78 Letters to the Editor / Prostaglandins, Leukotrienes and Essential Fatty Acids 80 (2009) 77–79

Heart Study [3] should have been included despite the fact that the reduction in cardiovascular disease (CVD) events in this study is virtually always attributed to the increased intake in alphalinolenic acid, not the reduced intake of linoleic acid. It is unclear why confounding in Lyon is acceptable but confounding in Oslo is not. The Sydney Heart Study [1] was excluded because it did not report cardiovascular disease endpoints, only total mortality. Ramsden et al are correct that Rose et al., [2] should have been included in the meta-analysis. In this 2-year study, 54 heart patients were instructed to reduce animal fats and to substitute 80 g of either olive oil (n ¼ 26) or corn oil (n ¼ 28) per day. A control group (n ¼ 26) made no changes in their diets. Major coronary events occurred in 43%, 48% and 25% of each group, respectively. A chi-square test of these proportions gives a p ¼ 0.31, and the most relevant comparison (between the two oil interventions) found no difference at all. Hence this study did not show increased CV events associated with LA intake as Ramsden et al. indicate. Although Rose should have been included in the metaanalysis, it would not have altered the outcome because of both its lack of effect and its small sample size. In 1995, Gordon [5] published a similar meta-analysis and reached the same conclusion: higher PUFA, lower saturated fat diets reduce CV events. The second issue raised by Ramsden et al. is that diets higher in LA lower the omega-3 index, an emerging erythrocyte-based marker of CV risk [6]. Oddly, none of the three studies they refer to reported effects on the omega-3 index. Two were 30-day studies in pigs examining the effects of varying LA:ALA ratios on cardiac [7] and brain [8] phospholipid fatty acid composition. Neither assessed any CVD endpoint. The only human study cited [9] examined the effects of 2,4-week treatment periods on plasma phospholipid fatty acid composition after recommending diets high (10% en) or low (3.8% en) in LA to healthy volunteers. If one uses the plasma phospholipid EPA+DHA content as a surrogate of the omega-3 index, concerns about the study design emerge. Presumably owing to the 2-week pre-study restriction on fish intake, phospholipid EPA+DHA levels were slowly decreasing throughout the study regardless of LA or ALA intake. With two variables (LA:ALA ratios and EPA+DHA washout), the effects of the former alone are difficult to interpret. Nevertheless, others have reported that higher LA:ALA ratios do modestly lower membrane EPA and DHA levels

[10]. The relevant question in this context, however, is whether an LA-induced diminution of the omega-3 index increases risk for CVD or not; the other evidence cited in the review suggest that it may not. CVD is a multifactorial disease, and changes in one risk factor may be offset by corresponding changes in others. The best way to raise the omega-3 index is by eating more EPA and DHA, not by eating less LA. The former has been shown to reduce risk for CVD whereas the latter has not. References
[1] J.M. Woodhill, A.J. Palmer, B. Leelarthaepin, et al., Low fat, low cholesterol diet in secondary prevention of coronary heart disease, Adv. Exp. Med. Biol. 109 (1978) 317–330. [2] G.A. Rose, W.B. Thomson, R.T. Williams, Corn oil in the treatment of ischemic heart disease, Br. Med. J. 1 (1965) 1531–1533. [3] M. de Lorgeril, P. Salen, J.L. Martin, et al., Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study, Circulation 99 (1999) 779–785. [4] P. Leren, The effect of plasma cholesterol lowering diet in male survivors of myocardial infarction. A controlled clinical trial, Acta Med. Scand. Suppl. 466 (1966) 1–92. [5] D.J. Gordon, Lowering cholesterol and total mortality, in: B.M. Rifkin (Ed.), Lowering Cholesterol in High-Risk Individuals and Populations, Marcel Dekker, Inc., New York, 1995, pp. 33–48. [6] W.S. Harris, The omega-3 index as a risk factor for coronary heart disease, Am. J. Clin. Nutr. 87 (2008) 1997S–2002S. [7] S. Ghosh, E.M. Novak, S.M. Innis, Cardiac proinflammatory pathways are altered with different dietary n-6 linoleic to n-3 alpha-linolenic acid ratios in normal, fat-fed pigs, Am. J. Physiol. Heart Circ. Physiol. 293 (2007) H2919–H2927. [8] E.M. Novak, R.A. Dyer, S.M. Innis, High dietary omega-6 fatty acids contribute to reduced docosahexaenoic acid in the developing brain and inhibit secondary neurite growth, Brain Res. 1237 (2008) 136–145. [9] Y.A. Liou, D.J. King, D. Zibrik, et al., Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men, J. Nutr. 137 (2007) 945–952. [10] E. Mantzioris, M.J. James, R.A. Gibson, et al., Dietary substitution with an alinolenic acid-rich vegetable oil increases eicosapentaenoic acid concentrations in tissues, Am. J. Clin. Nutr. 59 (1994) 1304–1309.

