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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 [10]. The relevant question in this context, however, is whether an
the reduction in cardiovascular disease (CVD) events in this study LA-induced diminution of the omega-3 index increases risk for CVD
is virtually always attributed to the increased intake in alpha- or not; the other evidence cited in the review suggest that it may
linolenic acid, not the reduced intake of linoleic acid. It is unclear not. CVD is a multifactorial disease, and changes in one risk factor
why confounding in Lyon is acceptable but confounding in Oslo is may be offset by corresponding changes in others. The best way to
not. The Sydney Heart Study [1] was excluded because it did not raise the omega-3 index is by eating more EPA and DHA, not by
report cardiovascular disease endpoints, only total mortality. eating less LA. The former has been shown to reduce risk for CVD
Ramsden et al are correct that Rose et al., [2] should have been whereas the latter has not.
included in the meta-analysis. In this 2-year study, 54 heart
patients were instructed to reduce animal fats and to substitute References
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 [1] J.M. Woodhill, A.J. Palmer, B. Leelarthaepin, et al., Low fat, low cholesterol diet
coronary events occurred in 43%, 48% and 25% of each group, in secondary prevention of coronary heart disease, Adv. Exp. Med. Biol. 109
(1978) 317–330.
respectively. A chi-square test of these proportions gives a p ¼ 0.31,
[2] G.A. Rose, W.B. Thomson, R.T. Williams, Corn oil in the treatment of ischemic
and the most relevant comparison (between the two oil interven- heart disease, Br. Med. J. 1 (1965) 1531–1533.
tions) found no difference at all. Hence this study did not show [3] M. de Lorgeril, P. Salen, J.L. Martin, et al., Mediterranean diet, traditional risk
increased CV events associated with LA intake as Ramsden et al. factors, and the rate of cardiovascular complications after myocardial
infarction: final report of the Lyon Diet Heart Study, Circulation 99 (1999)
indicate. Although Rose should have been included in the meta- 779–785.
analysis, it would not have altered the outcome because of both its [4] P. Leren, The effect of plasma cholesterol lowering diet in male survivors of
lack of effect and its small sample size. In 1995, Gordon [5] myocardial infarction. A controlled clinical trial, Acta Med. Scand. Suppl. 466
(1966) 1–92.
published a similar meta-analysis and reached the same conclusion: [5] D.J. Gordon, Lowering cholesterol and total mortality, in: B.M. Rifkin (Ed.),
higher PUFA, lower saturated fat diets reduce CV events. Lowering Cholesterol in High-Risk Individuals and Populations, Marcel
The second issue raised by Ramsden et al. is that diets higher in 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.
LA lower the omega-3 index, an emerging erythrocyte-based marker J. Clin. Nutr. 87 (2008) 1997S–2002S.
of CV risk [6]. Oddly, none of the three studies they [7] S. Ghosh, E.M. Novak, S.M. Innis, Cardiac proinflammatory pathways are
refer to reported effects on the omega-3 index. Two were 30-day 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)
studies in pigs examining the effects of varying LA:ALA ratios H2919–H2927.
on cardiac [7] and brain [8] phospholipid fatty acid composition. [8] E.M. Novak, R.A. Dyer, S.M. Innis, High dietary omega-6 fatty acids
Neither assessed any CVD endpoint. The only human study contribute to reduced docosahexaenoic acid in the developing
brain and inhibit secondary neurite growth, Brain Res. 1237 (2008) 136–145.
cited [9] examined the effects of 2,4-week treatment periods on
[9] Y.A. Liou, D.J. King, D. Zibrik, et al., Decreasing linoleic acid with
plasma phospholipid fatty acid composition after recommending constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic
diets high (10% en) or low (3.8% en) in LA to healthy volunteers. If acid in plasma phospholipids in healthy men, J. Nutr. 137 (2007) 945–952.
one uses the plasma phospholipid EPA+DHA content as a surrogate [10] E. Mantzioris, M.J. James, R.A. Gibson, et al., Dietary substitution with an a-
linolenic acid-rich vegetable oil increases eicosapentaenoic acid concentra-
of the omega-3 index, concerns about the study design emerge. tions in tissues, Am. J. Clin. Nutr. 59 (1994) 1304–1309.
