Beyond the Mediterranean Diet: The Role of Omega-3 Fatty Acids in the Prevention of Coronary Heart Disease

Charles R. Harper, MD, Terry A. Jacobson, MD

Disclosures

Prev Cardiol. 2003;6(3) 

In This Article

Mechanisms of Action

The provocative cardioprotective results of the above clinical trials have sharpened interest in determining the mechanism of action of the n-3 fatty acids cardioprotective effects. It has been suggested that the n-3 fatty acids may be cardioprotective due to multiple mechanisms, but their role as potential antiarrhythmics has recently received added attention. It is hypothesized that n-3 PUFAs stabilize the electrical activity of cardiac myocytes by inhibiting sarcolemmal ion channels resulting in a prolonged relative refractory period.[32] This antiarrhythmic effect was demonstrated by Leaf et al.[33] in work with dogs. Ligating the left main coronary artery while an inflatable cuff was placed around the left circumflex artery produced a surgically induced MI. The dogs were trained to run on a treadmill and screened for susceptibility to ventricular fibrillation when the cuff was inflated. Thirteen dogs were indentified that were susceptible to ventricular fibrillation. These dogs were entered into the study. Intravenous infusion of fish oil before the exercise ischemia test prevented ventricular fibrillation in 10 of 13 dogs. In the control exercise ischemia test conducted both 1 week before and 1 week after the infusion of fish oil, animals were given a soybean oil infusion instead and developed ventricular fibrillation requiring defibrillation. Using the same protocol above, the dogs were also given an intravenous infusion of the plant-derived n-3 fatty acid ALA. Beneficial antiarrhythmic results similar to the fish oil group were also obtained with ALA.

Endothelial function is also favorably affected by n-3 fatty acids, as the vasodilatory effect of nitrous oxide is enhanced by EPA. Treating humans with fish oil has been shown to decrease oxygen-derived free radical production in neutrophils.[34] It has been suggested that this reduction in free radicals increases the bioavailability of nitrous oxide. Studies using ultrasonic tracking of brachial artery flow-mediated vasodilatation have demonstrated improved large artery endothelium-dependent dilatation in patients treated with fish oil.[35] Endothelial function may also be improved by reducing the endothelial expression of vascular cell adhesion molecules thus resulting in a reduction in leukocyte binding to the endothelium.[36]

The n-3 fatty acids also have significant antithrombotic properties. EPA has been shown to inhibit the synthesis of thromboxane A2, a prostaglandin that causes platelet aggregation and vasoconstriction.[36] EPA results in reduced platelet adhesion and reactivity, which manifests itself by increased bleeding time and decreased adhesion of platelets to glass beads.[37] Other antithrombotic effects reported include reductions in fibrinogen and increases in tissue-type plasminogen activator ( Table III ).

Ingestion of EPA and DHA has also been shown to inhibit atherosclerotic plaque formation in animal studies. Two important cells in the development of an atherosclerotic plaque are smooth muscle cells and macrophages. Platelet-derived growth factor (PDGF) is a key chemoattractant and mitogen for smooth muscle cells and macrophages. PDGF production and PDGF mRNA synthesis are decreased by ingestion of n-3 fatty acids.[38]

The influence of n-3 fatty acids on lipid metabolism is predominantly antiatherogenic. Fish oil (a rich source of EPA and DHA) has been shown to lower total cholesterol and triglyceride concentration by inhibiting very low-density lipoprotein and triglyceride synthesis in the liver.[39] Large doses of fish oil have been shown to have profound effects in reducing triglycerides in hypertriglyceridemic patients. Apolipoprotein B production is also reduced by fish oil consumption in comparison with vegetable oils not containing n-3 fatty acids.[39] Pretreatment with n-3 fatty acids also markedly reduces postprandial lipemia. Postprandial lipemia typically occurs after a fatty meal and the postpran-dial lipoproteins are atherogenic. Postprandial lipemia is also thrombogenic, as it increases levels of activated factor VII, a procoagulant. It is interesting to note that olive oil results in the same degree of increase in factor VII as butter while fish oil prevents this postprandial increase.[40]

Unlike vegetable oils rich in n-6 fatty acids, n-3 fatty acids do not lower HDL cholesterol levels. In contrast, they have been shown to result in a favorable change in HDL cholesterol metabolism. It appears that n-3 fatty acids cause an increase in the large cholesterol rich HDL2 subtype, while decreasing the smaller triglycerol-enriched HDL3 sub-type.[41,42] HDL2 is considered to be the most antiatherogenic HDL subtype.

Some questions have been raised about potential atherogenic changes in lipid metabolism caused by the n-3 fatty acids. LDL cholesterol levels have been shown to occasionally increase with n-3 PUFA supplementation; however, this effect does not occur consistently and only occurs at higher doses.[39] Also, some concern has been raised about in vitro studies that demonstrate that n-3 PUFA supplementation may increase LDL cholesterol susceptibility to oxidation. However, it has been demonstrated that this oxidation can be reduced by supplementation with the antioxidant vitamin E.[39]

In summary, the n-3 PUFAs have predominantly antiatherogenic properties ( Table III ). Most of these antiatherogenic effects have been demonstrated with the marine-derived n-3 PUFA. The majority of studies with ALA have evaluated the efficiency with which ALA is converted to the longer-chain n-3 fatty acids, EPA and DHA. More studies are needed to delineate the potential cardioprotective mechanisms of ALA.

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