William S. Harris Sanford Research/USD, 1100 East 21st St, Suite 700, Sioux Falls, SD 57105, USA E-mail address:

What happened to do no harm? The issue of dietary omega-6 fatty acids In 1999, scientists from around the globe gathered to address dietary recommendations for omega-3 and omega-6 fatty acids [1]. Their recommendation emphasized the importance of reducing omega-6 fatty acids in order to reduce adverse health effects of excesses of arachidonic acid (AA) and its eicosanoid products. Therefore, they set an upper limit for linoleic acid (LA), to no more than 6.67 g/day, based on a 2000 kcal diet of 3.0% of energy. Yet, based on the current series of papers published on LA [2–4], one might be led to believe there has been a substantial body of evidence to refute the recommendation, which is not the case. The research cited is taken out of context and/or is based on very small studies, many of which were published over a decade ago, as described below. Comments on three papers published in PLEFA September 2008 (vol. 79, issue 3) The health implications of changing linoleic acid intakes by Jay Whelan (pp. 165–167).

Linoleic acid and coronary heart disease by William S. Harris (pp. 169–171). Too much linoleic acid promotes inflammation—doesn’t it? by Kevin L. Fritsche (173–175). Comments by: Evelyn Tribole—1100 Quail Street, Suite 111, Newport Beach, CA 92660, USA. Fritsche [2] describes the CHIANTI study by Ferrucci et al. [5], as an example of no adverse impact on inflammation from eating too much LA. Subjects with the highest quartile of plasma arachidonic acid levels had lower pro-inflammatory markers and higher anti-inflammatory markers. But an important detail from this study is ignored—the subjects from this Mediterranean region eat a low LA diet, averaging 7 g/day. In this context, it is not surprising that plasma AA was associated with beneficial inflammation biomarkers—because it does so in the presence of eating a balanced proportion of omega-6 and omega-3 fatty acids. The results of this study support the benefits of eating a lower LA diet! Harris [3] concludes that, ‘‘Reducing LA intakes to less than 5% energy would be more likely to increase, not decrease, risk for

Letters to the Editor / Prostaglandins, Leukotrienes and Essential Fatty Acids 80 (2009) 77–79 79

