque formation in the carotid artery than did the American men. Researchers also noted a very marked difference in the percentage of EPA and DHA fatty acids consumed, with Japanese men in Japan consuming almost 3 times as much EPA and DHA. The genetic difference between Japanese and American Caucasian men does not seem to be the deciding difference in these observations, but rather dietary and lifestyle influences of living in the United States, for both Japanese-Americans and Caucasian Americans. The authors concluded that the habitual consumption of large amounts of fish protects against atherosclerosis.
A 2003 study was conducted in patients awaiting surgery to remove atherosclerotic deposits blocking the carotid artery.13 Patients were given either placebo, fish oil, or sunflower oil daily from the time they entered the study until their surgery, an average of 42 days. Patients took a total of 6 capsules per day of whichever group they were in. The 6 fish oil capsules provided a total of 850 mg EPA and 500 mg DHA. Researchers found that the fish oil had been incorporated into the plaques and had resulted in thick fibrous caps with no signs of inflammation and fewer macrophages, thus producing a more stable plaque. Plaques from the placebo and sunflower oil groups had thin fibrous caps, more inflammation, and more macrophages.
Several studies have shown that regular fish consumption helps protect against stroke, although it is not clear if this involves both ischemic and hemorrhagic strokes. One study has attempted to answer this question.14 A food-frequency study involved 43,671 male health professionals aged 40 to 75 years. During a 12-year follow-up period, 608 strokes occurred (377 ischemic, 106 hemorrhagic, and 125 strokes of unknown origin). The annual overall stroke rate was low, at 0.1% overall and 0.07% for ischemic stroke. Men who consumed fish at least once per month had a 44% lower risk of having an ischemic stroke than did men who consumed fish less frequently. No significant associations were found between fish or long-chain omega-3 PUFA (polyunsaturated fatty acid) intake and the risk of hemorrhagic stroke.
The optimum protection was achieved at fish consumption once per week; more frequent fish consumption (5 or more times per week) did not reduce stroke risk further. Significant protection against ischemic stroke was achieved at a level of fish intake of as little as 50–200 mg/day of EPA/DHA.
The benefits of fish oil to prevent stroke may be even more significant for women. The Nurse’s Health Study involved almost 80,000 women between the ages of 34 and 59. After 14 years of follow-up, a total of 574 strokes had occurred (303 ischemic, 181 hemorrhagic, and 90 of unknown origin).15 Upon analysis, the researchers concluded that women who ate fish once a week lowered their risk of having any kind of stroke by 22%, and those who consumed fish 5 or more times per week reduced their risk by 52%. They estimated that women whose intake of total fish oils was 500 mg/day or more have a 30% lower risk of suffering a stroke than do women whose intake is below about 100 mg/day.
Recommended doses
500–1,000 mg/day EPA and 500–1,000 mg/day DHA
Mortality from Heart Disease
To determine the overall benefit of these agents on mortality, a group of researchers at the University Hospital Basel reviewed the most reliable published studies.16 They searched for high-quality, randomized, controlled trials between 1965 and 2003, comparing lipid-lowering drugs or dietary interventions against placebo. This process left them with 35 trials on statins, 17 on fibrates, 8 on resins, 2 on niacin, 14 on omega-3 fatty acids, and 17 on other dietary interventions. This produced a total of 137,140 participants in treatments groups and 138,976 in control groups.
Many studies have been performed to determine the overall effect of omega-3 oils on mortality. This analysis of randomized, controlled trials showed that treatment with omega-3 fatty acids (fish and flaxseed oils) reduced overall risk of death by 23% as compared to placebo; treatment with statin medications reduced overall mortality by only 13%. Deaths from cardiovascular causes were also significant: They were 32% lower in the omega-3 fatty acid groups than in the placebo groups and 22% lower in the statin groups than the placebo groups.
Arrhythmias
The antiarrhythmic effects of omega-3 PUFA suggest prevention of fatal arrhythmias and improvements in heart rate variability, heart rates, and atrial fibrillation. In a prospective, nested case-control evaluation of healthy men from the Physician’s Health Study who were followed for up to 17 years, fatty acid composition of the blood was analyzed in 94 men who suddenly died as a result of cardiovascular disease.17 Blood levels of omega-3 fatty acids were inversely related to the risk of sudden death. The relative risk of sudden death was significantly lower in men with levels in the third and fourth quartile compared to those in the lowest quartile.
