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. Author manuscript; available in PMC: 2009 Sep 11.
Published in final edited form as: Circulation. 2008 Jul 7;118(4):339–345. doi: 10.1161/CIRCULATIONAHA.107.762419

α-Linolenic acid and risk of nonfatal acute myocardial infarction

Campos: α-Linolenic acid myocardial infarction

Hannia Campos 1, Ana Baylin 1, Walter C Willett 1
PMCID: PMC2742488  NIHMSID: NIHMS126251  PMID: 18606916

Abstract

Background

Intake of long chain n-3 fatty acids found in fish is low in many countries worldwide. α-Linolenic acid could be a viable cardioprotective alternative to these fatty acids in these countries.

Methods and results

Cases (n=1,819) with a first non-fatal acute myocardial infarction (MI) and population-based controls (n=1,819) living in Costa Rica, matched for age, sex and area of residence were studied. Fatty acids were assessed by gas chromatography in adipose tissue samples and by a validated food frequency questionnaire specifically designed for this population. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from multivariate conditional logistic regression models. α-Linolenic acid in adipose tissue ranged from 0.36% in the lowest decile to 1.04% in the highest decile. The corresponding median levels of intake were 0.42 and 0.86% energy. Greater α-linolenic acid (assessed either in adipose or by questionnaire) was associated with lower risk of MI. The ORs (95% CI) for nonfatal MI for the highest compared to the lowest deciles were 0.41 (0.25-0.67) for α-linolenic acid in adipose tissue and 0.61 (0.42-0.88) for dietary α-linolenic acid. The relationship between α-linolenic acid and MI was non-linear, where risk did not decrease with intakes greater than approximately 0.65% energy (1.79 g/d). Fish or EPA+DHA intake at the levels found in this population did not modify the observed association.

Conclusion

Consumption of vegetable oils rich in α-linolenic acid could confer important cardiovascular protection. The apparent protective effect of α-linolenic acid is most evident among subjects with low intakes.

Keywords: fatty acids, heart disease, adipose tissue, α-linolenic acid, diet

Numerous clinical and epidemiological studies show that greater intake of long-chain n-3 fatty acids from fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce all-cause mortality, cardiac and sudden death, and stroke (1). However, the availability of fish and other marine products that are the main sources of long-chain fatty acids is limited, and it has been questioned whether there are sufficient resources to provide these fatty acids in the amounts needed worldwide (2).

α-Linolenic acid, an essential n-3 fatty acid found in cooking vegetable oils, such as soybean and canola oils, and other products of plant origin, has been suggested as a viable alternative to fish oils, but data to support this initiative are scarce (3). In cohort studies, low α-linolenic acid intake has been associated with risk of fatal coronary heart disease (CHD) (4, 5) and sudden cardiac death (6). Some studies (7, 8), but not all (4, 6), suggest a strong inverse association between α-linolenic intake and non fatal acute myocardial infarction (MI). A clinical trial (9) reported a protective effect of a Mediterranean diet high in α-linolenic acid against cardiovascular mortality and the risk of recurrent MI, but this trial was not designed to specifically test the effects of α-linolenic acid.

CHD is generally high in countries where the estimated intake of EPA and DHA is extremely low (long chain n-3 fatty acid intake ≤ 0.07 % energy) (10). Because of price, availability, or cultural preference, many of these countries have little or no possibility of increasing fish intake (11). European countries with extremely low EPA and DHA intakes such as Bulgaria and Romania (10) can also have low intakes of α-linolenic acid from vegetable oils because they almost exclusively use sunflower oil that does not contain α-linolenic acid (12). Similarly, low intakes of α-linolenic acid can be found in developing countries where cardiovascular disease is on the rise (13) because they almost exclusively consume palm oil, another vegetable oil that lacks α-linolenic acid (14). Because of the large number of people living in these countries, the potentially protective effects of α-linolenic acid from vegetable oils need to be studied more extensively. Since the early 1980's, Costa Rica has experienced a decrease in the intake of palm oil and an increase the intake of soybean oil (14, 15). This transition has led to increased intake of α-linolenic acid in the population. In a previous analysis, our data suggested that α-linolenic acid in adipose tissue is associated with decreased risk of MI in the Costa Rican population (7). The proposed study expands this previous observation to test the hypothesis that 1) α-linolenic acid (both assessed by questionnaire and in adipose tissue) is associated with reduced risk of MI in a larger population, 2) the maximum benefit of α-linolenic acid is obtained within a specific range of intake, and 3) the association between α-linolenic acid and MI is independent of fish intake.

