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Editorial
Cardiovascular Risk and ␣-Linolenic Acid
Can Costa Rica Clarify?
William S. Harris, PhD
I
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case status and adipose ALA than estimated ALA intake
suggests (not surprisingly) that the biomarker is preferable to
the dietary estimate for defining exposure. On the other hand,
for EPA and DHA, adipose is a poorer biomarker of intake
because the body avidly sequesters these FAs into phospholipid membranes, not triglyceride storage depots. Hence,
erythrocytes (essentially pure phospholipids) are becoming
the standard for assessing long-chain n-3 FA status.5
The fact that, in this study, adipose ALA correlated very
poorly with either adipose EPA or erythrocyte EPA is telling.
It suggests that whatever benefits may be conferred by ALA,
they do not appear to be mediated by the conversion of ALA
to EPA as the current hypothesis holds. Furthermore, the
increased odds for myocardial infarction case status were
independent of EPA and DHA intake. These suggest that
there may be metabolic roles for ALA per se that do not
involve conversion to EPA, but such roles remain to be
demonstrated.
The findings of Campos et al are somewhat at odds with
those of others. In a recent meta-analysis of 6 such studies
(one of which included a subset of this Costa Rican population), no significant difference was found between coronary
heart disease (CHD) cases and controls in adipose ALA.6
However, the present study is, by far, the largest yet reported,
and including it in the meta-analysis would likely have
resulted in an overall significant case-control difference.
In exploring possible mechanisms of action for ALA,
Campos et al3 emphasize the connection with inflammatory
markers and refer primarily to studies in which significant
correlations were observed. Although acknowledging in passing that not all studies support a benefit of ALA on CHD or
an antiinflammatory link, they do not elaborate. But elaboration is instructive. For example, Bemelmans et al7 found no
difference on CHD risk factors between ALA and linoleic
acid, and a systematic review of 14 ALA studies examining
effects on classic CHD risk factors concluded that none
existed.8 A 2002 workshop convened by the Food Standards
Agency in the United Kingdom to evaluate the cardioprotective potential of ALA concluded with the following: “The
studies presented as part of the present workshop suggested
little, if any, benefit of ALA, relative to linoleic acid, on risk
factors for cardiovascular disease; the effects observed with
fish-oil supplementation were not replicated by ALA supplementation.”9 More recently, Nelson et al10 reported that ALA
at 5% energy (⬇5 times the “adequate” intake) reduced
adiponectin levels in humans and did not influence inflammatory markers.11 Finally, a 15-year follow-up of 1551 men
in the Kuopia Heart Study found no relation between dietary
ALA and CHD mortality.12 All of these negative studies do
not mean that ALA has no cardioprotective properties; they
nterest is increasing in the potential cardioprotective role of
␻-3 (n-3) fatty acids (FAs). Most of the evidence supporting this hypothesis has been derived from studies of the
longer-chain members of the n-3 family, eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), found in fish
oils.1 The value of the shorter-chain cousin, ␣-linolenic acid
(ALA), found in certain plant oils (flaxseed, soybean, canola,
walnut) has been less clear.2 If ALA were able to do the same
“heavy lifting” that EPA and DHA do, this would be
welcomed news because the capacity to produce ALA is
essentially limitless, whereas there are only so many fish in
the sea. Campos and colleagues report in this issue of
Circulation the results of a major study conducted in Costa
Rica that provided new evidence that higher ALA intakes are
associated with reduced risk for nonfatal myocardial
infarction.3
Article p 339
Three weeks after surviving a heart attack, 1819 patients
provided an adipose tissue biopsy for analysis of FA stores
and completed a validated food frequency questionnaire. A
similar number of matching controls did the same. The
authors reported a strong inverse association between myocardial infarction case status and ALA tissue levels across the
range of 0.4% to 1% of total adipose tissue FAs, and this
corresponded to intakes between 0.4% and 0.9% of total
energy (or 1 to 2.4 g ALA per day). This is remarkably
similar to the current Acceptable Macronutrient Distribution
Range for ALA set by the Institute of Medicine, which is
itself a reflection of the median intake in the United States.4
Because little difference was found in odds ratios between the
2nd and 10th deciles of intake (ie, all the risk was confined to
the lowest decile) and no difference after the 5th decile for
ALA tissue levels, any benefits ALA might confer seem to be
achieved at quite modest intakes. This brings into question
the need to recommend increased ALA intakes.