Improvement in heart rate variability was observed in post-MI patients with impaired systolic function with 4.3 g/day of EPA and DHA for 12 weeks.18 Lower doses (810 mg/day of EPA/DHA) also appear to improve heart rate variability and produce reductions in resting heart rate.19 Moderate doses of 1,260 mg/day EPA/DHA also showed a reduction in the average heart rate in patients with complex ventricular arrhythmias.20 Fish oils' ability to inhibit voltage-dependent sodium channels and L-type calcium channels may also prevent fatal arrhythmias.21 The most significant effects on arrhythmias have been observed in atrial fibrillation (AF) studies. A 30% lower risk of AF was observed over a 12-year period in individuals who consumed high quantities of non-fried fish.22 Post surgical AF was reduced by >50% in individuals undergoing coronary artery bypass grafting, and patients also had a significant reduction in the number of days hospitalized.23 While not all studies have shown a correlation between the quantities of omega-3 fatty acids and anti-arrhythmic effects,24 the potential for benefit is significant.
One of the ongoing concerns related to the use of fish oils in AF patients who are likely taking some form of anticoagulant medication is the potential for increased risk of bleeding. What is the evidence that taking omega-3 fatty acids from fish oils in customary doses of 1-4 g/day can cause clinically significant bleeding? In a 1997 paper, the author reviewed the published research regarding omega-3 fatty acids and human thrombosis and hemostasis.25 He noted the lack of significant bleeding in cardiovascular studies to date and also noted a study in pregnant women using doses of 2.7 g/day.26 In addition, he highlighted a study in which fish oil–supplemented dialysis patients were not at increased risk for bleeding.27,28 There was one report of an increased risk for nosebleeds in children with hypercholesterolemia given 5 g/day of fish oils, but this was not replicated in a later study on dialysis in children.29
It appears that the published data is virtually consistent, finding that omega-3 fatty acid supplements do not increase the risk for clinically significant bleeding, even in those individuals who are receiving antiplatelet or antithrombotic medications. Anecdotal reports of increased bleeding tendency exist, but these have not been tested in a controlled study. Bays published a review in 2007 in which he concludes that there is little evidence of increased risk for clinically significant bleeding with omega-3 fatty acid supplementation, despite omega 3s' role in eicosanoid metabolism.30 He does caution of the theoretical possibility.
Recommended dose
810 mg–4.3 gm/day EPA/DHA
Heart Failure
Congestive heart failure (CHF) prevention and treatment has not escaped the benefits of fish oil either, although few studies have evaluated any association between omega-3 fatty acids and CHF. The most recent study evaluated circulating fatty acid concentrations to determine whether plasma phospholipid concentrations of EPA, DHA, and docosapentaenoic acid (DPA) were associated with CHF.31 This prospective cohort study, called the Cardiovascular Health Study, enrolled 2,735 older adults without apparent heart disease. Over the evaluation period of 14 years, 555 cases of CHF occurred. Plasma phospholipid EPA concentrations were inversely associated with incident CHF, and the risk was approximately 50% lower in the highest versus the lowest quartile of omega-3 fatty acid plasma concentrations. Also published in 2011, another study investigated the effects of omega-3 fatty acids on systolic left ventricular and endothelial function and markers of inflammation in chronic heart failure.32 In this double-blind, randomized, controlled pilot trial, patients with chronic heart failure were given 1 g/day, 4 g/day, or placebo for 3 months. Left ventricular ejection fraction increased in a dose-dependent manner in the 4 g and 1 g/day groups. Flow-mediated vasodilation increased significantly with the 4 g/day but was only a trend in the 1 g/day dose. Interleukin 6 significantly decreased with 4 g/day but was only a trend with 1 gm/day. Tumor necrosis factor alpha had a trend toward decrease with the 4 g/day but was unchanged in the 1 g/day group.
