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(Circulation. 1996;94:2337-2340.)
© 1996 American Heart Association, Inc.

Articles

Fish Consumption, Fish Oil, Lipids, and Coronary Heart Disease

Neil J. Stone, MD

From the Nutrition Committee of the American Heart Association

Key Words: AHA Medical/Scientific Statements • lipids • diet • coronary disease • fatty acids

	Introduction

Top Introduction What Are Omega-3 Fatty... Fish Intake and Risk... Fish Intake and CHD Conclusions References

 
Reducing intake of saturated fat and dietary cholesterol and avoiding excess calories, which can lead to obesity, remain the cornerstore of the dietary approach to decreasing risk of atherosclerotic vascular disease. During the past 20 years, however, there has been renewed interest in other dietary components that might favorably improve lipid profiles and reduce risk of coronary heart disease (CHD). Fish and fish oil, rich sources of omega-3 fatty acids, have sparked intense interest in both epidemiological studies, which suggest a favorable effect on CHD, and metabolic ward studies, which show a striking improvement in lipid profiles in hyperlipidemic patients. Confusion has resulted from clinical trials of fish oil in patients with CHD, which did not corroborate early observational findings, and newer results, which suggest clinical benefit due to a mechanism independent of lipid effects.

	What Are Omega-3 Fatty Acids?

Top Introduction What Are Omega-3 Fatty... Fish Intake and Risk... Fish Intake and CHD Conclusions References

 
Fish and other marine life are rich sources of a special class of polyunsaturated fatty acids known as the omega-3 or n-3 fatty acids.^{1 2} They are so named because the first of the several double bonds occur three carbon atoms away from the terminal end of the carbon chain. The three n-3 polyunsaturated fatty acids (n-3 PUFAs) are alpha linolenic acid (LNA), eicosapentenoic acid (EPA), and docosahexenoic acid (DHA). LNA is an 18–carbon chain fatty acid with three double bonds; in the form of tofu, soybean, and canola oil and nuts, it is an important plant-based source of n-3 PUFA for vegetarians and non–seafood eaters. EPA and DHA are very long–chain fatty acids obtained from marine sources. These, along with n-6 polyunsaturated fatty acids (n-6 PUFAs) that cannot be synthesized from nonlipid precursors such as linoleic acid, are considered essential fatty acids that must be consumed in the diet. The n-6 PUFAs are obtained primarily from plant sources, especially seeds. Arachidonic acid is a long-chain n-6 PUFA that is found in meats, fish, and plants or is synthesized from linoleic acid. Arachadonic acid and marine lipids both serve as key intermediates for eicosanoids like thromboxanes and prostacyclins, which are important for platelet and vessel wall physiology.

	Fish Intake and Risk Factors

Top Introduction What Are Omega-3 Fatty... Fish Intake and Risk... Fish Intake and CHD Conclusions References

 
Effects of Omega-3 Fatty Acids and Lipoproteins
The addition of omega-3 fatty acids to the diet lowers triglyceride levels, an effect that is pronounced in those with marked hypertriglyceridemia.³ The triglyceride-lowering effect is not seen with plant sources of n-3 PUFA.⁴ In those patients with type V hyperlipidemia, the use of fish oil supplements is an important therapeutic option.⁵ Connor⁶ listed the following putative mechanisms of dietary n-3 PUFA on lipoprotein metabolism in humans: (1) inhibition of VLDL triglyceride synthesis, (2) decreased apoprotein B synthesis, (3) enhancement of VLDL turnover with an increased fractional catabolic rate of VLDL, (4) depression of LDL synthesis, and (5) reduction of postprandial lipemia.

A critical review by Harris² has clarified the discrepancy among fish oil studies reporting effects on LDL cholesterol (LDL-C). He noted that in the majority of studies reporting reductions in LDL-C levels, the saturated fat intake was lowered when subjects switched from the control diet to the fish oil diet. When fish oil is consumed and saturated fat intake is constant, LDL-C levels either do not change or may increase.

Although fish oil is not recommended in the treatment of hypercholesterolemia, it does have a role in the treatment of lipoprotein disorders characterized by severe hypertriglyceridemia. It can be quite useful in those severely hypertriglyceridemic (triglyceride >1000 mg/dL) patients for whom attempts to correct secondary causes (through diet, exercise, and gemfibrozil) have proved inadequate.⁷ Although a negative aspect is the concomitant elevation in LDL-C that occurs when fish oils are given to these patients with lower plasma levels of triglyceride, this is usually not a problem for those with severe hypertriglyceridemia, because LDL-C values are usually quite low. It can be a problem for those with more modest elevations of triglycerides in whom the elevation of LDL-C will actually move the patient away from the desired LDL-C goal.

