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Editorials |
-Linolenic acid in health and disease1,2
There are 2 series of polyunsaturated fatty acids that are deemed essential: the n-6 and n-3 series. Although plants can synthesize both the basic n-6 and n-3 structures, animals lack this capacity and must obtain them from dietary sources. Deficiency of the n-6 fatty acid linoleic acid leads to poor growth, fatty liver, skin lesions, and reproductive failure (1). In contrast, the symptoms of n-3 
-linolenic acid deficiency are more obscure and have only been well demarcated in experimental animals and human infants. n-3 Fatty acid deficiency causes reduced vision, abnormal electroretinogram results, and, perhaps, impaired cognition and behavior (2).
The metabolism of -linolenic acid in humans has been well characterized. After -linolenic acid is ingested, the body converts it to very-long-chain polyunsaturated fatty acids: readily to eicosapentaenoic acid (20:5n-3) and more slowly to docosahexaenoic acid (22:6n-3). A major consequence of -linolenic acid deficiency is that its chief synthetic end product, docosahexaenoic acid, is not adequately produced (2). Because docosahexaenoic acid is a major component of the phospholipid membranes of the brain and retina, its deficiency in these organs then leads to abnormal function (3). n-3 Fatty acid deficiency is accentuated when there is simultaneously a high content of linoleic acid in the diet, which tends to inhibit the synthesis of docosahexaenoic acid from linolenic acid. Thus, diets rich in corn, safflower, sunflower, and peanut oils, all of which are high in linoleic acid and low in -linolenic acid, can lead to n-3 fatty acid deficiency (Table 1
). Thus, a high ratio of n-6 to n-3 fatty acids in the diet accentuates n-3 fatty acid deficiency.
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-linolenic acid on disease are well illustrated in the article by Hu et al (4) in this issue of the Journal. These authors analyzed data from the Nurses' Health Study and found that the intake of -linolenic acid in the diet protected against fatal ischemic heart disease and that this protection probably resulted from an antiarrhythmic effect of -linolenic acid. However, the protective effect of -linolenic acid did not extend to nonfatal myocardial infarction, for which there was a nonsignificant trend for an effect.
Although there may be a direct effect on cardiac arrhythmias from dietary -linolenic acid, it is likely that its effect was mediated, in part, through the syntheses of eicosapentaenoic acid and docosahexaenoic acid. An impressive array of data indicate a direct antiarrhythmic effect of eicosapentaenoic acid. For example, the diet higher in canola oil and canola oil margarine in the Lyon Heart Disease Study prevented cardiac deaths (5). Eicosapentaenoic acid has the most antiarrhythmic effect on induced ventricular tachycardia and fibrillation in intact animals and in cultures of isolated contracting myocardial cells (6). Conversion of -linolenic acid to eicosapentaenoic acid is fairly rapid and measurable within a few days after the dietary ingestion of linolenic acid and consists of desaturation, elongation, and further desaturation, with the rate-limiting enzyme step being the first desaturation step brought about by 
6-desaturase.
A more direct route to obtain the desirable action of eicosapentaenoic acid against cardiac arrhythmias would be the consumption of fish and fish oil, which contain large quantities of both eicosapentaenoic and docosahexaenoic acids. One gram of the common menhaden fish oil provides 
300 mg of these fatty acids. There are many epidemiologic studies and clinical trials to indicate the cardioprotective effects of fish oil n-3 fatty acids. Indeed, in the study of Burr et al (7) of >2000 men who had recovered from myocardial infarction, it was found that men who ate fish had a 39% reduction in mortality, although the risk of myocardial infarction was not affected, similar to the study by Hu et al. Epidemiologic studies have shown fewer deaths in men who ate more fish (8).
Another action of eicosapentaenoic acid to be considered is its antithrombotic effect. Inhibition of platelet cyclooxygenase, which converts arachidonic acid to thromboxane A2, results in less sticky platelets (9). Other potential effects of fish oil that could protect against ischemic heart disease include inhibition of macrophage migration, an antiinflammatory effect through restriction of cytokine production, inhibition of cellular growth factors in the arterial wall, and increased nitric oxide from the endothelium (10).