Methods

Study population

The catchment area for this study included thirty four counties in the Central Valley of Costa Rica that covered a full range of socioeconomic levels, as well as urban, peri-urban, and rural lifestyles. Eligible case subjects were adult residents who were diagnosed as survivors of a first acute MI by two independent cardiologists at any of the six recruiting hospitals in the catchment area between 1994 and 2004. All cases met the World Health Organization criteria for MI, which require typical symptoms plus either elevations in cardiac enzyme levels or diagnostic changes in the electrocardiogram. One free-living control subject for each case, matched for age (± 5 years), sex, and area of residence (county), was randomly selected using the information available at the National Census and Statistics Bureau of Costa Rica. Because of the comprehensive social services provided in Costa Rica, all persons living in the catchment area had access to medical care without regard to income. Therefore, control subjects came from the source population that gave rise to the cases, and are not likely to have been having cardiovascular disease that was not diagnosed because of poor access to medical care. Participation was 98% for cases and 88% for controls. The methods for this study have been previously published (14). All subjects gave informed consent on documents approved by the Human Subjects Committee of the Harvard School of Public Health and the University of Costa Rica.

Data collection

All study participants (n=1,817 case-control pairs) were visited at their homes, where data on socio-demographic characteristics, smoking, socioeconomic status, medical history, anthropometric measurements and biological samples were collected. Data and sample collection took place, on average, three weeks after hospital discharge. Dietary intake was assessed using a 135-item food frequency questionnaire (FFQ) that has been developed and validated specifically to assess fatty acid intake among the Costa Rican population (16, 17). All foods commonly consumed in Costa Rica were analyzed for their content of fatty acids, including α-linolenic acid, and data were incorporated into the nutrient database for analysis. The Costa Rican staple includes rice, beans, bread, and plantains, with a small side dish consisting of egg, meat, or cheese, and a chopped vegetable like squash. Salads usually consist of cabbage and tomato and meals area accompanied of sweetened beverages and coffee. Traditional cooking methods use vegetable oils or hard palm shortening to prepare rice and beans and to fry the side dishes. Physical activity was determined by asking subjects the average frequency and time spent on several occupational and leisure time activities during the last year as previously described (18). These activities were grouped into six categories according to their intensity, or MET (metabolic equivalent task). One MET is defined as the energy expenditure for sitting quietly or approximately 1 kcal per kg-1 body weight per hr-1. A subcutaneous adipose tissue biopsy was collected from the upper buttock with a 16-gauge needle and disposable syringe following procedures previously described (17). This simple procedure was carried out by numbing the area with ice and without the use of local anesthesia Samples were stored at −80°C and within 6 months they were transported over dry ice to the Harvard School of Public Health for analysis.

Fatty acid analysis

Fatty acids were quantified by gas-liquid chromatography as described previously (17). Peak retention times and area percentages of total fatty acids were identified by injecting known standards (NuCheck Prep, Elysium, MN), and analyzed with the Agilent Technologies ChemStation A.08.03 software. The between-run coefficient of variation was 8.5% for α-linolenic acid. Fatty acids in subcutaneous adipose tissue are known to reflect long-term intake (19) and in case-control studies are preferred over other biomarkers of fatty acid intake (20). In the Costa Rican population adipose tissue α-linolenic acid was an excellent biomarker of intake (16, 17).

