The effects of polyunsaturated fatty acids on coronary disease

Mark Tabaka, MHS, PA-C

March 17, 2009

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The effects of polyunsaturated fatty acids on coronary disease

COMPOSITION OF FATTY ACIDS

Fatty acids are long chains of hydrocarbons attached to a carboxyl group. Saturated fatty acids have single bonds between each of the carbon atoms and are saturated with hydrogen atoms at every available bond. Some foods high in saturated fatty acids include butter, whole milk and cream, eggs, red meats, chocolate, and solid shortenings. Monounsaturated fatty acids have one double bond. PUFAs have two or more double bonds. Fewer hydrogen atoms are present where carbon atoms are double bonded together³ (see Figure 1). Avocados; nuts; and olive, peanut, and canola oils are dietary sources of monounsaturated fatty acids. In addition to fish oil, vegetable oils, corn, sunflower, soy, and fatty fish are foods high in PUFAs.

PUFAs are divided into two subclasses. The first is alpha-linolenic acid, which has 18 carbon atoms with three double bonds (nomenclature 18:3) and is derived mainly from plant food sources such as canola and linseed oils. The second subclass is the long-chained PUFAs. Two of these are eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). EPA and DHA are found in fish and other marine food sources and appear to have the greatest impact on cardiovascular health. Humans have a limited ability to convert alpha-linolenic acid to EPA and DHA; consequently, EPA and DHA are deemed essential fatty acids and must be obtained from external sources.

OBSERVATIONAL DATA

Interest in PUFAs was sparked by epidemiologic observations that CAD morbidity and mortality rates were lower among populations that consumed diets high in PUFAs. In one study, the disease patterns of the Greenland Inuit was compared with those of the general population of Denmark.⁴ The researchers observed that despite their high-fat diet, MIrelated deaths were rare in the Inuit population compared to the general Danish population.⁴ The Inuit diet consisted mainly of fish, seal, whale, and walrus, all of which are high in n-3 fatty acids.⁵

A second study compared the Nanuvik Inuit population of Northern Quebec with that of Quebec's general popula-tion.⁶ Northern Quebec has a harsh environment and limited food sources. The Nanuvik Inuit's food sources are mainly marine mammals, fish, and land animals. Again, despite the higher fat content of their diet, CAD mortality rates among the Nanuvik Inuit were less than half those of the general population of Quebec (66.3 vs 140.2 per 100,000 person-years, respectively). Particularly noteworthy is that mortality rates for heart disease were lower in spite of a high prevalence of obesity and cigarette smoking among the Inuit population.⁶

Analysis of serum phospholipids showed that concentrations of PUFAs, particularly EPA and DHA, in the Inuit
diet were 1.7 times those of Quebec's general population.6 This significant difference correlated with a clear difference in marine food consumption. Dietary surveys showed that gram for gram, marine food consumption among the Nanuvik Inuit was 10 times that of the customary diet among the Quebec general population.⁶

Another interesting observation was that dietary PUFA levels were higher among older members of the Inuit community compared to the younger ones. Younger Inuit consumed a higher proportion of market foods, whereas the older members of the community maintained a traditional Inuit diet. As a result, the mortality rates from CAD were shown to have an inverse relationship with the mean age of the population sample. The study concluded that the traditional Inuit diet, which is high in marine products and PUFAs, provided clear protection from CAD within the Inuit population.⁶

The integration of Western culture appears to have had a detrimental effect on the cardiovascular health of native peoples.⁶ McLaughlin and colleagues showed that changing risk patterns in Alaska natives had a dramatic effect on their health.⁷ The average mortality rate from CAD was significantly lower for Alaskan native men than for non-natives (relative risk [RR] = 0.69) from 1979 to 1990; however, from 1991 to 2002, the differences in mortality rates were less significant (RR = 1.03). Data suggest that during this time the diet and lifestyle of Alaska natives had started to change. Widespread development, including the availability of supermarkets, made the Alaskan diet and lifestyle more like that of Western cultures.⁷ The cardioprotective features of the native Alaskan diet were lost as the traditional diets were abandoned.

MECHANISMS OF ACTION

Observational studies indicate a direct relationship between PUFAs and lower cardiovascular morbidity and mortality rates; however, determining the exact mechanism of action is difficult.³ Potential cardioprotective mechanisms include antithrombosis, improved endothelial function, lower BP, and lower triglyceride levels. The most likely mechanisms appear to be the antiarrhythmic and antiatherosclerotic properties of PUFAs.³

Antiarrhythmic effects Studies have indicated that men who included fish in their diets had a 50% lower risk of sudden cardiac death compared with men who did not eat fish frequently. No effect was shown to exist on nonsudden cardiac deaths, suggesting an antiarrhythmic correlation.⁸

