ARTICLE IN PRESS
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 alpha-
linolenic 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 interven-
tions) 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 meta-
analysis, 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
doi:10.1016/j.plefa.2008.12.003
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).
[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 a-
linolenic acid-rich vegetable oil increases eicosapentaenoic acid concentra-
tions 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: harrisw@sanfordhealth.org
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
 ARTICLE IN PRESS
Letters to the Editor / Prostaglandins, Leukotrienes and Essential Fatty Acids 80 (2009) 77–79
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 polyunsatu-
rated 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.
doi:10.1016/j.plefa.2008.12.004
79
[5] L. Ferrucci, A. Cherubini, S. Bandinelli, B. Bartali, A. Corsi, F. Lauretani, et al.,
Relationship of plasma polyunsaturated fatty acids to circulating inflamma-
tory 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 supplemen-
tation 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 Malmö diet and cancer cohort?, Int.
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.
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: etribole@gmail.com