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Alpha-Linolenic Acid Reduces Risk of Nonfatal MI CME

News Author: Michael O'Riordan
CME Author: Laurie Barclay, MD

Complete author affiliations and disclosures, and other CME information, are available at the end of this activity.

Release Date: July 11, 2008; Valid for credit through July 11, 2009

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Learning Objectives

Upon completion of this activity, participants will be able to:

Describe the association between alpha–linolenic acid intake and acute myocardial infarction in a Costa Rican case-control study.
Describe the association between linoleic acid intake and blood pressure in the International Study of Macro-Micronutrients and Blood Pressure.

Authors and Disclosures

Michael O'Riordan
Disclosure: Michael O'Riordan has disclosed no relevant financial relationships.

Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

From Heartwire — a professional news service of WebMD

July 11, 2008 — The consumption of a diet containing vegetable oils rich in alpha-linolenic acid (ALA) is associated with significant reductions in the risk of nonfatal myocardial infarction (MI), a new study has shown [1]. Investigators say the protective effect of ALA is evident among individuals with low intakes, suggesting the greatest benefit might be in developing countries, where fatty-acid consumption is limited.

"The potential for benefit is great when the baseline intake is low," said lead investigator Dr Hannia Campos (Harvard Medical School, Boston, MA). "In countries where people eat very little fish — and some of these countries have almost no sources of omega-3 fatty acids because they cook with corn or sunflower oils — the consumption of vegetable oils with ALA could have a major impact on heart disease."

In an editorial accompanying the published study [2], Dr William Harris (University of South Dakota, Sioux Falls) said that the data are suggestive and would be good news for individuals who will not or cannot eat fish, but more studies are still needed. "If ALA were able to do the same 'heavy lifting' that [eicosapentaenoic acid] EPA and [docosahexaenoic acid] 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," he writes.

The results of the study and editorial are published online July 8, 2008 in Circulation.

Benefit is great when the baseline levels are low

ALA is an intermediate-chain n-3 polyunsaturated fatty acid that is often overshadowed by the more famous long-chain members of the n-3 family, namely EPA and DHA acids that are found in fish oils. ALA intake has increased during the past several decades, however, mainly through the consumption of vegetable oils such as soybean, canola, and flaxseed oil. Speaking with heartwire, Campos said some studies have shown that low ALA intake was associated with a risk of coronary heart disease and sudden cardiac death, and others, although not all, have suggested an inverse association between ALA consumption and risk of MI.

In this study, 1819 patients who survived an MI provided samples of adipose tissue for analysis of fatty-acid stores and completed a validated food questionnaire, with 1817 matching controls doing the same. ALA in the adipose tissues ranged from 0.36% in the lowest decile to 1.04% in the highest decile. The corresponding median levels for ALA intake were 1.11 g/day to 2.35 g/day.

In a multivariate model that included smoking, physical activity, history of diabetes, hypertension, fat intake, and waist-to-hip ratio, among others, there was an observed inverse relationship between adipose tissue ALA and dietary ALA intake and risk of nonfatal MI.

Deciles of adipose tissue, ALA intake, and risk of MI

Decile | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10
ALA intake, g/day | 1.11 | 1.25 | 1.38 | 1.38 | 1.52 | 1.62 | 1.79 | 1.83 | 2.08 | 2.35
Median, % ALA in adipose tissue | 0.36 | 0.45 | 0.5 | 0.55 | 0.6 | 0.64 | 0.7 | 0.77 | 0.88 | 1.04
Relative risk of MI (95% CI) | - | 0.94 (0.66 - 1.34) | 0.85 (0.59 - 1.24) | 0.59 (0.40 - 0.87) | 0.52 (0.34 - 0.78) | 0.51 (0.34 - 0.79) | 0.43 (0.30 - 0.67) | 0.45 (0.28 - 0.71) | 0.37 (0.23 - 0.59) | 0.41 (0.25 - 0.67)

"The relationship between ALA and myocardial infarction was nonlinear," said Campos. "We see a dose effect, but only up to about 0.7% of adipose tissue, which corresponds to about 1.8 g/day. Increasing intake further was not associated with increased protection. This is why we hypothesized that if we were to conduct a study in a population already within this range, you're not likely to see an effect."

Campos said modest intakes of ALA appear to convey benefit, with small amounts of flaxseed oil, even just half a teaspoon, or one to two teaspoons of soybean oil, sufficient to increase ALA intake to 1.8 g/day. More commonly, salad dressings using canola or soybean oil would be enough to increase intakes to cardioprotective levels.

