© 1999 American Heart Association, Inc.
Original Contributions |
Omega-3 Fatty Acids in Adipose Tissue and Risk of Myocardial Infarction
The EURAMIC Study
From the Department of Epidemiology and Biostatistics, National School of Public Health, "Instituto de Salud Carlos III" (E.G., J.M.M.-M.), Madrid, Spain; Department of Nutrition, National Public Health Institute (A.A., I.S., J.K.H.), Helsinki, Finland; Research Unit, "Fundación Jiménez Díaz" (F.J.J.), Madrid, Spain; Division of Human Nutrition and Epidemiology, Wageningen Agricultural University (P.V.V., F.J.K.), Wageningen, The Netherlands; Department of Consumer Research and Epidemiology, TNO Nutrition and Food Research Institute (A.F.M.K.), Zeist, The Netherlands; Department of Preventive Medicine and Public Health, University of Málaga (J.G.-A.), Málaga, Spain; Institute of Social and Preventive Medicine, Zürich University (B.C.M.), Zürich, Switzerland; University of North Carolina (L.K.), Chapel Hill; Epidemiology Unit, Hadassah Medical Organization and Hebrew University (J.D.K.), Jerusalem, Israel; Research Center for Preventive Medicine (V.P.M.), Moscow, Russia; Østfold Central Hospital (J.R.), Fredrikstad, Norway; Department of Preventive Medicine and Public Health, University of Granada (J.G.), Granada, Spain; Cardiovascular Research Unit, University of Edinburgh (R.A.R.), Edinburgh, United Kingdom; and Department of Health Risks and Prevention, Robert Koch Institute (M.T.), Berlin, Germany.
Correspondence and reprint requests to Eliseo Guallar, Departamento de Epidemiología y Bioestadística, Escuela Nacional de Sanidad, Instituto de Salud Carlos III. Sinesio Delgado 8, 28029 Madrid, Spain. E-mail eguallar{at}isciii.es
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Abstract |
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Abstract—Omega-3 fatty acids have potential antiatherogenic, antithrombotic, and antiarrhythmic properties, but their role in coronary heart disease remains controversial. To evaluate the association of omega-3 fatty acids in adipose tissue with the risk of myocardial infarction in men, a case-control study was conducted in eight European countries and Israel. Cases (n=639) included patients with a first myocardial infarction admitted to coronary care units within 24 hours from the onset of symptoms. Controls (n=700) were selected to represent the populations originating the cases. Adipose tissue levels of fatty acids were determined by capillary gas chromatography. The mean (±SD) proportion of
-linolenic acid was 0.77% (±0.19) of fatty acids in cases
and 0.80% (±0.19) of fatty acids in controls (P=0.01).
The relative risk for the highest quintile of -linolenic
acid compared with the lowest was 0.42 (95% confidence interval [CI]
0.22 to 0.81, P-trend=0.02). After adjusting for
classical risk factors, the relative risk for the highest quintile was
0.68 (95% CI 0.31 to 1.49, P-trend=0.38). The mean
proportion of docosahexaenoic acid was 0.24% (±0.13) of fatty acids
in cases and 0.25% (±0.13) of fatty acids in controls
(P=0.14), with no evidence of association with risk of
myocardial infarction. In this large case-control study we could not
detect a protective effect of docosahexaenoic acid on the risk of
myocardial infarction. The protective effect of -linolenic
acid was attenuated after adjusting for classical risk factors (mainly
smoking), but it deserves further research.
Key Words: myocardial infarction • -linolenic acid • docosahexaenoic acid • case-control studies • adipose tissue.
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Introduction |
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Omega-3 fatty acids are long-chain polyunsaturated fatty acids with important metabolic and structural properties.
