Omega-3 Fatty Acids and Atherosclerosis

August 17, 2012

By Michael Malone

Faculty Peer Reviewed

Omega-3 long chain polyunsaturated fatty acids (PUFAs) have been popularized in recent years as beneficial nutrients with cardioprotective effects. Omega-3 PUFAs are so named because of a double bond between the 3rd and 4th carbon of the polycarbon chain. They are “poly-unsaturated” with hydrogen atoms, as their carbon chains contain multiple double bonds. Three omega-3 long chain PUFAs are typically discussed in the context of medical therapy, the first being alpha-linolenic acid (ALA). ALA is an essential precursor omega-3 that is converted by the body into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).[1] However, this conversion is not very efficient in humans.[2] Omega-3s are best obtained through the diet, but they are available as supplements as well.[1] Omega-3s are common in poultry and most famously found in fish such as salmon, herring, trout, and sardines. ALA is a component of many plant products such as flax seed oil and to a lesser extent canola and soy oils.[3] Increased consumption of omega-3 PUFAs increases their proportion in blood and tissue lipid pools.[4] Serum concentrations of omega-3s can be measured.

Treatment of Hypertriglyceridemia

Omega-3 PUFAs are widely used to treat hypertriglyceridemia, defined as a triglyceride level greater than 150 mg/dL. The NHANES 3 National Health and Nutrition Examination Survey determined that around 35% of men and 25% of women in the US have triglyceride levels over 150 mg/dL. Triglyceride levels greater than 500 mg/dL are associated with an increased risk of pancreatitis.[1] Triglycerides can be lowered through physical exercise, low-calorie diets, and limiting consumption of alcohol. Omega-3 PUFAs can lower triglycerides when used alone or in combination with niacin or fibrates. They can also be used in conjunction with statins, which have a mild ability to reduce triglyceride levels on their own.[3] When omega-3 supplementation was combined with a statin, non-HDL-C levels were reduced much more than on a statin alone. In addition, VLDL-C, triglycerides, and total cholesterol decreased and HDL-C increased–all by more significant amounts than with just a statin alone.[5] Of the 3 omega-3 PUFAs discussed, EPA and DHA have shown the greatest efficacy.[6] The mechanism by which omega-3 PUFAs lower triglycerides is still unknown, but they reduce the hepatic synthesis of VLDLs, which are almost entirely triglycerides, and accelerate lipoprotein lipase, which hydrolyzes triglycerides.[1] With prescription strength omega-3s, triglycerides can be lowered 30-40%.[5] Aggressively lowering LDL-C with statins has been shown to stabilize atherosclerotic plaques.[7]

Clinical Associations

While omega-3 PUFAs are approved for the treatment of hypertriglyceridemia, evidence suggests that they have many other biological activities. Low levels of omega-3 PUFAs have been associated with numerous diseases. One study found that obese children have lower omega-3 concentrations in their serum phospholipids than age-matched lean controls[2] while another found correlations between low omega-3 PUFAs and markers of metabolic syndrome.[8] Low levels of omega-3s were significantly associated with acute coronary syndrome. They were also independently correlated with the presence and degree of lumen occlusion of lipid-rich, atherosclerotic plaques.[9] In other studies, omega-3s were correlated with decreased risk of sudden death and non-fatal myocardial infarction.[4]

Role in Atherosclerotic Disease

The role of omega-3 PUFAs in the treatment of atherosclerosis is not as clear as its role in triglyceride therapy, but there is strong evidence to suggest clinical efficacy. As stated earlier, EPA and DHA have the greatest therapeutic effect and were the omega-3s most often studied. Omega-3 PUFAs influence gene transcription.[10] It is thought that when omega-3s incorporate into the cellular membrane, they disrupt cholesterol rafts, changing the fluidity of cell membranes.[11] This releases endothelial relaxing factors, like nitric oxide, decreasing vascular tone.[12] It has been shown that after 3 months of omega-3 supplementation in obese adolescents with demonstrated vascular inflammation, vasoconstrictive responses and endothelial function improved.[8]

