These fatty acids are essential for human health and development. This means that they are not synthesized in the body and must be obtained through diet. Yet they are not readily available in commonly consumed foods, and most Americans don't consume enough of them. Now, a plethora of supportive clinical and epidemiological data suggests that this one simple, convenient, cost-effective step in patient care may yield impressive outcomes.

Omega-3 essential fatty acids (EFAs) differ from omega-6 fatty acids, the other family of essential fats, in biological activity and dietary availability. Omega-6 fats are prevalent in the common diet. In fact, overconsumption of omega-6 fatty acids in conjunction with underconsumption of omega-3 fatty acids has become a nutritional concern. Health benefits from omega-9, a non-essential but important fatty acid found in olive oil, has recently received heart-smart accolades in the literature, too.

The evidence suggesting a beneficial role for omega-3 fatty acids, particularly marine-source eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the amelioration and risk reduction of heart disease is provocative and compelling. What follows is a review of clinical research that links ingestion of omega-3 fatty acids with cardiovascular health.

Research evidence shows that dietary omega-3 fatty acids: .Reduce triglycerides. .Complement statin drug therapy. .Are associated with lower levels of C-reactive protein. .Favorably reduce blood pressure. .Reduce risk of stroke. .Improve survival chances post-MI. .Improve endothelial function and support arterial health. .Report good safety data with minimal or no side effects.

Omega-3 Fatty Acids and Triglycerides

It is well known that patients with hyperlipidemia are at increased risk for cardiovascular disease. Over 15 years ago, a small clinical study of omega-3 supplementation (6 g/day) in patients with hyperlipidemia showed decreased triglycerides after supplementation . Lower doses appear also appear effective. A 1996 study in which subjects received 1 g/day of omega-3 EFAs had fasting plasma triacylglycerol concentrations reduced by an average of 21.2%; their postprandial triacylglycerol concentrations also were reduced significantly at this dose.

In a study comparing fish oil supplementation with flaxseed oil, the fish oil reduced triglycerides 24%-27% while the flaxseed-oil group saw no change. In addition, no changes in HDL- or LDL-cholesterol status were reported . A recent randomized double-blind placebo-controlled study of 84 subjects showed that fish oil supplementation (1.5 g EPA and 1 g DHA/day) led to a significant decrease in plasma triacylglycerol, plasma apolipoprotein B-48, and platelet phospholipid arachidonic acid concentrations and a significant increase in plasma HDL concentrations.

Among postmenopausal women, a clinical trial showed that fish oil supplementation (2.4 g EPA and 1.6 g DHA/day) not only lowered triglyceride levels significantly (26%) but also improved the triglyceride/HDL ratio. Both women taking hormone replacement therapy (HRT) and not taking HRT were included in the study; results did not differ significantly between the HRT and non-HRT groups.

And in a review of human trials, ~4 g/d of omega-3 fatty acids from fish oil was reported to decrease serum triglyceride concentrations by 25-30% . It appears that both EPA and DHA have triglyceride-lowering effects .

The triglyceride-lowering effects of omega-3 supplements are also impressive in people with diabetes. A meta-analysis in 2000 of 823 diabetic subjects (mostly type-2 men between 55-65 years of age) found that fish oil supplementation significantly lowered triglycerides (weighted mean: -0.56mmol/l), especially in those with hypertriglyceridemia (weighted mean: -0.73 mmol/l). The authors of the review concluded that fish oil supplementation is a helpful and reasonable therapeutic strategy in patients with high TG levels; in addition, they reported that in those with normal TG levels, no clinically significant effects on glycemic control were found.

Omega-3 Fatty Acids and CRP

A randomized, double-blind, placebo-controlled study evaluated the effects of simvastatin combined with 3 g/day omega-3 fatty acids on high sensitive C-reactive protein (HsCRP), lipidemia, and fibrinolysis in coronary heart disease (CHD) and CHD risk-equivalent patients with mixed dyslipidemia. The study found significant reductions of HsCRP, TG, total cholesterol (TC), and TC/HDL in the omega-3 fatty acids/statin group compared to the baseline. HsCRP and triglyceride reductions were more significant in the omega-3 fatty acids group than in the placebo group. Interestingly, in the omega-3 fatty acids group, the values and percentage of TG reduction had a significantly positive relation with HsCRP reduction .

Women on hormone replacement therapy have been shown to have significantly increased levels of C-reactive protein (CRP) and interleukin-6 as well as higher TG concentrations than women not taking HRT. A recent, randomized, placebo-controlled study of 30 healthy women on HRT showed that fish oil supplementation (7 g/day) significantly decreased CRP and Il-6 levels as well as significantly lowering TG levels . And a cross-sectional study of 727 women from the Nurses' Health Study showed that those with the highest level of omega-3 EFA intake had 29% lower levels of CRP, 23% lower levels of IL-6 and improvements in other parameters. The authors cited the omega-3s as having a beneficial impact on inflammation and endothelial activation .