Arrhythmias usually occur by one of three mechanisms: abnormal automaticity, such as junctional or ventricular escape rhythms; triggered activity from early afterdepolarizations (EAD) or delayed afterdepolarizations (DAD), such as long QT associated arrhythmias; or re-entry disorders, such as Wolff-Parkinson-White syndrome.^5,9 Abnormal automaticity occurs when the myocyte spontaneously depolarizes without external stimulation, usually from a decreased activation threshold.¹⁰ PUFAs have been shown to prevent abnormal automaticity by inhibiting the influx of sodium ions into myocytes, thus increasing the cell's activation threshold and the length of its refractory period. This increase in the refractory period reduces the potential for spontaneous depolarization.⁵

PUFAs have been shown to help prevent triggered activity from EADs or DADs. Remnants of a preceding action potential can trigger depolarization because of a decreased action potential threshold. Areas of ischemia result in increased calcium ion influx into myocytes, resulting in an increased posi-tive charge inside the cell lowering the action potential threshold. Lowering the threshold makes the cell much more sensitive to depolarization.⁹PUFAs have been shown to inhibit the flow of calcium ions into the cell, which prevents arrhythmias from occuring.⁵

Antiatherosclerotic effects Although the complications of atherosclerosis do not appear until later in life, the process begins much earlier, possibly in the third or fourth decade. Diets high in cholesterol and saturated fats lead to the accumulation of lipid particles in the intima of blood vessels that cause oxidative stress and the release of cytokines. Cytokines express adhesion molecules. This action initiates a chain of damaging events. Under normal circumstances, leukocytes do not adhere to the endothelium; however, adhesion molecules cause leukocytes to attach and cross the endothelial barrier. Monocytes and T lymphocytes enter the intima, ingest the lipids, and ultimately become foam cells, which replicate and become fatty streaks in the vessel wall. These fatty streaks represent the first step of atherosclerosis development.¹¹

Recent experiments suggest that exposure to either EPA or DHA limits monocyte adhesion to endothelial cells, thus reducing the number of monocytes that enter into the intima. Mayer and colleagues showed monocyte adhesion was significantly lower when certain cells were preincubated with EPA or DHA, compared to cells incubated without the n-3 fatty acids.¹² This finding suggests that consuming n-3 fatty acids lowers the number of adhesion molecules, thus protecting against the early development of fatty streaks.¹³

Fatty streaks generate chemo-attractants that signal the individual smooth muscle cells to migrate into the intima from the media. These cells assist in collagen, proteoglycans, and elastin fiber production, creating the extracellular matrix that forms a fibrous cap over the plaque.¹¹ Scientists believe that certain T lymphocytes trigger apoptosis of smooth muscle cells, leading to a decrease in the synthesis of collagens at various points in the cap. Mechanical forces from the lipid pool and the release of catabolic enzymes slowly degrade the fibrous cap at these points; ultimately, cracks form and the cap ruptures.¹¹

Clots quickly form once the collagen is exposed to the blood. Platelets form a layer over the exposed area. In a chain of events, platelets are activated and cytoplasmic granules are released; this, in turn, activates more platelets.¹⁴ Platelet activation also synthesizes thromboxane A2 (TxA2), a powerful vasoconstrictor. TxA2 induces circulating platelets to bind together and accumulate in the developing clot. Activated platelets liberate arachidonic acid (AA) from the cell membranes of the endothelium. Cyclooxygenase (COX) associated with the cell membranes then catalyzes AA into TxA2.¹⁴

EPA and DHA replace some of the AA in the endothelial cell membrane when concentrations of PUFAs are increased, which restricts the amount of AA available for release and reduces COX activity. These two factors combine to reduce syntheses of TxA2. Platelet aggregation and the risk of a clot forming are decreased.^15,16

INTERVENTIONAL STUDIES

The Diet and Reinfarction Trial (DART) was the first to show a direct relationship between diets high in PUFAs and protection against CAD.¹⁷ DART was a randomized, controlled trial designed to examine the effects of dietary changes in the prevention of a recurrent MI. The study population was 2,033 nondiabetic males with a recent history of nonfatal MI. The participants were randomly assigned to receive or not receive three types of dietary advice: (1) decrease fat intake to less than 30% of total daily calories; (2) eat at least two servings of fatty fish per week; and (3) increase fiber intake to 18 g daily. Each factor was independent of the other two so that a total of eight groups were possible, including a group that received no advice at all. Dieticians telephoned and visited the groups to reinforce the initial instructions. Each group was re-evaluated at 6 and 24 months via dietary questionnaires and measurements of fatty acid and serum cholesterol levels.¹⁷

Major end points of the study were determined to be total mortality and ischemic heart disease events, defined as nonfatal MI or death. All death certificates were reviewed, and if the cause of death suggested MI, the hospital notes were examined as well.¹⁷

Lowering fat intake did not produce any difference in mortality rates; however, the groups advised to increase their fish intake showed a 29% decrease in the relative risk of death from CAD (P < .05) at 2 years. This change was seen as early as 6 months after fish was added to the subjects' diets. Interestingly, nonfatal MI did not change significantly, owing perhaps to the ability of PUFAs to prevent fatal ventricular fibrillation.¹⁷

The Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Prevenzione Trial (GISSI-P) was the first large-scale, national mega-trial to confirm the findings of DART and demonstrate the cardioprotective effects of PUFAs.¹⁸ GISSI-P was a multicenter, open-label study that included 11,324 recent MI survivors who were randomly assigned to one of four treatment groups: PUFA supplements, vitamin E supplements, both, or neither for 3.5 years. The combined end point was death, nonfatal MI, and nonfatal stroke. Another end point was specific cardiovascular death, nonfatal MI, and nonfatal stroke. A four-way analysis of the results showed that the relative risk of death in the group receiving the PUFA supplements (95% CI 2-26; P = .023) was 15% lower than that in the control group (absolute risk reduction of 2.3%) and the relative risk of cardiovascular death (95% CI 5-32; P = .008) was 20% lower than that in the control group (absolute risk reduction of 2.2%). No effects were seen in the group that received only vitamin E supplements, and no additional effects were seen by adding vitamin E to PUFA. The results of this study established a direct relationship between an increased intake of PUFAs and a lower risk of CAD. The GISSI-P trial found a significant reduction in cardiac-related deaths as early as 6 to 8 months after increasing dietary consumption of PUFAs.¹⁸

CONFLICTING EVIDENCE

Some more recent studies appear to contradict the conclusions of these earlier studies. DART 2 was designed to determine if diet could lower the risk of sudden cardiac death.¹⁹ The results were somewhat unexpected, however, as the study showed a significantly higher mortality rate in the group that increased its consumption of fatty fish and fish oils compared with those participants who did not. Several factors raise questions about the comparability of the two trials and the validity of the DART 2 conclusion.¹⁹ Raitt and colleagues conducted a double-blind study to examine the theory that PUFA benefits are derived from their antiarrhythmic effects.²⁰ The results showed that individuals receiving fish oil had a significantly shorter time to arrhythmia, indicating that PUFAs are possibly proarrhythmic. Certain aspects of this trial also call into question its comparability to previous trials. The study itself concluded that it did not question the benefit of PUFAs in persons with recent MI.²⁰

DIETARY RECOMMENDATIONS

The American Heart Association established guidelines regarding appropriate daily PUFA intake.²¹ The recommendations include the following suggestions:

• Healthy persons without heart disease should eat fatty fish at least twice a week. Fish such as salmon,herring, and mackerel provide the highest amounts of EPA and DHA (see Table 1).

• Persons with documented CAD should have approximately 1 g of PUFAs in their diets each day. Because obtaining this high level from dietary sources alone might be difficult to achieve, fish oil supplements are an option.

• Persons who need to lower their triglyceride levels should take PUFA supplements and be monitored by a clinician. The recommended EPA plus DPA supplement regimen is 2 to 4 g daily.

Of note, no studies have conclusively determined that naturally occurring sources of PUFA are better than fish oil supplements or that supplements are better than natural fish oils. However, the DART trial participants who could not tolerate eating fish took fish oil supplements, and all the GISSI-P trial participants consumed fish oil supplements.^17,18 Fish oil is most commonly available in 1-g capsules that provide approximately 180 mg of EPA and 120 mg of DHA. The recommended regimen is 1 capsule, 3 times a day.^22,23

SIDE EFFECTS AND SAFETY

Although PUFAs can proportionally increase bleeding times, no cases of difficulties related to this have been documented. 22 The DART study produced a small but significant 2.1% (P < .01) increase in total cholesterol in the study groups advised to eat fish. However, this increase was only seen during the first 6 months and was not significant over the course of the 2-year study.¹⁷

A valid concern regarding higher levels of mercury and dioxins in certain types of fish exists.²² This concern has prompted the US Environmental Protection Agency and the FDA to issue an advisory regarding the consumption of some types of fish. The recommendations are available at www.cfsan.fda.gov/~dms/admehg3.html.24 Patients should be advised to review these guidelines before increasing their dietary fish intake.²³

CONCLUSION

Based on the current literature, certain conclusions can be drawn: (1) moderate intake of fish oils appears to lower overall mortality in persons at higher risk for CAD during the period immediately following an MI; (2) the benefits of PUFAs are derived from their antiarrhythmic effects on the heart over and above any favorable effect they may have on serum lipids; (3) EPA and DHA supplements can significantly reduce cardiac related and all cause mortality, although the ideal dosages are as yet unclear.

Since the discovery of the cardiac effects of PUFAs, interest in using them to treat and prevent CAD has increased. Although further studies are needed, sufficient justification exists to warrant at least discussing these benefits with appropriate patients. PAs should also be prepared to correct any misconceptions patients may have about the actual health benefits of PUFAs and to discuss the associated risks and possible unforeseen outcomes. JAAPA

Mark Tabaka practices emergency medicine at Bristol Hospital, Bristol, Connecticut. He has indicated no relationships to disclose relating to the content of this article.

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