The use of adipose tissue ALA as a marker for intake was
validated in this study, with these 2 showing a strong
correlation across the full range of values. Nevertheless, the
more graded relation between odds for myocardial infarction
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Metabolism and Nutrition Research Center, Sanford Research, University of South Dakota, Sioux Falls.
Correspondence to William S. Harris, PhD, Metabolism and Nutrition
Research Center, Sanford Research, University of South Dakota, 1100 E
21st St, Suite 700, Sioux Falls, SD 57105. E-mail [email protected]
(Circulation. 2008;118:323-324.)
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.791467
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July 22, 2008
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simply indicate that definitive demonstration of such has
remained elusive.
Two randomized prospective trials are cited to support the
hypothesis that increased ALA intakes reduce risk for coronary events: the Lyon Diet Heart Study (also known as the
Mediterranean Diet study)13 and a study by Singh et al.14
These, unfortunately, provide a shaky foundation. The former
involved a complete dietary pattern change, not just a change
in ALA, and even though changes in plasma ALA correlated
with benefit, this in no way indicates that the change in ALA
caused the benefit. This could simply be a case of “true, true,
and unrelated,” meaning that a higher ALA intake truly raised
plasma ALA levels, a higher ALA intake was part of the
dietary pattern that improved outcomes, but higher ALA
plasma levels were unrelated mechanistically to the outcomes. The study by Singh et al is more problematic and must
be discounted on the grounds of questionable validity.15 Our
best hope of discovering a true effect of ALA on CHD risk
lies with the Alpha-Omega Study. This study, in which
cardiac mortality is being followed for 40 months in 4800
Dutch heart disease patients randomized to 400 mg of EPA
plus DHA, 2 g of ALA, both, or neither (NCT00139464), will
be the first to prospectively test whether ALA can reduce risk
for clinical end points. This study is expected to be completed
in late 2009.
ALA may yet prove to be a practical substitute for EPA and
DHA, particularly in individuals who will not or cannot
consume the marine n-3 FAs. Although the Campos study is
clearly suggestive, the jury is still out until randomized trials
shed more light on who can do the heavy lifting for whom.
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Disclosures
Dr Harris reports having received research grants from Reliant and
Monsanto, having served on the speakers’ bureau of Reliant (GlaxoSmithKline), and having served on a scientific advisory board for
Monsanto Co and Reliant (GlaxoSmithKline).
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Jordan HS, Lau J. n-3 Fatty acids from fish or fish-oil supplements, but
not ␣-linolenic acid, benefit cardiovascular disease outcomes in primary-
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Harris WS. Alpha-linolenic acid: a gift from the land? Circulation.
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Campos H, Baylin A, Willett WC. ␣-Linolenic acid and risk of nonfatal
acute myocardial infarction. Circulation. 2008;118:339 –345.
Food and Nutrition Board. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino
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Harris WS, Poston WC, Haddock CK. Tissue n-3 and n-6 fatty acids and
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Bom VJ, May JF, Meyboom-de Jong B. Effect of an increased intake of
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KEY WORDS: epidemiology 䡵 fatty acids 䡵 myocardial infarction 䡵 nutrition
Cardiovascular Risk and α-Linolenic Acid: Can Costa Rica Clarify?
William S. Harris
Circulation. 2008;118:323-324; originally published online July 7, 2008;
doi: 10.1161/CIRCULATIONAHA.108.791467
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