An earlier study of almost 5,000 men and women >65 years of age found an inverse association of dietary baked or broiled fish and the incidence of CHF.33 The Atherosclerosis Risk in Community study also showed an inverse relationship between omega-3 intake and heart failure in women,34 as did the prospective study of nearly 60,000 Japanese people over 13 years.35 Additionally, in the large placebo-controlled GISSI-HF trial, 7,000 patients with class II to IV HF showed a modest but statistically significant reduction in total mortality (-9%) and total mortality for CV diseases (-8%).36 Doses used were the highly concentrated fish oil capsule Lovaza, containing 850–882 mg of EPA and DHA per capsule; patients were randomized to fish oil, a statin, both, or placebo. In reviewing these studies and others, it appears that especially therapeutic doses are needed to obtain the maximal clinical benefits in HF.
Recommended dose
At least 1 g/day of EPA/DHA for modest effects, but consider up to 5 g/day
Dyslipidemia
The ethyl ester formulation Lovaza has been approved by the FDA at a dose of 4 g/day for the treatment of very high triglyceride levels (>500 mg/dL). While it is not completely understood, it is thought that the mechanism of action for this triglyceride-lowering effect is the activation of peroxisome proliferators-activator receptor (PPARs). We do know that omega-3 PUFAs reduce hepatic synthesis of triglycerides and increase fatty acid beta-oxidation in the liver. A dose of 3–4 g/day of EPA/DHA typically reduces triglyceride levels by 30–40%.37 This dose has also been shown to reduce triglycerides >500 mg/dl by 45%, as well as lower non-high-density lipoprotein cholesterol by 14% and increase high-density lipoprotein (HDL) cholesterol by 9%.38
Practitioners who are not yet well read in cardiovascular and fish oil research mistakenly think fish oil therapy reduces LDL levels, but in general this is not the case—especially in those with high triglycerides—even though the JELIS study showed a modest 10% reduction in LDL beyond that produced by the low-dose statins.10 Fish oils can in fact increase LDL, especially when given with a fibrate and occasionally with niacin. But, the omega-3 enriched LDL particles end up being larger, fluffier, and less atherogenic.39
Recommended dose
3–4 g/day EPA/DHA
Hypertension
Fish oil has a positive impact on blood pressure. Particularly where fish and omega-3 fatty acid consumption is low, there may be an increased risk of developing hypertension.40 Numerous small reductions in blood pressure have been observed with intake of omega-3 fatty acids.41–44
A meta-analysis of 36 trials of fish oil supplementation and blood pressure in men and women, with an average dose of 3.7 grams per day, demonstrated a small hypotensive effect, especially in older adults who have hypertension.45 Another meta-analysis of 31 trials also reported a statistically significant dose-response effect with reductions of -1.3/-0.7 mm mercury at doses of 3 g/day or less and -2.9/-1.6 mm mercury at 3.3–7 g/day.46 Higher doses have greater effects, and DHA may have a greater benefit than EPA.47
Obese patients with hypertension or dyslipidemia and those with and without diabetes were studied in a 13-day protocol of programmed fasting and fish oil supplemention of 2.7 g/day EPA and 1.8 g/day DHA.48 Blood pressure lowered in both groups from 159/81 to 146/73 mmHg in those without diabetes and 158/83 to 142/76 mmHg in those with diabetes. Triglycerides reduced significantly in both groups, by 51 mg/dl in those without diabetes and 56 points in those with diabetes. HDL also increased significantly in the diabetics.
Recommended dose
3 g/day of EPA/DHA
Interactions with Drug-Nutrients-Botanicals
Clinicians should consider the potential issues involved where patients may be taking fish oil supplementation as well as anticoagulants, antiplatelet agents, antihypertensives, hypoglycemic agents, and cholesterol-lowering agents, including over-the-counter and prescription medications, herbs, and supplements. Given the small theoretical and actual potential for harm, clinicians should be encouraged to use resources that keep them up to date in this area of patient care.
Summary
Optimal doses and ratios of EPA and DHA for the above cardiovascular diseases are difficult to determine and need to continue to evolve based on more research. Clinicians should remember that both are present in most fish, and oily fish in general have a ratio of 2:1 DHA/EPA, but many supplements have a ratio of 2:3 DHA/EPA. DHA is more abundant in the myocardium than EPA, but as demonstrated by several of the studies mentioned, higher doses of EPA seem to be key in the clinical effect. When using omega-3 fatty acids from fish oils, it greatly assists the clinician to not only be familiar with the research, but also to know the amounts of total fish oils, and where possible, the amounts of DHA and EPA most beneficial, in order to enhance our clinical results in both prevention and intervention.