Note that the dietary sources of -linolenic acid may have increased since the data for the present study were compiled by Hu et al in 1984. The largest source of -linolenic acid in the diet then was salad dressings that contained soy oil. At that time, rapeseed oil was not considered suitable for human consumption because it contained large quantities of the monounsaturated fatty acid erucic acid, which had toxic effects in rats. After genetic engineering removed most of the erucic acid, the use of rapeseed oil leaped into prominence as canola oil. Canola oil, used in margarines as well, has 9% of its total fatty acids as -linolenic acid, so that daily consumption of 15 g (1 tbsp) canola oil or canola oil margarine provides as much as 1 g -linolenic acid/d. Other rich dietary sources of -linolenic acid include English walnuts and flaxseed oil (Table 1
). -Linolenic acid is also a prominent fatty acid of green leafy vegetables; however, because these vegetables have such a low fat content, the net amount of -linolenic acid ingested from these sources is small. Human milk is a good source of the n-3 fatty acids and the amounts in human milk (2.2% of total fatty acids) provide a good basis for considering similar amounts in the diets of children and adults. In recognition of the importance of n-3 fatty acids in human nutrition, the producers of infant formulas are including soy oil, an excellent source of -linolenic acid, as one of the fat ingredients instead of corn and coconut oils, which are poor sources. Likewise, intravenous fat preparations use soy oil instead of safflower oil, which is poor in the n-3 fatty acids.
In summary, dietary -linolenic acid is especially important in the development of the brain and the retina and has antiarrhythmic actions to prevent cardiac arrest in patients with ischemic heart disease. There are now ample food sources that supply adequate amounts of -linolenic acid and other n-3 fatty acids, which provide important health benefits.
FOOTNOTES
See corresponding article on page 890.
1 From the Division of Endocrinology, Diabetes, and Clinical Nutrition, the Department of Medicine, Oregon Health Sciences University, Portland, OR.
2 Address reprint requests to WE Connor, Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201. E-mail: connorw{at}ohsu.edu.
REFERENCES
-linolenic acid and risk of fatal ischemic heart disease among women. Am J Clin Nutr 1999;69:890–7.This article has been cited by other articles:
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  P. L. L. Goyens, M. E. Spilker, P. L. Zock, M. B. Katan, and R. P. Mensink Compartmental modeling to quantify {alpha}-linolenic acid conversion after longer term intake of multiple tracer boluses J. Lipid Res., July 1, 2005; 46(7): 1474 - 1483. [Abstract] [Full Text] [PDF]
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 B. P. Ander, A. R. Weber, P. P. Rampersad, J. S. C. Gilchrist, G. N. Pierce, and A. Lukas Dietary Flaxseed Protects against Ventricular Fibrillation Induced by Ischemia-Reperfusion in Normal and Hypercholesterolemic Rabbits J. Nutr., December 1, 2004; 134(12): 3250 - 3256. [Abstract] [Full Text] [PDF]
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 K.W. Lee and G.Y.H. Lip The role of omega-3 fatty acids in the secondary prevention of cardiovascular disease QJM, July 1, 2003; 96(7): 465 - 480. [Abstract] [Full Text] [PDF]
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 A. Baylin, E. K. Kabagambe, A. Ascherio, D. Spiegelman, and H. Campos Adipose Tissue {alpha}-Linolenic Acid and Nonfatal Acute Myocardial Infarction in Costa Rica Circulation, April 1, 2003; 107(12): 1586 - 1591. [Abstract] [Full Text] [PDF]
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 L. Djousse, J. S Pankow, J. H Eckfeldt, A. R Folsom, P. N Hopkins, M. A Province, Y. Hong, and R C. Ellison Relation between dietary linolenic acid and coronary artery disease in the National Heart, Lung, and Blood Institute Family Heart Study Am. J. Clinical Nutrition, November 1, 2001; 74(5): 612 - 619. [Abstract] [Full Text] [PDF]
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R. U Almario, V. Vonghavaravat, R. Wong, and S. E Kasim-Karakas Effects of walnut consumption on plasma fatty acids and lipoproteins in combined hyperlipidemia Am. J. Clinical Nutrition, July 1, 2001; 74(1): 72 - 79. [Abstract] [Full Text] [PDF]
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 M. de Lorgeril, P. Salen, F. Laporte, and J. de Leiris Alpha-linolenic acid in the prevention and treatment of coronary heart disease Eur. Heart J. Suppl., June 1, 2001; 3(suppl_D): D26 - D32. [Abstract] [PDF]
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 F. B. Hu, J. E. Manson, and W. C. Willett Types of Dietary Fat and Risk of Coronary Heart Disease: A Critical Review J. Am. Coll. Nutr., February 1, 2001; 20(1): 5 - 19. [Abstract] [Full Text] [PDF]
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