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(Stroke. 1995;26:778-782.)
© 1995 American Heart Association, Inc.

Articles

Serum Fatty Acids and the Risk of Stroke

Joel A. Simon, MD, MPH; Josephine Fong, MS; John T. Bernert, Jr, PhD Warren S. Browner, MD, MPH

From the General Internal Medicine Section (111A1), Medical Service, Department of Veterans Affairs Medical Center (J.A.S., W.S.B.), and the Division of Clinical Epidemiology, Department of Epidemiology and Biostatistics, University of California (J.A.S., J.F., W.S.B.), San Francisco, Calif; and the Clinical Biochemistry Branch, Division of Environmental Health Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Ga (J.T.B.).

Correspondence to Joel A. Simon, MD, General Internal Medicine Section (111A1), Medical Service, Department of Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121.

	Abstract

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Background and Purpose To examine the relationship between serum fatty acids, which reflect dietary intake, and stroke, we conducted a nested case-control study of 96 men with incident stroke and 96 control subjects matched by age, clinical center, treatment group, and date of randomization who were enrolled in the Multiple Risk Factor Intervention Trial.

Methods After confirming the stability of the stored serum samples, we measured serum cholesterol ester and phospholipid fatty acid levels as the percentage of total fatty acids by gas-liquid chromatography and examined their association with incident stroke. Using stepwise conditional logistic regression that controlled for risk factors for stroke, we determined which fatty acids were independent correlates of stroke.

Results In univariate models, a standard deviation (SD) increase (1.37%) in phospholipid stearic acid (18:0) was associated with a 37% increase in the risk of stroke, whereas an SD increase (0.06%) in phospholipid -3 -linolenic acid (18:3) was associated with a 28% decrease in the risk of stroke (all P<.05). Only -linolenic acid in the cholesterol ester fraction was associated with the risk of stroke in multivariate models: an SD increase (0.13%) in the serum level of -linolenic acid was associated with a 37% decrease in the risk of stroke (P<.05). Systolic blood pressure and cigarette smoking were also independently associated with stroke risk.

Conclusions Our findings suggest that higher serum levels of the essential fatty acid -linolenic acid are independently associated with a lower risk of stroke in middle-aged men at high risk for cardiovascular disease.

Key Words: cardiovascular disease • diet • fatty acids • risk factors

	Introduction

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Fatty acid consumption is associated with the risk of coronary heart disease (CHD).¹ In general, long-chain saturated fatty acids (14 or more carbon atoms) tend to increase CHD risk, whereas polyunsaturated fatty acids tend to decrease CHD risk.¹ These effects may be mediated in part by fatty acid–induced changes in serum lipid levels, hemostasis, and blood pressure.^{2 3 4} Many studies have documented an association between fatty acids and risk of CHD.^{1 5}

Risk factors for stroke include age, hypertension, diabetes mellitus, and cigarette smoking.¹ High serum cholesterol level is a risk factor for thrombotic stroke, whereas low serum cholesterol level and alcohol consumption are risk factors for hemorrhagic stroke.^{1 6} Dietary factors, such as fat consumption, may also influence the risk of stroke. Although the consumption of animal fat and saturated fat have been reported to increase the risk of stroke,¹ paradoxical findings (the risk of stroke among Japanese men decreases as dietary saturated fat consumption increases) have also been reported.^{7 8} Because the assessment of dietary fat intake is imprecise, alternative methods of estimating intake have been proposed,⁹ including measuring diet-derived fatty acids in the cholesterol esters and the phospholipids of serum lipoproteins.

To examine the possible association between serum fatty acids and the risk of stroke, we conducted a nested case-control study of men enrolled in the Multiple Risk Factor Intervention Trial (MRFIT). Using stored frozen serum samples that were collected at the outset of the study, we measured and compared the serum fatty acid levels in 96 men who suffered a stroke during an average of 6.9 years of follow-up with the levels in 96 men who did not, adjusting for known risk factors for cerebrovascular disease.