Statistical analysis

All data were analyzed with the Statistical Analysis Systems software (SAS Institute Inc., Cary, NC). The significance of differences in crude means and frequencies for health characteristics and potential confounders were assessed by paired t-tests and the McNemar's test. Odds ratios (OR) and 95% confidence intervals (CI) for deciles for adipose tissue or calorie-adjusted α-linolenic acid intake were estimated from multiple conditional logistic regression models. In subgroup analysis OR and 95% CI were calculated by tertiles of fish intake (g/d) or EPA+DHA (g/d). Confounders included in the final models were smoking status (never, past, <10 cigarettes/day, 10-20 cigarettes/day, >20 cigarettes/day), physical activity (quintiles), household income (quintiles), history of diabetes (yes/no), history of hypertension (yes/no), waist-to-hip ratio (quintiles), calorie-adjusted saturated fat intake (quintiles), and linoleic acid (quintiles), and trans fatty acids (quintiles) in adipose tissue. Other potential confounders examined but not included in the final models were body mass index, intake of vitamin E, folate, fiber, total energy, alcohol intake and dietary or adipose γ-linolenic acid, arachidonic acid, EPA and DHA. The authors had full access and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Results

Table 1 shows the basic characteristics of the population. The nutrient composition (% energy) was 32% total fat, 55% carbohydrate, and 13% protein. The saturated, monounsaturated and polyunsaturated content of the diet was 10%, 12% and 6%. Rice, beans, sweet beverages, plantain, beef, eggs, milk, bananas, palm shortening and soybean oil were the major energy contributors. α-Linolenic acid intake and in adipose tissue was significantly lower in cases than controls (p<0.001). Fish intake was similar in cases and controls and the variation within each group was large. The most widely consumed fish by both cases and controls was marine tropical white fish (∼70%), followed by canned tuna. Other fish and seafood contributed less than 0.5%. The distribution of potential confounders by each decile of adipose tissue α-linolenic acid is shown in Table 2. α-Linolenic acid in adipose tissue ranged from 0.36% in the lowest decile to 1.04% in the highest decile. Corresponding median levels for α-linolenic acid intake were 1.11 and 2.35 g/d, and 0.42 and 0.86 as a percent of calories. There was a positive trend between adipose tissue α-linolenic acid and physical activity and intake of fiber, trans fat, and linoleic acid as well as with trans fat, linoleic acid and EPA in adipose tissue. An inverse trend was observed between adipose tissue α-linolenic acid and intake of saturated and monounsaturated fat and DHA in adipose tissue. Those with history of hypertension or diabetes were less likely to be in the highest deciles of adipose tissue α-linolenic acid compared to the lowest. Subjects in the lowest decile of ALA had the lowest intake of fish.

Table 1.

General characteristics of the study population

Controls Cases
Mean SD Mean SD
n=1,819 n=1,819
Matching variables
Age, y 58 ± 11 58 ± 11
Women, % 27 27
Area of residence, % rural 26 26
General characteristics
Body mass index, kg/cm2 26.4 ± 4.3 25.9 ± 4.0
Waist-to-hip ratio 0.95 ± 0.07 0.97 ± 0.07
Physical activity, METs/d 1.55 ± 0.65 1.50 ± 0.67
Monthly household income, US$ 580 ± 425 506 ± 393
History of diabetes, % 15 24
History of hypertension, % 30 39
Current smokers, % ≥ 1 cig/d 21 40
Current drinkers, % 40 37
Total fat, % energy 31.8 ± 5.8 32.4 ± 5.9
Saturated fat, % energy 10.4 ± 2.7 11.1 ± 2.9
Monounsaturated fat, % energy 11.8 ± 3.8 11.9 ± 3.5
Polyunsaturated fat, % energy 6.2 ± 2.0 6.0 ± 2.0
Trans fat, % energy 1.42 ± 0.7 1.45 ± 0.7
Carbohydrates, % energy 55.4 ± 7.3 54.3 ± 7.6
Protein, % energy 13.0 ± 2.1 13.2 ± 2.2
Cholesterol, mg/1000 kcal 118 ± 53 126 ± 58
Fiber, g/1000 kcal 10.0 ± 2.5 9.5 ± 2.4
Fish, g/d* 17.3 ± 15.5 18.3 ± 18.3
α-Linolenic acid
 Intake, g/d* 1.63 ± 0.63 1.57 ± 0.63
 Intake, % energy 0.60 ± 0.23 0.58 ± 0.23
 Intake, % total fat 1.93 ± 0.77 1.82 ± 0.75
 Adipose, % total fat 0.65 ± 0.21 0.62 ± 0.21
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METs, metabolic equivalent tasks, EPA, eicosapentaenoic acid, and DHA docosahexaenoic acid.