In another study, a dietary questionnaire administered to patients referred for coronary angiography showed those with the lowest CRP levels had the highest intake of omega-3 fatty acids and significantly higher DHA plasma levels .

Omega-3 Fatty Acids and Hypertension

Fish oil also has a favorable impact on blood pressure, and low consumption of omega-3 fatty acids may increase incidence of hypertension, particularly in the United States where fish intake is low . A meta-analysis of 36 trials of fish oil supplementation (median dose 3.7 g/day) and blood pressure in adult men and women showed that fish oil has a small hypotensive effect on BP, especially in those who are older and have hypertension. The mean duration of these trials was 11.7 weeks. The reductions in blood pressure were significant, with systolic being reduced by 2.1 mmHg and diastolic reduced by 1.6 mmHg . Another meta-analysis of 31 trials and a total of 1,356 patients reported statistically significant dose-response effects: -1.3/-0.7 mm Hg at doses < or = 3 g/d, -2.9/-1.6 mm Hg at 3.3 to 7 g/d . It has been shown that even relatively small BP reductions may reduce stroke and coronary event risk.

In a clinical trial of 19 obese, hypertensive, and dyslipidemic patients with diabetes (OHD+DM) or without (OHD-DM), a 13-day protocol of programmed fasting and fish-oil feeding (2.7 g/day EPA and 1.8 g/day DHA) lowered BP in both groups, from 159/81 to 146/73 mmHg in the OHD-DM group, and 158/83 to 142/76 mm Hg in the OHD+DM group. Serum TG levels were also reduced, from 159 to 108 mg/dl in the OHD-DM group, and from 209 to 153 mg/dl in the OHD+DM group. In addition, HDL increased significantly in the OHD+DM group. A favorable reduction in hemostasis parameters (platelet aggregation) was seen among the non-diabetic patients only.

Use of Omega-3 Fatty Acids in Conjunction with Statins

Data suggests that fish-oil supplementation is a safe and effective adjunct therapy with statin medications. For example, a randomized, double-blind, placebo-controlled trial studied 59 patients with established coronary heart disease and hypertriglyceridemia who were taking statins. Results showed that those who also took fish oil had significantly lowered levels of serum triglycerides and VLDL than the control group, which took corn oil. There were no observed changes in LDL or HDL levels, and the supplementation did not alter glycemic control.

Several randomized, double-blind, placebo-controlled studies examined the addition of omega-3 fatty acids to the statin regime. One study using simvastatin and 3.36 g/day of omega-3s showed further decreases in serum triglycerides, total cholesterol, and apolipoprotein E in the fish-oil supplemented group . A second study added 1.68 g/day fish-oil supplementation to an atorvastatin regime. Results showed that the addition of omega-3 EFAs further increased HDL-cholesterol and reduced systolic blood pressure while the small dense LDL-articles and postprandial hypertriglyceridemia were reduced compared with baseline .

And a Japanese study of patients who had been on a statin drug for an average of 30 months showed that their serum total cholesterol and triglyceride concentrations were significantly decreased after three months of ingestion of fish oil, and their HDL concentrations increased .

Omega-3 Fatty Acids, Secondary Prevention, Arrhythmias, and Sudden Death

Fifteen large studies enrolling more than 60,000 subjects have shown a decrease in mortality from ischemic heart disease in those consuming fatty fish or omega-3 fatty acids . For example, one study followed 11,000 myocardial infraction survivors for 3.5 years. Those who took 1 /day of omega-3 EFAs had a 20% decrease in total deaths, a 30% decrease in cardiovascular deaths, and a 45% decrease in sudden deaths . Two studies have reported that chronic intake of fish or fish oil reduces infarct size as estimated by the frequency of Q-wave infarcts and by peak creatine kinase and lactate dehydrogenase activities after MI.

An American research team conducted a prospective, nested case-control analysis among men who were followed for up to 17 years as part of the Physicians' Health Study. Men with higher blood levels of omega-3 fatty acids had significantly lower risk of sudden death from cardiovascular disease . In a clinical trial of patients with premature ventricular complexes (PVC), omega-3 fatty acid supplementation did not significantly suppress the number of PVCs; however, it decreased heart rate by 2.1 beats/min. In a randomized, double-blind, placebo-controlled study, 65 patients with cardiac arrhythmias without coronary heart disease or heart failure were subdivided into groups receiving encapsulated fish oil (3 g/day) or placebo (olive oil). The fish oil group had decreased serum triglycerides, total cholesterol, LDL cholesterol, plasma free fatty acids, and thromboxane B2 as well as an increase in HDL cholesterol. In addition, a reduced incidence of atrial and ventricular premature complexes, couplets, and triplets were documented. No changes were seen in the placebo group.