In addition to changing the endothelial response, omega-3 PUFAs seem to modulate the inflammatory response through inhibition of cyclooxygenase-2 (COX-2). While this mechanism is unclear, omega-3 PUFAs incorporate directly into the plaque. Decreased COX-2 activity is associated with decreased release of matrix metalloproteinases (MMPs), which have been implicated in the thinning of the atherosclerotic plaque cap that makes the plaque more prone to rupture.[5] It has been demonstrated that when patients were treated with omega-3s prior to surgery, carotid artery plaques had decreased levels of RNA for MMPs 7,9, and 12.[4] The same study found that in the 3-week treatment period the plaques showed a decreased number of foam cells and T-cells and had less inflammation and increased stability. However, over the short, 3-week presurgical treatment period, there was no change in primary outcome.[4] In another placebo-controlled study, obese adolescents treated with EPA for one year had improved vascular function; reduced inflammation; and decreased levels of lymphocytes, monocytes, TNF-alpha, interleulin-1, and interleukin-6.[8]

COX-2 inhibition affects platelet aggregation as well. EPA has been shown to reduce platelet aggregation and may have a beneficial effect on certain cardiovascular thrombotic disorders.[13] These effects may be enhanced by reduction in serum lipid levels. Elevated postprandial triglycerides were shown to be associated with increased plasminogen activator 1 and factor 7, increasing thrombosis risk and CHD events.[1] By altering lipid levels and regulating inflammatory mediators, endothelial function, inflammation, plaque stability, and platelet aggregation, omega-3 PUFAs have demonstrated a multifaceted, protective effect against atherosclerosis.

The Omega-6/Omega-3 Ratio

Like omega-3s, omega-6 PUFAs are essential fatty acids. Omega-6s have a double bond, but at the 6-carbon location. Arachidonic acid and linoleic acid (not to be confused with the omega-3 ALA) are examples of omega-6 PUFAs. They are commonly found in vegetable oils. The omega-6/omega-3 ratio found in the Western diet is considered high, with a ratio of 15-20/1 rather than the 1/1 found in the diet of many animals and pre-industrial era humans.[10]

Both omega-3s and omega-6s influence gene expression, but in antagonistic ways.[10] While omega-3s inhibit COX-2 products, omega-6s can be metabolized to form eicosanoid metabolic products such as prostaglandins, thromboxanes, leukotrienes, hydroxy fatty acids, and lipoxins.[14] Thus, whereas omega-3s have anti-inflammatory properties, omega-6s are pro-thrombotic and pro-aggretory, causing inflammation, oxidation of LDL, and platelet aggregation. Increasing ratios of omega-6/omega-3 PUFAs in platelet phospholipids have been correlated with an increased death rate from cardiovascular disease.[10] However, many studies have shown that low omega-6 levels are not as clear a predictor of health as high omega-3 levels are, suggesting that adverse health effects associated with high omega-6/omega-3 ratios in the Western diet is more a function of decreased omega-3 intake than the excess consumption of omega-6s.[2]

Lovaza

In addition to omega-3 supplements that are commercially available, there is now an FDA-approved prescription omega-3 supplement available in the US. Lovaza (Pronova BioPharma ASA, Lysaker, Norway) is 38% DHA, 47% EPA, and 17% other fish oils (840 mg of DHA and EPA) and is approved to treat hypertriglyceridemia. Fish-oil supplements commonly have a fishy smell and aftertaste that can be bothersome to some individuals.[6] These pharmacological agents are well tolerated with statins,[5] which are often co-prescribed. There is some concern that omega-3s, due to their anticoagulant effects, may increase the risk of bleeding or of hemorrhagic stroke, especially when combined with other agents like aspirin or warfarin. However, multiple clinical trials do not suggest that a true increased bleeding risk exists with PUFAs, even in combination with other anticoagulants.[6] Lovaza (pronounced “lo-vay-za”) is currently only contraindicated in patients with hypersensitivity to its components and used cautiously in patients allergic to fish or shellfish.

Recommendations

The American Heart Association recommends that patients with or without heart disease eat a variety of fish at least twice a week, preferably fishes like salmon, herring, and trout that are high in omega-3 PUFAs. Patients with heart disease are advised to consume about 1 gram of EPA and DHA daily, preferably from food, but supplements are acceptable after consultation with a physician.[5] There are no clear benefits to a specific omega-6/omega-3 ratio, as long as omega-3 intake is kept high. There are also no significant side effects to increasing omega-3 content in the diet or in a pharmaceutical form.