Mechanisms at work

In terms of underlying mechanisms, some have speculated that the protective benefit is mediated by converting ALA to EPA, but Campos said the data from this study do not support that hypothesis, as ALA correlated poorly with adipose and erythrocyte EPA. There are data supporting ALA in reducing low-density lipoprotein (LDL)-cholesterol and triglyceride levels, but ALA is thought to reduce the expression of inflammatory markers, although the data at this point are still inconclusive, she said.

In an unrelated study published online July 7, 2008 in Hypertension, Japanese investigators, led by Dr Katsuyuki Miura (Shiga University of Medical Science, Otsu, Japan), observed an independent inverse correlation between dietary linoleic acid and systolic and diastolic blood pressure [3]. Among individuals with higher linoleic acid consumption — in this study, as high as 9 g/day — the effect on systolic and diastolic blood pressure was a reduction of approximately 1.4 mm Hg and 0.9 mm Hg, respectively.

In his editorial, Harris notes that the findings by Campos and colleagues are at odds with other studies, particularly a recent meta-analysis of six studies showing no significant difference between coronary heart disease patients and controls in adipose linoleic acid. The best bet for discovering the true effect of linoleic acid on coronary heart disease risk is the Alpha-Omega Study, a 4800-patient study in which subjects are randomized to 400 mg of EPA plus DHA, 2 g of linoleic acid, both, or neither. The primary end point is cardiac mortality, and results are expected in 2009.

The study by Campos and colleagues was supported by the National Institutes of Health. The study authors have disclosed no relevant financial relationships.

The study by Miura and colleagues is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, and the National Institutes of Health Office on Dietary Supplements (Bethesda, Maryland); the Chicago Health Research Foundation; and by national agencies in China, Japan (the Ministry of Education, Science, Sports, and Culture, Grant-in-Aid for Scientific Research), and the United Kingdom. The study authors have disclosed no relevant financial relationships.

Sources

Campos H, Baylin A, Willett WC. Alpha-linolenic acid and risk of nonfatal acute myocardial infarction. Circulation. 2008;DOI:10.1161/CIRCULATIONAHA.107.762419. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fcirc.ahajournals.org.
Harris WS. Cardiovascular risk and alpha-linolenic acid. Circulation. 2008;DOI: 10.1161/CIRCULATIONAHA.108.791467. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fcirc.ahajournals.org.
Miura K, Stamler J, Nakagawa H, et al. Relationship of dietary linoleic acid to blood pressure. Hypertension. 2008;52:DOI:10.1161/HYPERTENSIONAHA.108.112383. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fhyper.ahajournals.org.

The complete contents of Heartwire, a professional news service of WebMD, can be found at http://www.theheart.org/, a Web site for cardiovascular healthcare professionals.

Learning Objectives for This Educational Activity

Clinical Context

In many countries worldwide, there is low intake of long-chain n-3 fatty acids found in fish, namely EPA and DHA, which have been linked to a lower risk for all-cause mortality, cardiac and sudden death, and stroke. ALA could be a viable cardioprotective alternative to these fatty acids in these countries. The hypothesis of this case-control study conducted in a Costa Rican population by Campos and colleagues was that ALA is associated with lower risk for MI, that the maximal benefit of ALA is obtained within a specific range of intake, and that the association between ALA and MI is independent of fish intake.

Observational and interventional studies of the association of dietary linoleic acid with blood pressure have been inconsistent. The population-based International Study of Macro-Micronutrients and Blood Pressure (INTERMAP) conducted by Miura and colleagues attempted to resolve these inconsistencies by collecting standardized, high-quality data on large samples of diverse populations. The hypothesis of INTERMAP was that dietary linoleic acid intake of individuals is inversely related to their blood pressure.