-Linolenic acid (C18:3 omega-3; ALA), found in low amounts
in vegetable oils, is an essential nutrient in humans. Although ALA can
be elongated and desaturated to
eicosapentaenoic acid (C20:5 omega-3; EPA), EPA
and docosahexaenoic acid (C22:6 omega-3; DHA) are mainly obtained in
the diet from fatty fish and fish oils. Fish oil fatty acids are
incorporated into lipoproteins and cell membranes, where they affect
membrane characteristics and eicosanoid production, increasing
vasodilatation and inducing dose-dependent reductions in platelet
aggregability, leukocyte activation, and plasma
triglycerides, which might reduce the risk of
coronary disease.1 A protective effect of fish intake on coronary heart disease has been shown in some,2 3 4 5 6 but not all prospective studies.7 8 9 10 11 12 Similarly, studies of the association of plasma or tissue levels of fish oils and incidence of myocardial infarction have yielded conflicting results.13 14 15 16 17 A randomized trial of diet in patients after myocardial infarction found a significant reduction in mortality caused by ischemic heart disease in the group assigned to consuming fatty fish 2 to 3 times per week, but the number of ischemic events was not reduced.18
ALA may also reduce platelet aggregability,19 20 21 either by modulating the effect of arachidonic acid,22 23 or through desaturation and elongation to EPA.24 25 26 27 Although the association of ALA and cardiovascular endpoints has received less attention, low levels of ALA were associated with increased risk of cardiac events in 3 previous studies,3 13 14 but this association was not significant after adjusting for linoleic acid in one of the studies.14 Finally, a randomized trial found a significant 70% reduction in mortality in patients with myocardial infarction assigned to the group advised to follow a Mediterranean-type diet rich in oleic acid, ALA, and antioxidants compared with the group assigned not to receive such advice.28
The EURAMIC (EURopean multicenter case-control study on Antioxidants, Myocardial Infarction and breast Cancer) study evaluated the role of antioxidant vitamins in adipose tissue on the risk of myocardial infarction and breast cancer.29 This article presents the findings on the association between omega-3 fatty acid in adipose tissue and risk of myocardial infarction, a secondary hypothesis of the EURAMIC study.
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Methods |
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Design and Subjects
The EURAMIC study design has been reported in detail elsewhere.29 The target population consisted of men 70 years of age or younger, native residents speaking the official local language of 8 European countries or residents of Israel. Subjects were excluded if they had a previous diagnosis of myocardial infarction to reduce the likelihood of recent dietary changes. Those with a history of drug or alcohol abuse, or who had major psychiatric disorders, were institutionalized, or had modified their dietary pattern in the past year were also excluded.
The cases included men with a first acute myocardial infarction, confirmed by characteristic ECG changes and serum enzymes, hospitalized within 24 hours from the onset of symptoms. Cases were recruited from the coronary care units of participating hospitals. Controls were men without history of myocardial infarction, frequency-matched for age in 5-year intervals. In Finland, Israel, Germany, Scotland, and Switzerland, random sampling from local population registers was used for the selection of apparently healthy controls. Because of incomplete coverage or legal restrictions on the use of population registers, male controls were recruited in Russia and in the two Spanish centers from patients admitted to hospital for disorders not known to be associated with dietary factors. Where it was thought that low response rates from population-based samples would spoil the internal validity, control subjects were selected from the catchment area of the patient's general practitioner (The Netherlands) or by inviting friends and relatives of the patient (Norway). In The Netherlands, Russia, and Spain, recruitment methods were combined.
Cases and controls were recruited concurrently during 1991 and 1992. Informed consent was obtained from study participants in accordance with the ethical standards of the responsible local committees on human experimentation.
Data Collection
Information on smoking habits, history of hypertension, angina
pectoris, and diabetes was collected for all subjects by standard
questionnaires.30 Socioeconomic status, alcohol intake and
family history of cardiovascular diseases were assessed
through locally developed questionnaires. A nonfasting venous blood
sample was drawn for cholesterol analysis. In
cases, blood samples were drawn within 24 hours of hospital
admission.
A subcutaneous adipose tissue specimen was taken from the buttock by needle aspiration as described by Beynen and Katan.31 In cases, the adipose tissue sample was taken within 7 days of hospital admission. Samples were immediately frozen on dry ice or liquid nitrogen and stored at -70°C in the original plastic adaptors until analyzed. Adipose tissue and serum samples were transported on dry ice at -56°C to the analytical laboratories.