Omega-3 Fatty Acids and Arterial Health

In a randomized 7-week parallel, double-blind trial on systemic arterial compliance (SAC), a reflection of arterial elasticity, supplementation with omega-3 fatty acids increased SAC as well as reducing pulse pressure and total vascular resistance, effects that may reduce the risk of adverse cardiovascular events. Another randomized double-blind, placebo-controlled clinical trial of 223 patients with angiographically proven coronary artery disease showed less progression of the disease and more regression in the group consuming 1.5 g/day of omega-3 supplements. And in a recent double-blind, randomized, placebo-controlled study of 173 healthy volunteers, fish oil supplementation proved to have a beneficial effect on endothelial function. In a randomized, controlled study, 610 patients undergoing coronary artery bypass grafting were assigned either to a fish oil group, receiving 4 g/day fish oil, or to a control group. All patients received antithrombotic treatment, either aspirin or warfarin. The primary end point was 1-year graft patency, which was assessed by angiography in 95% of patients. Dietary supplementation with omega-3 fatty acids reduced the incidence of vein graft occlusion, and an inverse relation between relative change in serum phospholipid omega-3 fatty acids and vein graft occlusions was observed .

Omega-3 Fatty Acids and Stroke Risk

An epidemiological study based on the Nurses' Health Study cohort found a significant inverse association between omega-3 fatty intake from fish or fish oil and risk of stroke, primarily thrombotic infarction. Women in the highest quintile of omega-3 consumption had a significantly reduced risk of total stroke. This was particularly true of women who were not taking aspirin. Additionally, in a randomized controlled study of patients awaiting carotid endarterectomy, subjects were divided into three groups: those who received fish oil (1-4 g/day), sunflower oil, a palm/soybean oil blend (the control group). Results showed that the plaques of the fish oil supplementation group had thicker, more fibrous caps and no signs of inflammation.

In addition, the number of macrophages in their plaques was lower than in the other two groups. The authors concluded that "atherosclerotic plaques readily incorporate omega-3 EFAs from fish-oil supplementation, inducing changes that can enhance stability" of atherosclerotic plaques .

Safety and side effects

Some concerns have been expressed about the oxidative susceptibility of LDL following omega-3 supplementation. In a randomized, placebo-controlled trial of 62 healthy volunteers, supplementation with omega-3 EFAs as fish oil did not influence the oxidative susceptibility of LDL . Additional studies have shown that supplementation with these EFAs does not lead to increased lipid peroxidation.

Some concern has been raised about the concomitant ingestion of omega-3 fatty acids with antithrombotic therapies. Investigators indicate that doses greater than 3 g/day of fish oil or high dietary fish intake may inhibit platelet aggregation and increase bleeding. However, the benefits of supplementing with purified omega-3 fatty acids appear to exceed potential risks in most individuals, and omega-3 supplementation from fish oil is recommended by the American Heart Association.

The AHA does recommend that "patients taking more than three grams of these fatty acids from supplements should do so only under a physician's care." Other potential side effects include an adverse or 'bad' aftertaste from inferior products and gastrointestinal disturbances in some patients at high doses38. Whether from fish or fish oil supplement, omega-3 EFAs are dietary polyunsaturated fatty acids and, as such, require functional digestion.

Conclusion

The research cited above represents the impressive body of data regarding marine-sourced omega-3 fatty acid supplements and their potential for benefiting numerous aspects of cardiovascular health. Given the challenges facing the practitioner with patients' dietary compliance along with environmental concerns surrounding the current fish supply, many health care providers are looking to purified fish oil supplements for consistent dosage, improved compliance, and clinical efficacy.

American Heart Association recommends: .All adults eat fish (particularly fatty fish) at least two times a week. .For patients with documented CHD, the AHA recommends 1 g/day of EPA and DHA (combined). .An EPA+DHA supplement (2-4 g/day) may be useful in patients with hypertriglyceridemia.

Addendum

Why fish instead of flax? The oil in flax seeds (and walnuts) contain alpha-linolenic acid (ALA), an omega-3 fatty acid. ALA is usually reported as the essential omega-3 in biochemistry textbooks because, technically, ALA is a precursor to EPA and DHA, the fatty acids naturally occurring in fish. However, recent human clinical research indicates that humans do not readily convert (elongate and desaturate) ALA to the more functional EPA and DHA fatty acids . EPA and DHA from fish oil are readily accessible for use in the body.