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 William S. Harris
ratios and EPA+DHA washout), the effects of the former alone are Sanford Research/USD, 1100 East 21st St, Suite 700, Sioux Falls,
difficult to interpret. Nevertheless, others have reported that higher SD 57105, USA
LA:ALA ratios do modestly lower membrane EPA and DHA levels E-mail address:


What happened to do no harm? The issue of dietary omega-6 Linoleic acid and coronary heart disease by William S. Harris
fatty acids (pp. 169–171).
Too much linoleic acid promotes inflammation—doesn’t it? by
In 1999, scientists from around the globe gathered to address Kevin L. Fritsche (173–175).
dietary recommendations for omega-3 and omega-6 fatty acids [1].
Their recommendation emphasized the importance of reducing Comments by: Evelyn Tribole—1100 Quail Street, Suite 111,
omega-6 fatty acids in order to reduce adverse health effects of Newport Beach, CA 92660, USA.
excesses of arachidonic acid (AA) and its eicosanoid products. Fritsche [2] describes the CHIANTI study by Ferrucci et al. [5],
Therefore, they set an upper limit for linoleic acid (LA), to no more as an example of no adverse impact on inflammation from eating
than 6.67 g/day, based on a 2000 kcal diet of 3.0% of energy. Yet, based too much LA. Subjects with the highest quartile of plasma
on the current series of papers published on LA [2–4], one might be arachidonic acid levels had lower pro-inflammatory markers and
led to believe there has been a substantial body of evidence to refute higher anti-inflammatory markers. But an important detail from
the recommendation, which is not the case. The research cited is this study is ignored—the subjects from this Mediterranean
taken out of context and/or is based on very small studies, many of region eat a low LA diet, averaging 7 g/day. In this context, it is
which were published over a decade ago, as described below. not surprising that plasma AA was associated with beneficial
inflammation biomarkers—because it does so in the presence of
Comments on three papers published in PLEFA September 2008 eating a balanced proportion of omega-6 and omega-3 fatty acids.
(vol. 79, issue 3) The results of this study support the benefits of eating a lower LA
The health implications of changing linoleic acid intakes by Jay Harris [3] concludes that, ‘‘Reducing LA intakes to less than 5%
Whelan (pp. 165–167). 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 [5] L. Ferrucci, A. Cherubini, S. Bandinelli, B. Bartali, A. Corsi, F. Lauretani, et al.,
Heart Study [6] put their subjects on a low omega-6 fat diet, with Relationship of plasma polyunsaturated fatty acids to circulating inflamma-
tory markers, J. Clin. Endocrinol. Metab. 91 (2006) 439–446.
a maximum 7 g (4.6% calories), which resulted in a striking [6] M. de Lorgeril, P. Salen, J.-L. Martin, I. Monjaud, J. Delaye, N. Mamelle,
reduction in all-cause mortality, including sudden cardiac death Mediterranean diet, traditional risk factors, and the rate of cardiovascular
and cancer. Notably, studies have demonstrated harm from eating complications after myocardial infarction: final report of The Lyon Diet Heart
Study, Circulation 99 (1999) 779–785.
high LA diets on cardiovascular health [7–9]. [7] J.H. Dwyer, H. Allayee, K.M. Dwyer, et al., Arachidonate 5-lipoxygenase
Whelan [4] states that a number of studies fail to link promoter genotype, dietary arachidonic acid, and atherosclerosis, N. Engl. J.
enrichment of AA in tissues with deleterious outcomes. Yet four Med. 350 (2004) 29–37.