CHD’’. Yet, that is not what the research shows. The Lyon Diet Heart Study [6] put their subjects on a low omega-6 fat diet, with a maximum 7 g (4.6% calories), which resulted in a striking reduction in all-cause mortality, including sudden cardiac death and cancer. Notably, studies have demonstrated harm from eating high LA diets on cardiovascular health [7–9]. Whelan [4] states that a number of studies fail to link enrichment of AA in tissues with deleterious outcomes. Yet four out of five of these studies [10–13] were performed on only 10 healthy men! He also says that there is no adverse effect from eating dietary LA intake on breast cancer. Large studies from the USA, France and Sweden indicate otherwise [14–16]. For example, in a case-control study on nearly 1700 women [14], researchers demonstrated that women with a genotype influencing the LOX enzyme, had a two-fold increase in breast cancer risk if they ate high levels of LA (417.4 g/day). Yet, this genotype had no influence on breast cancer risk, if these women ate a lower LA diet. Conclusion: At best, these papers [2–4] serve as editorials reflecting opinions of individual scientists. And at worst, these papers are disservice to the scientific process and public health, as they have been published without counterpoint or a serious review of the literature. The issue of an optimal level of dietary omega-6 fats is far from settled. But a plethora of papers published in the last decade [17] merit a serious discussion on the public health issue of dietary omega-6 fats; the most commonly consumed polyunsaturated fat in industrialized countries. References
[1] A.P. Simopoulos, A. Leaf, N. Salem, Workshop statement on the essentiality of and recommended dietary intake for omega-6 and omega-3 fatty acids, Prostaglandins Leukot. Essent. Fatty Acids 63 (2000) 119–121. [2] K.L. Fritsche, Too much linoleic acid promotes inflammation—doesn’t it?, Prostaglandins Leukot. Essent. Fatty Acids 79 (2008) 173–175. [3] W.S. Harris, Linoleic acid and coronary heart disease, Prostaglandins Leukot. Essent. Fatty Acids 79 (2008) 169–171. [4] J. Whelan, The health implications of changing linoleic acid intakes, Prostaglandins Leukot. Essent. Fatty Acids 79 (2008) 165–167.

[5] L. Ferrucci, A. Cherubini, S. Bandinelli, B. Bartali, A. Corsi, F. Lauretani, et al., Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers, J. Clin. Endocrinol. Metab. 91 (2006) 439–446. [6] M. de Lorgeril, P. Salen, J.-L. Martin, I. Monjaud, J. Delaye, N. Mamelle, Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of The Lyon Diet Heart Study, Circulation 99 (1999) 779–785. [7] J.H. Dwyer, H. Allayee, K.M. Dwyer, et al., Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis, N. Engl. J. Med. 350 (2004) 29–37. [8] C.Q. Lai, D. Corella, S. Demissie, et al., Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: The Framingham Heart Study, Circulation 113 (2006) 2062–2070. [9] H. Allayee, A. Baylin, J. Hartiala, et al., Nutrigenetic association of the 5-lipoxygenase gene with myocardial infarction, Am. J. Clin. Nutr. 88 (2008) 934–940. [10] D.S. Kelley, P.C. Taylor, G.J. Nelson, B.E. Mackey, Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men, Lipids 33 (1998) 125–130. [11] D.S. Kelley, P.C. Taylor, G.J. Nelson, P.C. Schmidt, B.E. Mackey, D. Kyle, Effects of dietary arachidonic acid on human immune response, Lipids 32 (1997) 449–456. [12] G.J. Nelson, P.C. Schmidt, G. Bartolini, D.S. Kelley, S.D. Phinney, D. Kyle, et al., The effect of dietary arachidonic acid on plasma lipoprotein distributions, apoproteins, blood lipid levels, and tissue fatty acid composition in humans, Lipids 32 (1997) 427–433. [13] G.J. Nelson, P.C. Schmidt, G. Bartolini, D.S. Kelley, D. Kyle, The effect of dietary arachidonic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans, Lipids 32 (1997) 421–425. [14] J. Wang, et al., 5-Lipoxygenase and 5-lipoxygenase-activating protein gene polymorphisms, dietary linoleic acid, and risk for breast cancer, Cancer Epidemiol. Biomarkers Prev. 10 (2008) 2748–2754. [15] E. Sonestedt, U. Ericson, B. Gullberg, et al., Do both heterocyclic amines and omega-6 polyunsaturated fatty acids contribute to the incidence of breast ¨ cancer in post-menopausal women of the Malmo diet and cancer cohort?, Int. J. Cancer 123 (7) (2008) 1637–1643. ´ ` [16] A.C. Thiebaut, V. Chajes, M. Gerber, et al., Dietary intakes of omega-6 and omega-3 polyunsaturated fatty acids and the risk of breast cancer, Int. J. Cancer (2008) published online: 9 September 2008. [17] A.P. Simopoulous, The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases, Exp. Biol. Med. 233 (6) (2008) 674–688.

Evelyn Tribole 1100 Quail Street, Suite 111, Newport Beach, CA 92660, USA E-mail address:


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