Study Highlights

Campos and Colleagues

The first study evaluated the association of ALA and the risk for nonfatal acute MI in 1819 participants living in Costa Rica with a first nonfatal acute MI and in 1819 population-based control subjects matched for age, sex, and area of residence.
Fatty acids were evaluated with gas chromatography of adipose tissue samples and with a validated food frequency questionnaire (FFQ) specifically designed for this population.
Multivariate conditional logistic regression models calculated odds ratios (ORs) and 95% confidence intervals (CIs).
In adipose tissue, ALA ranged from 0.36% in the lowest decile (0.42% of energy intake) to 1.04% in the highest decile (0.86% of energy intake).
Whether evaluated in adipose tissue or by FFQ, greater ALA was associated with a lower risk for MI.
For the highest vs the lowest decile, ORs for nonfatal MI were 0.41 (95% CI, 0.25 - 0.67) for ALA in adipose tissue and 0.61 (95% CI, 0.42 - 0.88) for dietary ALA.
There was a nonlinear relationship between ALA and MI in that risk did not decrease further with intakes of more than approximately 0.65% energy (1.79 g/day).
At the levels found in this population, intake of fish, EPA, and DHA did not modify the observed association.
The investigators concluded that intake of vegetable oils rich in ALA could provide important cardiovascular protection and that the apparent protective effect is strongest among subjects with low intakes.
The main limitation of this study is the retrospective case-control design.

Miura and colleagues

INTERMAP is a cross-sectional epidemiologic study in which investigators looked at associations of linoleic acid intake in individuals with their blood pressure.
The study cohort consisted of 4680 men and women, aged 40 to 59 years, from 17 population samples in China, Japan, United Kingdom, and the United States.
For each participant, nutrient intake data were based on 4 in-depth, multipass 24-hour dietary recalls and 2 timed 24-hour urine collections.
At 4 visits, systolic and diastolic blood pressures were measured a total of 8 times per participant.
Several models controlled for possible dietary or other confounders.
For all of the participants, there was a nonsignificant inverse relationship of linoleic acid intake (percent kilocalories) to systolic and diastolic blood pressures according to linear regression analyses.
In a subgroup of 2238 individuals not following a special diet or consuming nutritional supplements, without diagnosed cardiovascular disease or diabetes, and not taking antihypertensive medication, the relationship was stronger.
For this "nonintervened" subgroup, estimated systolic and diastolic blood pressure differences with 2 SD higher linoleic acid intake (3.77% kcal) were –1.42/–0.91 mm Hg (P < .05 for both), after adjustment for 14 variables.
With 2 SD higher intake (4.04% kcal) of total polyunsaturated fatty acid intake, blood pressure differences were –1.42/–0.98 mm Hg (P < .05 for both).
The investigators concluded that dietary linoleic acid intake may help prevent and control adverse blood pressure levels in general populations.
Limitations of this study include cross-sectional design, underestimation of effect size because of limited reliability in nutrient measurement, and limited ability to fully control for higher-order collinearity.

Pearls for Practice

In the case-control study by Campos and colleagues, greater ALA was associated with a lower risk for MI, whether evaluated in adipose tissue or by FFQ. There was a nonlinear relationship between ALA and MI in that the risk did not decrease further with intakes of more than approximately 0.65% energy (1.79 g/day).
In the INTERMAP study conducted by Miura and colleagues, there was a nonsignificant inverse relationship of linoleic acid intake to systolic and diastolic blood pressures. In a subgroup of individuals not following a special diet or consuming nutritional supplements, without diagnosed cardiovascular disease or diabetes, and not taking antihypertensive medication, the relationship was stronger.

According to the Costa Rican case-control study by Campos and colleagues, which of the following statements about the association of ALA with the risk for MI is not correct?
| Greater ALA in adipose tissue or by FFQ was associated with a lower risk for MI
| The apparent cardiovascular protective effect is strongest among subjects with low ALA intakes
| The relationship between ALA and MI was linear
| Intake of fish, EPA, and DHA did not modify the observed association

According to the INTERMAP study conducted by Miura and colleagues, which of the following statements about the relationship of linoleic acid intake to blood pressure is correct?
| For all of the participants, linoleic acid intake was significantly inversely related to systolic blood pressure
| For all of the participants, linoleic acid intake was significantly inversely related to diastolic blood pressure
| For the "nonintervened" subgroup, estimated systolic/diastolic blood pressure differences with 2 SD higher linoleic acid intake were –1.42/–0.91 mm Hg after adjustment
| The investigators concluded that dietary linoleic acid intake does not affect blood pressure

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News Author

Michael O'Riordan
is a journalist theheart.org, part of the WebMD Professional Network. Previously, he worked for WebMD Canada. Michael studied at Queen's University in Kingston and the University of Toronto and has a master's degree in journalism from the University of British Columbia, where he specialized in medical reporting. He can be contacted at [email-masked].

Disclosure: Michael O'Riordan has disclosed no relevant financial relationships.

CME Author

Laurie Barclay, MD
is a freelance reviewer and writer for Medscape.

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Brande Nicole Martin
is the News CME editor for Medscape Medical News.

Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

Medscape Medical News 2008. ©2008 Medscape

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