	Subjects and Methods

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Subjects
MRFIT was a CHD primary prevention trial that studied the effects of lowering cholesterol and blood pressure and of smoking cessation in men at high risk for CHD. Between December 1973 and February 1976, 12 866 men in the United States, aged 35 to 57 years, were enrolled and then examined annually.^{10 11} Participants were randomly assigned to a special-intervention or usual-care group after screening was completed. Men in the usual-care group (n=6438) continued their usual medical care and were evaluated yearly by MRFIT staff.¹⁰

Men in the MRFIT special-intervention and usual-care groups were selected for our study. Case subjects were defined as men with fatal or nonfatal incident strokes that occurred during an average of 6.9 years of follow-up (n=96). Clinic and hospital records, next-of-kin interviews, death certificates, and autopsy reports were used to establish stroke deaths. Nonfatal stroke was defined on the basis of diagnoses made by the clinic physicians at each annual visit.¹² A total of 96 men without stroke who were matched by age (±3 years), date of randomization, treatment group, and clinical center were selected as control subjects.

Measurements
At baseline, participants were weighed after removing their shoes and outdoor clothing. Using a random-zero manometer, seated blood pressure was measured three times with a blood pressure cuff appropriate for arm circumference, and the average of the second and third readings was recorded. Tobacco use (cigarettes per day) and alcohol use (drinks per week) were determined by self-report, and nutrient intake at baseline was estimated using a 24-hour diet recall.¹³

Fasting plasma total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and glucose levels were determined at baseline.¹⁴ At the Centers for Disease Control and Prevention, we measured lipoprotein fatty acid levels from serum samples obtained at baseline and frozen at -55°C for the entire interim period. Serum aliquots were extracted by the procedure of Folch et al.¹⁵ The cholesterol esters and phospholipids were isolated by thin-layer chromatography and transesterified to methyl esters.¹⁶ The fatty acid methyl esters were purified on a small silicic acid column and analyzed by capillary gas-liquid chromatography on a 0.2 mmx50 m FFAP column mounted in a Hewlett-Packard 5880 gas chromatograph.¹⁷ The instrument was calibrated before each series of analyses using a quantitative standards mixture (GLC-68A) from Nu Chek Prep. Specific fatty acid levels were expressed as the percentage of total fatty acids in the cholesterol ester and phospholipid fractions. Fatty acid composition was measured for stroke case and control subjects at the same time by investigators who were blinded to stroke status. We measured the fatty acid composition of serum cholesterol esters and phospholipids rather than serum triglycerides because they provide better estimates of usual dietary intake patterns.¹⁶

The stability of the frozen serum specimens was evaluated before this analysis. Twelve randomly selected samples were analyzed for their malondialdehyde¹⁸ and conjugated diene content.¹⁹ Folch extracts of the samples were assayed for fluorescent degradation products, vitamin A and E content,²⁰ and fatty acid profiles. Comparison of the results with reference pools and fresh serum specimens indicated that very little oxidative damage had occurred. There were minor but statistically significant increases in malondialdehyde and conjugated diene content in comparison with fresh serum specimens (P<.02).

Statistical Analysis
We used paired t tests to compare the means of continuous variables in stroke case and control subjects, and we estimated the association of each variable with stroke using conditional logistic regression.²¹ Variables that were associated with stroke at a significance level of P.10 and the MRFIT selection criteria variables (plasma cholesterol level, diastolic blood pressure, and cigarette smoking) were entered into each multivariate model. We used backward stepwise regression procedures to retain only those variables associated with stroke at P.05.²² We examined the relation of serum fatty acids to risk of stroke in models that excluded measures of total dietary fat.

We calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate risk, using the standard deviations (SDs) from the sample as the unit for change in each predictor variable.²³ The fatty acid variables generally had a roughly normal distribution. Two-tailed values of P<.05 were considered to be statistically significant, unadjusted for multiple comparisons.²⁴ All statistical analyses were performed using SAS software.²⁵

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Participants in MRFIT were middle-aged men selected for their high levels of serum cholesterol, diastolic blood pressure, and cigarette smoking, which placed them at increased risk for CHD. The mean±SD age of the age-matched subjects was 50.3±5.6 years. Tobacco, monounsaturated and total dietary fat consumption, and systolic blood pressure were greater in the stroke case subjects compared with the control subjects (all P<.05). Otherwise, there were no significant differences in the mean values of MRFIT baseline variables when case and control subjects were compared (Table 1).