Fish oil supplementation does not appear to impair glucose tolerance in nondiabetic coronary bypass patients.⁸ Among diabetics, initial studies showed deterioration of glucose tolerance with fish oil consumption.⁹ Nonetheless, Connor and coworkers¹⁰ designed a longer term study in which body weights were unchanged between fish oil and olive oil groups and no deterioration in glucose homeostasis was demonstrated in those individuals with diabetes. Westerveld and colleagues¹¹ conducted a randomized, blinded, placebo-controlled trial that also documented reduced platelet aggregation as well as triglyceride lowering in the fish oil group. In both trials the fall in triglyceride level was accompanied by a rise in LDL-C similar to that seen in studies of patients with combined hyperlipidemia.¹² This rise in LDL-C level was not seen when a low dose of omega-3 fatty acids was given to 20 ambulatory subjects with non–insulin-dependent diabetes mellitus in a randomized, double-blind, prospective, controlled clinical trial.¹³ Although sample size may have been inadequate to show an LDL-C effect, fish oil significantly inhibited platelet aggregation and thromboxane A₂ production, while it reduced triglyceride levels by 44 mg/dL and decreased upright systolic blood pressure by 8 mm Hg compared with safflower oil. Finally, a recent study looking at vascular reactivity suggested that fish oil ingestion in diabetics could favorably alter arterial wall compliance without affecting fasting blood sugar, cholesterol, or blood pressure.¹⁴ Clearly, further research on the use of n-3 PUFA in diabetics is required.

Effect of Omega-3 Fatty Acids on Hypertension
A meta-analysis of placebo-controlled studies showed that fish oil reduced blood pressure in a dose-response fashion in those with hypertension and hypercholesterolemia but not in those participants with normal blood pressures.¹⁵ The effects were small, and it is not clear whether this effect is sustained over the long term.

Effect of Omega-3 Fatty Acids on Coagulation Profiles
A concise review of studies on the prevention of thrombosis in laboratory animals and in humans emphasized the important role of n-3 PUFA, which affects cellular responses in platelets, monocytes, and endothelial cells.¹⁶ The reduced platelet aggregation and prolonged bleeding times of the Greenland Eskimos suggested an important mechanism by which n-3 PUFAs could affect CHD.¹⁷ When bleeding times are measured, the effects of fish oil are additive to those of aspirin.¹⁸ Studies in swine fed high cholesterol diets with and without cod liver oil showed that there was less coronary atherosclerosis in the cod liver oil group but that there was no relationship to lipid changes. The pigs fed cod liver oil had significant decreases in serum thromboxane B₂ levels and increases in platelet fatty acid deposition of EPA.¹⁹ Fish oil supplements increased levels of tissue plasminogen activator (TPA) and decreased concentrations of plasminogen activator inhibitor, both enhancers of fibrinolysis.²⁰ One study comparing fish oil with rapeseed oil noted that fish oil decreased lipoprotein(a) by 14%.²¹ This effect was not seen in all male subjects who were hospitalized with CHD but did correlate with a large reduction in TPA. The Atherosclerosis Risk in Communities study compiled data from four US communities (15 000 participants, both black and white) on six hemostatic factors: fibrinogen, factor VII, factor VIII, von Willebrand factor, protein C, and antithrombin III.²² These were communities not known for their high intake of fish. Dietary intake of n-3 PUFA showed negative associations with levels of fibrinogen, factor VIII, and von Willebrand factor and a positive association with protein C (whites only). These findings may help explain, in part, the reduced incidence of vein graft occlusion seen in patients after coronary artery bypass grafting who receive n-3 PUFA.²³ In a randomized controlled trial of dietary supplementation with n-3 fatty acids in bypass patients who received usual anticoagulation with aspirin or warfarin, an inverse relation between relative change in serum phospholipid n-3 fatty acids and vein graft occlusions was observed. Thus, the prevention of thrombosis remains a promising area for n-3 PUFA research.

Effect of Omega-3 Fatty Acids on Immune Response
The potent anti-inflammatory effects of fish oils and their effects on the immune response are beyond the scope of this review. Worthy of mention are the detailed studies of Meydani et al²⁴ on immune responses seen with dietary fish supplementation. They showed decreased cell-mediated immunity when the Step II National Cholesterol Education Program (or AHA) diet was supplemented with a high fish intake as compared with one low in fish intake (121 to 188 g of fish per day versus 33 g of fish per day). The clinical significance of this important finding needs further investigation.

	Fish Intake and CHD

Top Introduction What Are Omega-3 Fatty... Fish Intake and Risk... Fish Intake and CHD Conclusions References

 
Observational Studies
Early studies of Greenland Eskimos (Inuit) highlighted their lower coronary mortality compared with their Danish counterparts. The Eskimos' diet included a strikingly higher intake of n-3 PUFAs rich in marine sources such as seal and whale that resulted in lower blood cholesterol, lower triglycerides, lower LDL-C, lower VLDL cholesterol, increased HDL cholesterol, increased bleeding times, and lower rates of CHD. In addition, prospective epidemiological studies from the Netherlands, Chicago, and the Multiple Risk Factor Intervention Trial confirmed that men who ate at least some fish per week had a lower mortality from CHD than those men who ate none.^{25 26 27 28} On the other hand, two studies describing populations with high intakes of fish did not show such a beneficial effect.^{29 30}

Clinical Trials
There is no convincing role for fish oil supplements in the prevention of CHD. The strongest evidence indicating a beneficial effect of fish intake on CHD came from the Diet and Reinfarction Trial (DART), in which men who were instructed to eat fish after myocardial infarction (MI) had a 29% decline in all-cause mortality as compared with those in the placebo group.³¹ No significant lowering of cholesterol was seen, and very few men were taking aspirin. Yet the Health Professionals Follow-up Study,³² a large-scale prospective cohort study, reported no association between increasing fish intake and CHD. The authors concluded that increasing fish intake beyond one or two servings per week is not likely to improve the primary prevention of CHD.