Conclusion

The idea that disease biology can be fine-tuned by diet is powerful. The potential mechanisms by which omega-3 PUFAs benefit atherosclerosis include lowering triglyceride levels, improving the effects of statin therapy, improving endothelial function, blocking pro-inflammatory pathways, and impairing platelet aggregation though COX-2 inhibition. Omega-3 prophylaxis has already shown therapeutic effects both in patients with prior MI or atherosclerosis and in those at risk for these conditions.

Commentary by Dr. Arthur Schwartzbard

Recent randomized controlled trials of omega-3 supplementation have not consistently demonstrated a reduction in cardiovascular events. To date, these agents look most effective at reducing triglycerides, and Lovaza is FDA approved to reduce triglycerides in patients whose triglycerides exceed 500 mg/dL. These agents are also advised for patients who do not consume at least 1-2 servings of fish weekly. This class has also been useful in patients with HIV dyslipidemia with markedly elevated triglycerides. It is possible that some of the lack of cardiovascular event reduction may be due to the rise in LDL cholesterol that has been noted with many of these agents. A new preparation of fish oil has been recently shown to also reduce LDL, and is currently in phase 3 trials.

Michael Malone is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Dr. Arthur Schwartzbard, MD, Assistant Professor, Department of Medicine, Division of Cardiology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther. 2008;6(3):391-409. http://www.ncbi.nlm.nih.gov/pubmed/18327998

2. Deckelbaum RJ. n-6 and n-3 Fatty acids and atherosclerosis: ratios or amounts? Arterioscler Thromb Vasc Biol. 2010;30(12):2325-2326. http://www.ncbi.nlm.nih.gov/pubmed/21084701

3. O’Keefe JH, Carter MD, Lavie CJ. Primary and secondary prevention of cardiovascular diseases: a practical evidence-based approach. Mayo Clin Proc. 2009;84(8):741-757. http://www.ncbi.nlm.nih.gov/pubmed/19648392

4. Cawood AL, Ding R, Napper FL, et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010;212(1):252-259. http://www.ncbi.nlm.nih.gov/pubmed/20542512

5. Bays HE, McKenney J, Maki KC, Doyle RT, Carter RN, Stein E. Effects of prescription omega-3-acid ethyl esters on non–high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc. 2010;85(2):122-128. http://www.ncbi.nlm.nih.gov/pubmed/20118387

6. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C-43C. http://www.ncbi.nlm.nih.gov/pubmed/17368277

7. Kadoglou NP, Sailer N, Moumtzouoglou A, Kapelouzou A, Gerasimidis T, Liapis CD. Aggressive lipid-lowering is more effective than moderate lipid-lowering treatment in carotid plaque stabilization. J Vasc Surg. 2010;51(1):114-121. http://www.ncbi.nlm.nih.gov/pubmed/19837545

8. Dangardt F, Osika W, Chen Y, et al. Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents. Atherosclerosis. 2010;212(2):580-585. http://www.ncbi.nlm.nih.gov/pubmed/20727522

9. Amano T, Matsubara T, Uetani T, et al. Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study. Atherosclerosis. 2011.;218(1):110-116. http://www.ncbi.nlm.nih.gov/pubmed/21684546

10. Simopoulos AP. The omega-6/omega-3 fatty acid ratio, genetic variation, and cardiovascular disease. Asia Pac J Clin Nutr. 2008;17 Suppl 1:131-134. http://www.ncbi.nlm.nih.gov/pubmed/18296320

11. Layne J, Majkova Z, Smart EJ, Toborek M, Hennig B. Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases. J Nutr Biochem. 2011;22(9):807-811. http://www.ncbi.nlm.nih.gov/pubmed/21292468

12. Okuda Y, Kawashima K, Sawada T, et al. Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. Biochem Biophys Res Commun. 1997;232(2):487-491. http://www.ncbi.nlm.nih.gov/pubmed/9125207

13. Hirai A, Terano T, Hamazaki T, et al. The effects of the oral administration of fish oil concentrate on the release and the metabolism of [14C]arachidonic acid and [14C]eicosapentaenoic acid by human platelets. Thromb Res. 1982;28(3):285-298. http://www.ncbi.nlm.nih.gov/pubmed/6294902

14. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 2008;233(6):674-688. http://www.ncbi.nlm.nih.gov/pubmed/18408140.

15. American Heart Association. Vitamin and mineral supplements. http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/Vitamin-and-Mineral-Supplements_UCM_306033_Article.jsp.  Updated September 24, 2011.  Accessed July 28, 2011.

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