*

Adjusted for total energy by using the residual method.

All variables except trans fat and fish are significantly different between cases and controls p<0.05

Table 2.

Population characteristics by deciles of adipose tissue α-linolenic acid among controls

Deciles of adipose tissue α-linolenic acid
1 2 3 4 5 6 7 8 9 10 P
Median, % total fatty acids 0.36 0.45 0.5 0.55 0.6 0.64 0.7 0.77 0.88 1.04 for tend
α-Linolenic acid intake g/d* 1.11 1.25 1.38 1.38 1.52 1.62 1.79 1.83 2.08 2.35 <0.0001
α-Linolenic acid intake, % energy 0.42 0.46 0.51 0.51 0.57 0.6 0.65 0.67 0.76 0.86 <0.0001
Waist-to-hip ratio 0.95 0.94 0.96 0.96 0.95 0.94 0.95 0.95 0.95 0.95 0.36
Physical activity, METs/d 1.49 1.54 1.52 1.49 1.46 1.45 1.58 1.65 1.61 1.71 <0.0001
Monthly household income, US$ 428 510 581 619 676 640 625 599 526 517 0.26
Current smokers, % ≥ 1 cig/d 29 25 17 18 23 16 20 21 25 15 0.21
Current drinkers, % 39 42 43 40 45 41 46 41 38 32 0.56
History of diabetes, % 22 13 17 12 17 14 15 12 12 14 0.003
History of hypertension, % 38 32 31 28 31 27 27 30 33 25 0.01
Daily dietary intake
Energy, kcal per day 2,430 2,425 2,428 2,431 2,490 2,450 2,497 2,437 2,438 2,492 0.62
Saturated fat, % energy 12 11 11 11 11 10 10 9 10 9 <0.0001
Monounsaturated fat, % energy 12 12 12 12 12 12 12 11 11 11 0.002
Linoleic acid, % energy 5 5 6 6 7 7 7 7 7 7 <0.0001
Trans fat, % energy 1.2 1.39 1.44 1.34 1.41 1.46 1.49 1.45 1.55 1.49 0.0003
EPA, % energy 0.04 0.04 0.04 0.05 0.04 0.05 0.05 0.04 0.04 0.05 0.11
DHA, % energy 0.06 0.07 0.07 0.08 0.07 0.08 0.08 0.07 0.08 0.07 0.16
Cholesterol, mg/1000 kcal 127 124 122 120 111 116 116 109 123 118 0.04
Fiber, g/1000 kcal 9 10 10 10 10 10 10 10 10 11 <0.0001
Fish, g* 14 16 16 19 17 18 19 17 18 18 0.03
Adipose tissue % total fatty acids
 EPA 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 <0.0001
 DHA 0.15 0.15 0.14 0.15 0.15 0.15 0.14 0.14 0.14 0.14 0.005
 Linoleic 10 12 14 14 15 16 17 18 18 21 <0.0001
 Trans 2.15 2.42 2.6 2.55 2.67 2.69 2.7 2.72 2.72 2.75 <0.0001
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METs, metabolic equivalent tasks, EPA, eicosapentaenoic acid, and DHA docosahexaenoic acid.

*

Adjusted for total energy by using the residual method. N=1,819

Values are means except where the prevalence is indicated as %.

An inverse relationship was observed between adipose tissue α-linolenic acid and the risk of nonfatal acute MI, in a multivariate model that included smoking, physical activity, household income, history of diabetes, history of hypertension, waist-to-hip ratio, saturated fat intake, and linoleic and trans fatty acids in adipose tissue (Figure 1A). Compared to the lowest decile of adipose tissue α-linolenic acid, the ORs (95% CI) for MI for the second to the tenth deciles were: 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), and 0.41 (0.25-0.67). Similar results were obtained between dietary α -linolenic acid and the risk of nonfatal acute MI (Figure 1B). Compared to the lowest decile of dietary α -linolenic acid intake, the ORs (95% CI) for MI for the second to the tenth deciles were: 0.74 (0.53-1.04), 0.67 (0.48-0.94), 0.69 (0.49-0.98), 0.64 (0.45-0.91), 0.73 (0.51-1.05), 0.71 (0.50-1.02), 0.74 (0.51-1.06), 0.63 (0.44-0.91), and 0.61 (0.42-0.88). These associations were very similar to those observed in models that just included the matching variables age, gender, and area of residence. The inverse association between α-linolenic acid and the risk of nonfatal acute MI was non-linear regardless of whether the analyses were conducted using α-linolenic acid assessed in adipose tissue or by FFQ. For adipose tissue α-linolenic acid, no further reductions in risk were obtained beyond the seventh decile. Larger confidence intervals were obtained with dietary questionnaires compared to adipose tissue, indicating higher measurement error when diet is assessed by questionnaire.