A nested case-control study was conducted among the 14 916 participants in the Physicians' Health Study.³³ Each participant with MI was matched by smoking status and age with a randomly chosen control participant who had not developed CHD. Fish oil intake was estimated by measuring plasma levels in cholesterol esters and phospholipids. No association was found between fish oil levels and the incidence of MI even when results were adjusted for major cardiovascular risk factors. Although early trials suggested that fish oil held some promise if ingested early before angioplasty, a clinical trial large enough to find a significant effect did not, despite a dose of 8 g/d of n-3 PUFA.³⁴ This trial did document the safety of fish oil supplementation without any evidence of excess bleeding in the patients who all took aspirin. Moreover, a clinical trial with angiographic end points showed that among normocholesterolemic men with CHD, fish oil treatment (6 g n-3 PUFA for 2 years) did not produce significant changes in the diameter of the coronary arteries.³⁵

Effects of Omega-3 Fatty Acids on Sudden Death
DART peaked interest in whether a diet rich in fish oil could reduce risk of sudden death because of the striking difference in sudden deaths seen early in the trial, suggesting a possible action on either thrombosis or arrhythmic death rather than on atherosclerosis.⁹ Support for the latter hypothesis came from the Lyon Trial,³⁶ which compared a "Mediterranean-type" diet rich in LNA with the AHA Step I diet in patients with known MI. Although no improvement in lipids, lipoproteins, and body mass index was seen, there was a striking difference in mortality, with eight sudden deaths in the control group and none in the alpha LNA–rich diet group. The risk ratio of cardiac death was 0.19 (95% CI, 0.06 to 0.65), with P<.002. These findings were extended by the carefully done population-based case-control study from Seattle and King County, Washington.³⁷ Among 334 patients with primary cardiac arrest, the intake of n-3 PUFA per month was significantly less than that seen in age- and sex-matched community controls. The data suggested that an intake of 5.5 g of n-3 PUFA per month (equivalent to one fatty fish meal per week) was associated with a 50% reduction in the risk of primary cardiac arrest after adjustment for potential confounding factors. Moreover, studies of red blood cell membrane n-3 PUFA in both patients and controls allowed calculation of risk based on this sensitive parameter of dietary n-3 PUFA intake. These findings were consistent with experimental evidence suggesting that the n-3 PUFAs have an important effect on vulnerability to ventricular fibrillation in the setting of myocardial ischemia.³⁸ Of additional interest are recent data showing suppression of premature ventricular contractions (PVCs) in middle-aged patients with frequent PVCs randomly assigned to take either fish oil (as cod liver oil containing 2.4 g of n-3 PUFA) or sunflower seed oil.³⁹ Clearly, further studies are needed to explore the potential of fish oil in the prevention of sudden cardiac death.

	Conclusions

Top Introduction What Are Omega-3 Fatty... Fish Intake and Risk... Fish Intake and CHD Conclusions References

 
When considering cardiovascular health, it seems premature to recommend general usage until compelling evidence for the beneficial action of fish oil supplements is at hand. Although doses of 3 to 8 g of n-3 PUFA per day in those with CHD were not associated with significant adverse effects in recent clinical trials,^{8 34} evidence for beneficial effects in CHD patients is either lacking or needs additional study. Currently, fish oil capsules can only be recommended for the infrequent patients with severe, treatment-resistant hypertriglyceridemia who are at increased risk for pancreatitis. Potential side effects should be kept in mind (Table^{1 40} ). On the other hand, inclusion of marine sources of the n-3 PUFA in the diet seems reasonable because they are good sources of protein without the accompanying high saturated fat seen in fatty meat products. Moreover, as Harris has noted, the potential for benefit remains high, since dietary fish oils affect "a myriad of potentially atherogenic processes."⁴¹ This requires the continued support of cardiovascular research on the n-3 PUFA.

View this table: [in this window] [in a new window]   Table 1. Potential Side Effects of Fish Oil Capsules1,37,38,40

	Footnotes

 
Single reprints are free: Call 1-800-242-8721 (US only) or write American Heart Association, Public Information, 7272 Greenville, Dallas, TX 75231-4596.

"Fish Consumption, Fish Oil, Lipids, and Coronary Heart Disease" was approved by the Science Advisory and Coordinating Committee of the American Heart Association in July 1996.

Single reprints are free: Call 1-800-242-8721 (US only) or write American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596.

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Top Introduction What Are Omega-3 Fatty... Fish Intake and Risk... Fish Intake and CHD Conclusions References

 

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