View this table: [in this window] [in a new window]   Table 1. Mean Baseline Variables Among Stroke Case and Control Subjects From the Multiple Risk Factor Intervention Trial, 1973-1976

The principal fatty acids in the serum cholesterol ester fraction were oleic acid (18:1) and the -6 fatty acid linoleic acid (18:2) (Table 2). There was a wider distribution of fatty acids in the phospholipid fraction, including the -3 fatty acids eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6). Serum cholesterol ester and phospholipid levels of the saturated fatty acid stearic acid (18:0) were higher and levels of -3 polyunsaturated fatty acid -linolenic acid (18:3) were lower in stroke case subjects compared with control subjects (P<.05).

View this table: [in this window] [in a new window]   Table 2. Percentage Fatty Acid Composition of Cholesterol Esters and Phospholipids in 96 Stroke Case Subjects and 96 Control Subjects From the Multiple Risk Factor Intervention Trial

These serum fatty acids were significantly associated with stroke risk (Table 3). Each SD increase in the saturated fatty acid stearic acid (18:0) was associated with an approximate 35% increase in stroke risk, whereas each SD increase in the -3 fatty acid -linolenic acid (18:3) was associated with a 30% reduction in stroke risk. However, after we controlled for the effect of cigarette smoking, the cholesterol ester stearic acid was no longer significantly associated with risk of stroke (OR, 1.32; 95% CI, 0.96 to 1.82).

View this table: [in this window] [in a new window]   Table 3. Associations Between Serum Fatty Acids and Stroke Risk in 96 Stroke Case and 96 Control Subjects Matched by Age, Clinical Center, Treatment Group, and Date of Randomization From the Multiple Risk Factor Intervention Trial

Only the -3 polyunsaturated fatty acid -linolenic acid (18:3) derived from the cholesterol ester fraction remained associated with stroke in the final multivariate model. To examine the possibility that smoking modified the association between serum fatty acids and stroke, we included smokingxfatty acid interaction terms in the stepwise regression model. We found no evidence for such interactions. Systolic blood pressure and cigarette smoking were also independent predictors of stroke risk. In the final model, the risk of stroke decreased 37% for each SD increase (0.13%) in serum level of cholesterol ester -linolenic acid (OR, 0.63; 95% CI, 0.43 to 0.92). The risk of stroke increased 89% for each SD increase (16 mm Hg) in systolic blood pressure (OR, 1.89; 95% CI, 1.02 to 3.48) and over twofold for each SD increase (20 cigarettes per day) in smoking (OR, 2.22; 95% CI, 1.46 to 3.37).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The level of the saturated fatty acid stearic acid (18:0) was directly associated with stroke risk, whereas the level of the polyunsaturated -3 fatty acid -linolenic acid (18:3) was inversely associated with stroke risk. After we controlled for the effects of smoking, blood pressure, and plasma cholesterol level, only -linolenic acid remained significantly associated with the risk of stroke. Indeed, after adjustment, the magnitude of the association became greater (adjusted OR of 0.63 versus crude OR of 0.72). -Linolenic acid appears to be an independent predictor of stroke risk.

The -3 fatty acids, derived from -linolenic acid, and the -6 fatty acids, derived from linoleic acid (18:2), are the two principal classes of polyunsaturated fatty acids. -Linolenic acid is an essential fatty acid found predominantly in linseed, canola, soybean, and walnut oils.^{2 26} The effect of consuming 84 g of walnuts per 10 500 kJ (2500 kcal) intake results in a doubling of the cholesterol ester concentration of -linolenic acid (18:3).²⁷ A recent secondary CHD prevention trial using an -linolenic acid–rich diet intervention containing canola margarine demonstrated a cardiovascular death risk reduction of 76% after an average of 27 months of follow-up.²⁸ The results of this study were not accounted for by differences in plasma lipid or blood pressure levels. Although the specific effect of -linolenic acid on platelet aggregation is unknown,² the protective effect that we and others²⁸ have observed may reflect a reduction in platelet aggregability and blood viscosity attributed to this class of fatty acids.^{4 29} Two members of the -3 fatty acid family—eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6)—are known to have platelet inhibitory activity. Although they are principally derived from the consumption of seafood, they may also be derived from -linolenic acid.⁴