Figure 1.

Figure 1

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Graphs show the odds ratios and 95% confidence intervals for MI by deciles of α–linolenic acid in adipose tissue (A) or intake (B), adjusted for smoking status, physical activity, household income, history of diabetes, history of hypertension, waist-to-hip ratio, saturated fat intake, and linoleic and trans fatty acids in adipose tissue.

Figure 2 shows the correlation between adipose tissue and dietary α-linolenic acid. The median intake of α-linolenic acid in the seventh decile of α-linolenic acid in adipose tissue was 1.79 g/d or 0.65% energy. The correlations between dietary α-linolenic acid and adipose EPA, DPA, and DHA were r=0.05, -0.06 and -0.11, respectively. We also examined the correlation between dietary α-linolenic acid and EPA, DPA and DHA in plasma or erythrocytes in a subset of 200 study participants. The correlations were r=0.16, r=0.20, and r=-0.03, respectively for plasma and r=-0.08, r=0.03, and r=-0.09, respectively for erythrocytes.

Figure 2.

Figure 2

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Graph shows median levels and 95% confidence intervals for dietary α–linolenic acid by deciles of α–linolenic in adipose tissue. Line denotes the level at which no further association between α–linolenic and risk of MI was observed in Figure 1.

It has been shown that the association between α-linolenic acid and risk of MI is most evident among those consuming low levels of fish (EPA+DHA < 100 mg/d) (21). We examined this hypothesis by evaluating the association between adipose tissue α-linolenic acid by tertiles of fish intake or dietary EPA+DHA. Table 3 (top panel) shows the association between α-linolenic acid in adipose tissue and MI by tertiles of fish intake. The highest tertile of α-linolenic acid in adipose tissue was associated with a 50% lower risk among those with the lowest fish intake (median = 3.3 gr/d), a 52% lower risk among those in the mid tertile of fish intake (median = 13.4 gr/d), and with a 55% lower risk among those with the highest fish intake (32.4 gr/d). The association between α-linolenic acid in adipose tissue and risk of MI by tertiles or dietary EPA+DHA is shown in the bottom panel. The highest tertile of α-linolenic acid in adipose tissue was associated with a 49% lower risk among those with the lowest intake of EPA+DHA (0.13 gr/d), a 44% lower risk among those in the mid tertile of EPA+DHA intake (0.24 gr/d), and with a 58% lower risk among those with the highest intake of EPA+DHA (0.52 gr/d).

Table 3.

Multivariate odds ratio and 95% confidence intervals for risk of MI by tertiles of adipose tissue α--linolenic acid, fish intake, and dietary EPA+DHA

Tertiles of adipose tissue α-linolenic acid
(Median, % total fatty acids)
Fish intake median grams per day 1
(0.44)		 2
(0.61)		 3
(0.83)
3.3 1.00 ref. 0.68 (0.48, 0.97) 0.50 (0.34, 0.74)
13.4 1.00 ref. 0.62 (0.44, 0.88) 0.52 (0.35, 0.77)
32.4 1.00 ref. 0.65 (0.46, 0.93) 0.55 (0.37, 0.80)
EPA+DHA intake median grams per day
0.13 1.00 ref. 0.66 (0.46, 0.94) 0.49 (0.34, 0.73)
0.24 1.00 ref. 0.51 (0.36, 0.72) 0.44 (0.29, 0.65)
0.52 1.00 ref. 0.73 (0.51, 1.03) 0.58 (0.39, 0.85)
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Model included smoking, waist-to-hip ratio, income, history of diabetes, history of hypertension, intake of saturated fat, physical activity, and adipose tissue trans and linoleic acid. N= 3,668

Discussion

We conducted a case-control study to assess the relationship between adipose tissue α-linolenic and the risk of nonfatal acute MI in Costa Rica. We found that both dietary and adipose levels of α-linolenic acid were associated with a large and significant reduction in the risk of nonfatal acute MI. The relationship between α-linolenic acid and MI was non-linear, where risk did not decreased with intakes greater than approximately 0.65% energy (1.79 g/d). These results suggest that increasing intake of vegetable oils rich in α-linolenic acid could reduce risk of MI. Our data are consistent with a clinical trial (9) reporting a protective effect of a Mediterranean diet rich in α-linolenic acid against the risk of MI. Although this trial was not specifically designed to test the effects of α-linolenic acid, investigators found that when measuring plasma fatty acids two months after randomization, plasma α-linolenic acid was significantly and independently associated with improved prognosis (9). A study in India found that the use of mustard oil, which is rich in α-linolenic acid, was associated with lower MI risk when compared to sunflower oil (8). The ORs for MI were 0.49 when mustard oil was used for cooking and 0.29 when it was used for frying. This apparent protective effect is consistent with the present study. The ORs for MI comparing the seventh to the first deciles were 0.43 for adipose tissue and 0.71 for dietary intake. However, other studies have found that while increased α-linolenic acid intake was associated lower risk of fatal ischemic heart disease and sudden cardiac death it was not associated with MI (4, 6).

Our data indicate that α-linolenic acid is associated with decreased MI risk at low intake levels, and that the amount of α-linolenic acid associated with maximum benefit is small. The difference in intake of α-linolenic acid between the lowest and 7th quintiles was 0.68 g/d. Soybean and canola oil, which are good plant sources of α-linolenic acid contain ∼6-8% α-linolenic acid. This suggests that the amount of α-linolenic acid contained in about two teaspoons of these oils, taken daily, could be enough to reduce risk of non-fatal acute MI when the baseline level of intake is low. This level of intake can also be easily achieved with intake of flaxseed oil (∼1-2 mls) or walnuts (∼6 to 10 halves).

The association between α-linolenic acid and MI observed in this study could be due to potential anti-inflammatory properties of α-linolenic acid found in some studies (22, 23), although not all (24, 25). In epidemiologic studies (22, 23), increased α-linolenic acid intake in the range observed in this study (∼0.6 gr/d) is associated with decreased plasma concentration of markers of inflammation, C-reactive protein (CRP) (22, 23), vascular cell adhesion molecule-1 (VCAM-1) (23), and E-selectin (23). Consistent with these findings, intervention studies found that α -linolenic acid lowers CRP plasma concentration (26-28), VCAM-1 (26, 29, 30), and E-selectin (26, 30). However, results from intervention studies were obtained with very high intakes of α-linolenic acid (range 5-15 gr/d) and their relevance to the current study is uncertain. The potential anti-inflammatory effects of α-linolenic acid could be mediated, in part, through its conversion to EPA and DHA by the action of desaturase and enlongase enzymes (31). However, the finding that this conversion is generally low (<8%), (25, 32), and the observation of poor correlations between dietary α-linolenic acid and long-chain fatty acids in adipose tissue, plasma, or erythrocytes in this study, suggest that α-linolenic acid could exert direct protective anti-inflammatory effects. It has been shown that α -linolenic acid decreases the nuclear transcription factor kB, a major transcription factor that is involved in the regulation of inflammatory genes (33, 34). Furthermore, α -linolenic acid inhibits the production of nitric oxide, and downregulates inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-R gene expression in murine macrophages (34).

There are other metabolic effects of α-linolenic acid that could potentially explain our findings. In the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study, individuals who reported ∼ 0.6 g/d higher linolenic acid intake had lower blood pressure (35), lower plasma triglycerides concentration (36), fewer calcified atherosclerosis plaques (37), and less carotid atherosclerosis (38). In one intervention study, increasing α -linolenic acid by 3 g/d resulted in lower plasma LDL cholesterol and apoB concentrations (39). Other studies that used higher doses (7-15 g/d), found similar results (25, 26). These findings however, have not been consistent (40).

It is possible that α-linolenic acid would have a more prominent role among populations with low fish intake, because EPA can inhibit the action of delta-5 and delta-6 desaturase activity which is required for α-linolenic acid conversion (41). Consistent with this hypothesis, one study showed that, 1 g/d intake of α-linolenic acid was associated with a 50% lower risk of nonfatal MI among men consuming very low (<100 mg/d) long-chain n-3 fatty acids from fish, but no association was found among those with higher intake (21). However, consistent with results from the NHLBI Family Heart Study (42), we found that an association with reduced risk of nonfatal MI was evident regardless of fish intake or long chain fatty acids EPA+DHA, which were on average above 100 mg per day even in the lowest tertile (median = 130 mg/d). Nevertheless, fish intake overall is low in the studied population, and it is still possible that no association would be found in populations with very high intakes.

The data presented here suggest that despite the increase in soybean oil consumption in the last 20 years, a large portion of the Costa Rican population does not meet the recommended α-linolenic acid intake. In the United States, an adequate intake for α-linolenic acid has been set at 1.6 g/d for men and 1.1 g/d for women (43). Furthermore, a range of α-linolenic acid intake between 0.6 and 1.2% of energy (1.3-2.6 g/d for a 2000 kcal diet) has been proposed in the US as an Acceptable Macronutrient Distribution Range (AMDR). The AMDR represents the range of an energy source that is associated with reduced risk of chronic disease while providing adequate intake of essential nutrients. Our data indicate that 50% of the Costa Rican population was below the minimum AMDR. It is possible that this group, where the median α-linolenic acid intake ranged between 0.42 and 0.57% energy, may benefit the most from increase intake in α-linolenic acid. Further increases to intakes as high 0.86% energy were not associated with extra protection.

The main limitation of this study is the use of a retrospective case-control design where causal effects cannot be studied. Case-control studies that use dietary questionnaires are also more prone to reporting bias than prospective studies because responses from the cases could be modified by the MI. This study used of both dietary questionnaires and biomarkers as an indicator of dietary information. The most reliable conclusions may be drawn when both methods yield similar results as in the present study. Given the potential benefits of α-linolenic acid, large clinical trials in populations with low α-linolenic acid intakes are warranted.

In summary, increased α-linolenic acid is associated with reduced risk of nonfatal acute MI. This relationship is non-linear, where risk did not decrease with intakes between 1.79 g/d (0.65% energy) and 2.35 g/d (0.86% energy). Furthermore, fish or EPA+DHA intake at the levels found in this population did not modify the observed association. Thus, it is possible that consumption of vegetable oils rich in α-linolenic acid could confer important cardiovascular protection in many countries where intake is low.

Acknowledgments

This study was supported by grant HL 49086 and HL60692 from the National Institutes of Health.

Footnotes

Clinical perspective: Long-chain n-3 fatty acids from fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular mortality, but availability of fish is limited and probably insufficient to meet worldwide needs. α-Linolenic acid, an essential n-3 fatty acid found in cooking vegetable oils, such as soybean and canola oils, and other products of plant origin, could be a viable alternative to fish oils. We determined whether α-linolenic acid was associated with risk of nonfatal acute myocardial infarction (MI) in 1,819 case-control pairs from a population-based study in Costa Rica. Increased dietary α-linolenic acid assessed by questionnaire and in adipose tissue was associated with 39% and 59% lower risk of MI, respectively. The relationship between α-linolenic acid and MI was non linear, and it was only evident at low intake levels. Risk of MI decreased by 57% when median intakes of 1.79 g/d (0.65% energy) were compared to 1.11 g/d (0.42% energy), but it did not decrease further with intakes greater than 1.79 g/d. The amount of α-linolenic acid associated with risk reduction was small, and it could be obtained with two teaspoons of soybean or canola oils, which are common plant sources of α-linolenic acid. This level of intake could also be easily achieved with intake of flaxseed oil (∼1-2 mls) or walnuts (∼6 to 10 halves). Fish or EPA+DHA intake at the levels found in this population did not modify the observed association. In sum, consumption of vegetable oils rich in α-linolenic acid could confer important cardiovascular protection.

Disclosures: None

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