Biochemical Analysis
The fatty acid composition of adipose tissue was assayed
centrally at the National Public Health Institute, Helsinki
(Finland).32 Adipose tissue samples were saponified and
acidified with HCl, and free fatty acids were extracted with hexane and
methylated with acidic methanol. Fatty acid composition was determined
by gas chromatography (HNU Nordion Oy, Finland, HRCG
412) with a 60-m-long SP-2380 column, an internal diameter of 0.32
mm, a phase layer 0.20 µm with a split injector. Helium was the
carrier gas. Fatty acid peaks from C12:0 through C22:6 were identified
by an SC-workstation (Sunicom Oy, Finland) in a temperature-programmed
run. All fatty acids are expressed as proportion of total fatty acid
peak area (%FA). Because of the very low levels of EPA in adipose
tissue, EPA was below the detection limit of the chromatograph
for most samples. Fish oil fatty acid levels were thus
represented exclusively by DHA.33 The
interassay coefficients of variation for ALA and DHA were 15% and
25%, respectively. Samples of cases and controls were analyzed
simultaneously and blind to disease status.
Serum total cholesterol levels were determined enzymatically (Kits of Boehringer-Mannheim GmbH). HDL cholesterol was determined after precipitation with dextran sulfate and magnesium chloride.
Statistical Methods
Among cases and controls, summary statistics for established
risk factors, omega-3 fatty acids and potential confounders were
calculated for the different centers. The distribution of omega-3 fatty
acid levels in controls was used to compute cut-off points and medians
for quintiles of exposure. For intracenter comparisons, quintiles were
based on the control distribution for each center, whereas the combined
sample was used for categorizations in overall analyses. The
levels of cardiovascular risk factors across quintiles
of omega-3 fatty acids were compared among controls by one-way ANOVA
and 
2 tests. The center- and age-adjusted
overall mean difference of omega-3 fatty acids and 95% confidence
intervals were estimated by linear regression.34
For multivariate analysis, multiple logistic regression was used to estimate the association of omega-3 fatty acid levels with the risk of myocardial infarction, adjusting for potential confounders.35 Relative risks were estimated as odds ratios in quintiles 2 to 5 using the lowest quintile as the reference category. Subsequently, the risk of myocardial infarction for the 75th compared with the 25th percentile of ALA and DHA were estimated from the logistic regression coefficients for fatty acids as continuous variables. Trend tests across quintiles of fatty acids were computed by including in the logistic models a variable with the median for the quintile of the fatty acid for each participant.35 All probability values reported are two-tailed. Statistical analyses were performed using the SAS package.36
To evaluate the impact of design characteristics on risk estimates, the analyses were repeated after excluding those centers not using population controls (Zeist, Sarpsborg, Moscow, Granada, and Málaga). In addition, the analyses were also repeated after excluding cases and controls with hypertension or with angina, who may have modified their dietary habits as a consequence of diagnosis. The conclusions were essentially the same (results not shown).
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Results |
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Sample Description and Risk Factors
Needle biopsies were performed in 1499 eligible subjects (742 cases, 757 controls), with an overall response rate of 81% in cases and 64% in controls. Needle biopsy was unsuccessful in 31 subjects (27 cases, 4 controls) and no material was available for fatty acid analysis in 52 additional participants (24 cases, 28 controls). Of the remaining 1416 samples, too little material (<5 mg of fatty acids) was available to reliably analyze DHA content in 77 samples (52 cases, 25 controls). Therefore, results are available for 1339 subjects (639 cases and 700 controls).
As expected, cases had a significantly higher body mass index and lower
HDL cholesterol levels; they were more likely to be
hypertensive, to have diabetes, to smoke, or to have angina or a family
history of coronary heart disease (Table 1
).29 The lower
concentration of total cholesterol among cases almost
certainly reflects the effect of acute myocardial infarction.
Therefore, total cholesterol was not considered further in
the analyses.
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Intercenter Variability
Adipose tissue concentrations of ALA and DHA among controls varied
across centers (Table 2). Norway and
Israel had the highest average concentrations of ALA (1.27±0.28%FA
and 1.18±0.30%FA, respectively), whereas Spain had the lowest
(0.44±0.12%FA in Granada and 0.41±0.07%FA in Málaga), a
3-fold range of variation. The age- and center-adjusted overall mean of
ALA in controls was 0.80±0.19%FA. Norway and Finland had the highest
average concentrations of DHA (0.43±0.22%FA and 0.34±0.19%FA,
respectively), whereas The Netherlands (0.14±0.08%FA), Switzerland
(0.15±0.07%FA) and Scotland (0.17±0.11%FA) had the lowest,
indicating a wide range of variability of fish intake across countries.
The overall mean concentration of DHA in controls, adjusted for age and
center, was 0.25±0.13%FA.
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Omega-3 Fatty Acid Levels and Risk Factors
The age- and center-adjusted relation between adipose tissue
omega-3 fatty acids and coronary risk factors was examined in
the control group (Table 3). There was an
inverse association between smoking and levels of ALA. The percentage
of current smokers varied between 59% in the lowest to 24% in the
highest quintile of ALA (P<0.001). Alcohol intake also
decreased with increasing levels of ALA (P=0.002), with a
difference of 106 g/wk between the first and the fifth quintiles of ALA
intake.
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DHA was positively associated with age (Pearson's r=0.17,
P<0.001), body mass index (r=0.10,
P=0.009), and history of hypertension (P=0.004).
Compared with the four highest quintiles, controls in the lowest
quintile of DHA had a lower intake of alcohol, but the differences were
not statistically significant (Table 3
).
ALA and DHA were positively associated with each other
(r=0.24, P<0.001) (Table 4). ALA was also positively related to
linoleic acid (r=0.33; P<0.001), and inversely
related to oleic acid (r=-0.15; P<0.001). DHA
was inversely associated with oleic acid (r=-0.11;
P=0.005) and positively associated with
arachidonic acid (r=0.17;
P<0.001).
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Omega-3 Fatty Acids and Risk of Myocardial Infarction
The center- and age-adjusted case-control difference in ALA was
-0.03%FA (95% CI -0.05 to -0.01; P=0.01) (Table 2). Average levels of ALA were higher in controls compared with
cases in 8 of 10 centers. After adjusting for age and center, there was
a decreased risk of myocardial infarction with increasing levels of ALA
in adipose tissue (P-trend= 0.02; Table 5). The relative risk of myocardial
infarction in the highest quintile of ALA was 0.42 (95% CI 0.22 to
0.81). This inverse relationship was attenuated after adjusting for
cardiovascular risk factors and for other major fatty
acids. The adjusted relative risk for the highest quintile of ALA
compared with the lowest was 0.68 (95% CI 0.31 to 1.49) and the
P for trend was 0.38 (Table 5). The attenuation of
this inverse trend was due almost entirely to the inclusion of smoking
in the logistic models. We further investigated the association of ALA
with risk of myocardial infarction within categories of smoking, but
the effect was similar among those who had never smoked, ex-smokers and
current smokers (P value for the ALA by smoking
interaction=0.52). Further adjustment for levels of antioxidant
vitamins in adipose tissue, such as -tocopherol or
ß-carotene, did not materially change the results (Table 5).
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On average, cases and controls had similar concentrations of DHA in
adipose tissue. The center- and age-adjusted case-control difference in
DHA was -0.01%FA (95% CI -0.02 to 0.00; P=0.14). In all
individual centers, the case-control differences were small and not
statistically significant (Table 2). Center- and age-adjusted
relative risks of myocardial infarction were similar across quintiles
of DHA (Table 6). There was no evidence
of a decreasing trend of risk of myocardial infarction with increasing
levels of DHA. Including DHA concentration as a continuous variable
in the logistic regression models, the adjusted relative risk comparing
the 75th percentile of the distribution of DHA to the 25th was 0.94
(95% CI 0.81 to 1.10; P=0.43). Based on the standard error
of this estimate, the power of the study to detect a 20% risk
reduction with an increase in DHA from the 25th to the 75th percentile
was 54%, and the power to detect a 30% risk reduction was 96%.
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To evaluate the hypothesis of an increase in risk in patients with very low levels of omega-3 fatty acids,37 we focused on the 533 subjects (267 cases, 266 controls) who were in the lowest quintile of either ALA or DHA. Within this subgroup, those who were in the first quintile of both fatty acids (n=46) had an adjusted relative risk of 0.60 (95% CI 0.27 to 1.33) compared with those in the lowest quintile of DHA but not of ALA (n=219), and a relative risk of 0.57 (95% CI 0.28 to 1.15) compared with those in the lowest quintile of ALA, but not of DHA (n=268). Finally, the relative risk of participants with undetectable levels of DHA (n=21) compared with the remaining individuals in the lowest quintile of DHA (n=244) was 0.44 (95% CI 0.17 to 1.19, P=0.11).
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Discussion |
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In this large international study there was no evidence of a protective effect of adipose DHA, reflecting long-term fish intake, on the risk of developing a myocardial infarction. We found an inverse association between ALA and risk of myocardial infarction, but it was attenuated after adjusting for classical cardiovascular risk factors. Finally, participants with undetectable or very low levels of omega-3 fatty acids were also not at increased risk of myocardial infarction.
The use of incident cases of first myocardial infarction, recruited within the 1st week after the event, and the use of adipose tissue samples for the assessment of exposure make it unlikely that disease development or recent dietary modification following medical advice had affected ALA and DHA levels. Furthermore, similar results were obtained after excluding participants with existing angina or with hypertension who could have modified their intake patterns.
The EURAMIC study used adipose tissue levels of ALA and DHA as an objective measure of their long-term, time-integrated intake. Fatty acid composition of adipose tissue reflects the dietary intake of essential fatty acids (ie, those that cannot be synthesized by man) maintained for extended periods.38 39 In one study, omega-3 fatty acid levels in adipose tissue were correlated with usual dietary intake estimated from dietary records and food-frequency questionnaires.40 Intake of ALA affects the level of EPA in tissues but the effect on DHA has been equivocal.24 25 26 27 Some of the confusion may arise because in some methods adipose triglycerides and phospholipids are not separated, and phospholipids tend to have much higher levels of DHA than triglycerides, making it easier to quantify DHA. Plasma phospholipids contain larger amounts of EPA and DHA, but may not reflect the intake of DHA over periods of months to years. Therefore, adipose tissue DHA appears to be the best single indicator of fish intake,33 although the positive association between ALA and DHA in our study suggests that ALA intake may have some effect of on adipose tissue DHA, too. The use of DHA as biomarker of fish intake, however, does not imply that the effects of fish intake are mediated through adipose DHA, but rather that subjects with increased levels of adipose DHA have been exposed regularly to higher amounts of fish oils during the previous 2 to 3 years. Furthermore, using adipose tissue measurements of omega-3 fatty acids may represent the only unbiased alternative to estimate effects in case-control studies, because other biomarkers may fail to reflect long-term intake, and direct intake assessment may be subject to differential recall bias. However, at least 2 limitations of the use of ALA and DHA as biological markers of intake should be considered. First, information on nutrient intake is not available, making it impossible to obtain calorie-adjusted estimates of risk.41 In two prospective studies, fish intake was positively associated with total calorie intake.4 5 Because of the inverse association of coronary heart disease with total calories and the effect of physical activity, adjusting for caloric intake in the present study would probably tend to increase, rather than decrease, relative risk estimates for DHA. Second, ALA and DHA are small peaks in the gas chromatogram, typically constituting <1% of total fatty acid peak area of adipose tissue. The reliability of chromatographic determinations is lower for such small peaks, introducing measurement error which tends to attenuate risk estimates.
Comparison with earlier studies is difficult because adipose omega-3 fatty acid composition was not determined, but relative contents in plasma lipid classes (cholesterol esters, phospholipids) were often determined instead. The relative amount of omega-3 fatty acids in these fractions differs. Nevertheless, the association of ALA with cardiovascular events has received relatively little attention. Cases of myocardial infarction had decreased ALA levels in plasma phospholipids,13 17 cholesterol esters,17 and platelet membranes14 in 3 previous studies, but risk-factor–adjusted estimates of risk were not available. In the MRFIT3 and in the Health Professionals Follow-up42 studies, intake of ALA was inversely related to risk of cardiovascular mortality, and adjusted estimates of risk for quintiles of ALA intake in those studies were similar to those in the EURAMIC study. Also, in a randomized trial of dietary prevention in patients after myocardial infarction, the group assigned to receive advice on a Mediterranean-type diet rich in oleic acid, ALA, and antioxidants had a 70% reduction in mortality after an average follow-up of 2.3 years, but the design of this study did not permit researchers to determine whether the protective effect was due to ALA or to other dietary differences.28
In the Zutphen study, a 40% reduction in coronary deaths was evident in men who ate only 1 to 14 g of fish per day compared with those who did not eat fish.2 Less marked risk reductions in coronary mortality with increasing fish intake were also shown in the Western Electric study5 and in the MRFIT control cohort.3 However, no beneficial effects of fish intake were shown in 2 cohorts of Norwegian7 and Japanese-American men8 (2 groups with high average levels of fish intake) as well as in 2 large cohorts of US health professionals.11 12
In a prospective study, plasma levels of fish oils in phospholipids or cholesterol esters were not associated with decreased risk of myocardial infarction in a cohort of US male physicians.15 These results were similar to the EURAMIC study and to those of a case-control study of myocardial infarction and platelet membrane EPA.14 A smaller prospective study found increased levels of fish oils in plasma phospholipids of myocardial infarction cases, but adjusted estimates of risk were not available from this study.13
In the Zutphen, Western Electric, and MRFIT studies, the benefits of fish intake appeared with amounts of omega-3 fatty acid intake too small to expect any eicosanoid-dependent physiological effect.2 3 5 This may be explained by an increase in risk in people with very low intake of omega-3 fatty acids,37 but in our study, participants with undetectable or very low concentrations of DHA or ALA were not at increased risk of myocardial infarction. Further studies should evaluate whether people with very low intake of omega-3 fatty acids are at increased risk of coronary heart disease.
A common characteristic of studies showing a protective effect of omega-3 fatty acids is their use of mortality endpoints as outcomes.2 3 5 6 18 28 43 In the Diet and Reinfarction Trial, participants who increased their intake of fatty fish had a significant 29% reduction in ischemic heart disease mortality, but had actually an increase in reinfarctions during 2 years of follow-up.18 Sudden cardiac death was associated with low red blood cell membrane levels of EPA and DHA in a population-based case-control study,43 and with low fish intake in the Physicians' Health Study,6 although a case-control study found similar levels of adipose ALA and DHA in cases of sudden death and in controls.16 These findings are in agreement with experimental evidence in animals that omega-3 fatty acids reduce the vulnerability of the ischemic myocardium to ventricular fibrillation.44 45 46 Our patients were admitted to coronary care units. We cannot exclude the possibility that the ALA and DHA levels in these patients were higher than in those who died during their first heart attack.
The results of the EURAMIC study do not support the hypothesis of a beneficial effect of fish intake on the risk of a first myocardial infarction, even among patients with low levels of omega-3 fatty acids. In view of other experimental, clinical, and epidemiological evidence, further research is needed to clarify the role of ALA in the primary and secondary prevention of coronary mortality.
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Acknowledgments |
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The EURAMIC (EURopean multicenter case-control study on Antioxidants, Myocardial Infarction and breast Cancer) Study was supported as an European Community Concerted Action by the Commission of the European Communities (contracts number MR4*/265/NL and MR4*/CT91/0369[SSMA]). The national studies were financed by grants from the British Heart Foundation, the Dutch Ministry of Health, the Spanish "Fondo de Investigaciones Sanitarias" (91E0575), the German Federal Health Office, the Norwegian Research Council, the Russian Ministry of Science, the Swiss National Science Foundation (32-31312-91 and 32-9257-87), the Yrjö Jahnsson Foundation, and the Israel Science Foundation.
Received February 9, 1998; accepted October 28, 1998.
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