Stearic acid (18:0) in the cholesterol ester fraction was associated with the risk of stroke, although after adjustment for cigarette smoking, the magnitude and strength of the association were attenuated (OR, 1.32; 95% CI, 0.96 to 1.82). Smoking may influence the consumption of stearic acid–rich foods or affect stearic acid absorption or metabolism.³⁰ Some studies have found increased stearic acid in the adipose tissue³¹ or red blood cell membranes of patients with stroke,³² but other studies that have examined platelet, plasma, or serum fatty acid levels have been unable to find any association between stearic acid and stroke.^{33 34 35} Stearic acid may not raise blood cholesterol levels,³⁶ but it may promote platelet aggregation.^{37 38}

We could not confirm the results of some studies that found serum or plasma levels of the -6 polyunsaturated fatty acid linoleic acid (18:2) to be inversely associated with the risk of stroke.^{33 39} Studies that have examined adipose tissue fatty acids³¹ and red blood cell fatty acids³² have also found that linoleic acid was inversely associated with stroke. Although the control subjects in our study had slightly higher levels of linoleic acid compared with the stroke case subjects, these differences were not significant (P>.30).

Other studies have been unable to detect any association between serum or plasma fatty acid levels and the risk of stroke.^{34 35} There are a number of possible factors that may account for the differences between these studies and ours. First, all of these studies had smaller sample sizes and consequently less power than our study. Second, with one exception,³² these studies did not perform multivariate analyses. Finally, unlike our study, most of these studies had nonprospective designs.^{31 32 33 34 35}

As expected, elevated blood pressure and cigarette smoking were independent risk factors for stroke.¹ Both systolic and diastolic blood pressures were associated with an increased risk of stroke (P<.10), but only systolic blood pressure was an independent predictor in the multivariate model; each increase of 16 mm Hg was associated with an 89% increase in stroke risk. Each SD increase in cigarette smoking (20 cigarettes per day) was associated with a 2.2-fold increase in the risk of stroke.

Our study had several limitations. Because we studied middle-aged American men at high risk for CHD, caution in generalizing our results is warranted. Second, although we assessed the stability of the stored frozen serum samples and found little oxidative damage, we cannot rule out the possibility that an analysis of fresh serum samples would have demonstrated associations between other fatty acids and risk of stroke. Third, CIs for most fatty acids were relatively wide, and associations between other fatty acids and stroke might be evident in a larger study. Fourth, because we did not measure levels of trans fatty acid isomers, we are unable to comment on the possible relation of these fatty acids to stroke. Finally, because of the large number of comparisons performed, it is possible that our findings may be the result of chance.

Because -linolenic acid is an essential fatty acid, our results suggest that a higher dietary intake of -linolenic acid (18:3) may lower the risk of stroke. This association was not mediated by differences in blood cholesterol or blood pressure level. Examination of the effect of -linolenic acid on platelet function and confirmation of our findings by other prospectively designed studies in other populations are warranted.

	Acknowledgments

 
This study was supported by the National Heart, Lung, and Blood Institute grant HL-32338-03. We gratefully acknowledge the help and advice of the MRFIT Editorial Committee and staff of the MRFIT coordinating center at the University of Minnesota. Use of trade names is for identification only and does not constitute endorsement by the Public Health Service or the US Department of Health and Human Services.

Received November 4, 1994; revision received January 26, 1995; accepted February 7, 1995.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simon, J. A. Articles by Browner, W. S. Search for Related Content PubMed PubMed Citation Articles by Simon, J. A. Articles by Browner, W. S. Pubmed/NCBI databases Substance via MeSH