[8] C.Q. Lai, D. Corella, S. Demissie, et al., Dietary intake of n-6 fatty acids
out of five of these studies [10–13] were performed on only 10 modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides,
healthy men! He also says that there is no adverse effect from remnant lipoprotein concentrations, and lipoprotein particle size: The
eating dietary LA intake on breast cancer. Large studies from the Framingham Heart Study, Circulation 113 (2006) 2062–2070.
[9] H. Allayee, A. Baylin, J. Hartiala, et al., Nutrigenetic association of the
USA, France and Sweden indicate otherwise [14–16]. For example,
5-lipoxygenase gene with myocardial infarction, Am. J. Clin. Nutr. 88 (2008)
in a case-control study on nearly 1700 women [14], researchers 934–940.
demonstrated that women with a genotype influencing the LOX [10] D.S. Kelley, P.C. Taylor, G.J. Nelson, B.E. Mackey, Arachidonic acid supplemen-
enzyme, had a two-fold increase in breast cancer risk if they ate tation enhances synthesis of eicosanoids without suppressing immune
functions in young healthy men, Lipids 33 (1998) 125–130.
high levels of LA (417.4 g/day). Yet, this genotype had no [11] D.S. Kelley, P.C. Taylor, G.J. Nelson, P.C. Schmidt, B.E. Mackey, D. Kyle, Effects of
influence on breast cancer risk, if these women ate a lower LA diet. dietary arachidonic acid on human immune response, Lipids 32 (1997)
Conclusion: At best, these papers [2–4] serve as editorials 449–456.
[12] G.J. Nelson, P.C. Schmidt, G. Bartolini, D.S. Kelley, S.D. Phinney, D. Kyle, et al.,
reflecting opinions of individual scientists. And at worst, these The effect of dietary arachidonic acid on plasma lipoprotein distributions,
papers are disservice to the scientific process and public health, as apoproteins, blood lipid levels, and tissue fatty acid composition in humans,
they have been published without counterpoint or a serious review Lipids 32 (1997) 427–433.
[13] G.J. Nelson, P.C. Schmidt, G. Bartolini, D.S. Kelley, D. Kyle, The effect of dietary
of the literature. The issue of an optimal level of dietary omega-6 fats arachidonic acid on platelet function, platelet fatty acid composition, and
is far from settled. But a plethora of papers published in the last blood coagulation in humans, Lipids 32 (1997) 421–425.
decade [17] merit a serious discussion on the public health issue of [14] J. Wang, et al., 5-Lipoxygenase and 5-lipoxygenase-activating protein gene
polymorphisms, dietary linoleic acid, and risk for breast cancer, Cancer
dietary omega-6 fats; the most commonly consumed polyunsatu- Epidemiol. Biomarkers Prev. 10 (2008) 2748–2754.
rated fat in industrialized countries. [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 Malmö diet and cancer cohort?, Int.
References J. Cancer 123 (7) (2008) 1637–1643.
[16] A.C. Thiébaut, V. Chajès, M. Gerber, et al., Dietary intakes of omega-6 and
omega-3 polyunsaturated fatty acids and the risk of breast cancer, Int. J.
[1] A.P. Simopoulos, A. Leaf, N. Salem, Workshop statement on the essentiality of Cancer (2008) published online: 9 September 2008.
and recommended dietary intake for omega-6 and omega-3 fatty acids, [17] A.P. Simopoulous, The importance of the omega-6/omega-3 fatty acid ratio in
Prostaglandins Leukot. Essent. Fatty Acids 63 (2000) 119–121. cardiovascular disease and other chronic diseases, Exp. Biol. Med. 233 (6)
[2] K.L. Fritsche, Too much linoleic acid promotes inflammation—doesn’t it?, (2008) 674–688.
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.
Evelyn Tribole
[4] J. Whelan, The health implications of changing linoleic acid intakes, 1100 Quail Street, Suite 111, Newport Beach, CA 92660, USA
Prostaglandins Leukot. Essent. Fatty Acids 79 (2008) 165–167. E-mail address: