Context Higher consumption of fish and omega-3 fatty acids has been associated
with a lower risk of coronary heart disease (CHD) in men, but limited data
are available regarding women.
Objective To examine the association between fish and long-chain omega-3 fatty
acid consumption and risk of CHD in women.
Design, Setting, and Participants Dietary consumption and follow-up data from 84 688 female nurses
enrolled in the Nurses' Health Study, aged 34 to 59 years and free from cardiovascular
disease and cancer at baseline in 1980, were compared from validated questionnaires
completed in 1980, 1984, 1986, 1990, and 1994.
Main Outcome Measures Incident nonfatal myocardial infarction and CHD deaths.
Results During 16 years of follow-up, there were 1513 incident cases of CHD
(484 CHD deaths and 1029 nonfatal myocardial infarctions). Compared with women
who rarely ate fish (<1 per month), those with a higher intake of fish
had a lower risk of CHD. After adjustment for age, smoking, and other cardiovascular
risk factors, the multivariable relative risks (RRs) of CHD were 0.79 (95%
confidence interval [CI], 0.64-0.97) for fish consumption 1 to 3 times per
month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88)
for 2 to 4 times per week, and 0.66 (95% CI, 0.50-0.89) for 5 or more times
per week (P for trend = .001). Similarly, women with
a higher intake of omega-3 fatty acids had a lower risk of CHD, with multivariable
RRs of 1.0, 0.93, 0.78, 0.68, and 0.67 (P<.001
for trend) across quintiles of intake. For fish intake and omega-3 fatty acids,
the inverse association appeared to be stronger for CHD deaths (multivariate
RR for fish consumption 5 times per week, 0.55 [95% CI, 0.33-0.90] for CHD
deaths vs 0.73 [0.51-1.04]) than for nonfatal myocardial infarction.
Conclusion Among women, higher consumption of fish and omega-3 fatty acids is associated
with a lower risk of CHD, particularly CHD deaths.
Low rates of cardiovascular disease in populations with a high intake
of fish, such as Alaskan Natives,1,2
Greenland Eskimos,3,4 and Japanese
people residing in fishing villages,5,6
have suggested that fish consumption may protect against atherosclerosis.
not all prospective cohort studies10,11
have found an inverse association between fish consumption and risk of coronary
heart disease (CHD). In addition, 2 secondary-prevention trials12,13
showed that increasing fish consumption or fish-oil supplementation reduced
coronary mortality among patients with preexisting coronary disease. Virtually
all previous studies on fish consumption and CHD were conducted in men; these
results may not apply to women. We therefore examined the association between
fish and long-chain omega-3 fatty acid intake and incidence of CHD among women
in the Nurses' Health Study cohort during 16 years of follow-up.
The Nurses' Health Study began in 1976, when 121 700 women who
were registered nurses (98% white) aged 30 to 55 years and living in 11 US
states completed questionnaires about their lifestyle and medical history.
Every 2 years, follow-up questionnaires were sent to update information and
identify new major illnesses. A total of 98 462 women returned the 1980
dietary questionnaire. We excluded women who left 10 or more items blank,
those with reported total food intakes judged to be implausible, and those
who had a history of cancer (except nonmelanoma skin cancer), angina, myocardial
infarction (MI), coronary revascularization, stroke, or other cardiovascular
diseases before 1980. After these exclusions, 84 688 women remained for
The semiquantitative food frequency questionnaire used in 1980 included
a survey of 61 foods, including a single question assessing fish intake.14 A common unit or portion size for each food (eg,
168-224 g [6-8 oz] for fish) was specified, and each woman was asked how often
on average during the previous year she had consumed that amount. Nine responses
were possible for each food item, ranging from "almost never" to "6 or more
times per day." In 1984, 1986, 1990, and 1994, the dietary questionnaire was
expanded to include 4 fish and seafood items: (1) dark-meat fish such as mackerel,
salmon, sardines, bluefish, or swordfish (84-140 g [3-5 oz]); (2) canned tuna
(84-112 g [3-4 oz]); (3) other fish (84-140 g [3-5 oz]); and (4) shrimp, lobster,
or scallops as the main dish (98 g [3.5 oz]). The average daily intake of
nutrients was calculated by multiplying the frequency of consumption of each
item by its nutrient content per serving and totaling the nutrient intake
for all food items.
The calculation of long-chain omega-3 fatty acids has been described
in detail elsewhere.15 Briefly, to calculate
intake of omega-3 fatty acids (eicosapentaenoic acid and docosahexanoic acid),
we assigned grams per serving as follows: 1.51 for dark-meat fish, 0.42 for
canned tuna fish, 0.48 for other fish, and 0.32 for shrimp, lobster, or scallops.
These omega-3 fatty acid values were derived by weighting the mean values
of omega-3 fatty acids for the most common types of fish according to US landing
data in 1984 (US Department of Commerce). To make the intake of marine omega-3
fatty acids from the 1980 questionnaire as comparable as possible with the
later, more detailed questionnaires, we assigned 1.16 g of long-chain omega-3
fatty acids per portion (168-224 g [6-8 oz]) on the 1980 questionnaire. This
number was calculated as a weighted average of omega-3 fatty acid composition
from dark-meat fish, canned tuna, and other fish by using the relative consumption
of these types of fish on the 1984 dietary questionnaire. Intake of long-chain
omega-3 fatty acids was primarily from fish (87% of the total intake) and
secondarily from chicken (7%) and liver (2%), which is similar to that in
the US food supply data.13
The reproducibility and validity of the 1984 dietary questionnaire were
assessed in a random sample of 127 men aged 45 to 70 years and living in the
Boston area by comparing the data from the questionnaire with the data from
2 one-week dietary records, collected approximately 6 to 8 months apart,16 and with the fatty acid composition of adipose tissue.17 Spearman rank correlation coefficients for the fish
items between 2 questionnaires administered 1 year apart were 0.63 for dark-meat
fish, 0.54 for canned tuna, 0.48 for other fish, and 0.67 for shrimp, lobster,
or scallops as a main dish.16 The mean total
fish intake was 3.7 servings weekly according to the questionnaire and 3.6
servings weekly according to 2 one-week dietary records (Spearman rank correlation
coefficient, 0.61; P<.001). The energy-adjusted
intake of eicosopentaenoic acid from fish also was correlated with the percentage
of eicosopentaenoic acid in adipose tissue (Spearman rank correlation, 0.49; P<.001).17 Information
on fish oil supplements was not requested until 1990 in the Nurses' Health
Study; at that point, the prevalence of consumption of this supplement was
The end point for this study was incidence of CHD (including CHD deaths
and nonfatal MI) occurring after return of the 1980 questionnaire but before
June 1, 1996. We sought to review medical records for all self-reported MIs.
Records were reviewed by physicians with no knowledge of the self-reported
risk factor status. The diagnosis of MI was confirmed by using World Health
Organization criteria: symptoms in addition to either diagnostic electrocardiographic
changes or elevated cardiac enzyme levels.18
Infarctions that required hospital admission and for which confirmatory information
was obtained by interview or letter, but for which no medical records were
available, were designated as probable (17%).
Deaths were identified from state vital records and the National Death
Index or reported by next of kin and the postal system. Follow-up for death
was more than 98% complete.19 Fatal coronary
disease was defined as fatal MI if it was confirmed by hospital records or
autopsy, if coronary disease was listed as the cause of death on the death
certificate and was the underlying and most plausible cause, and if evidence
of previous coronary disease was available. We designated as presumed coronary
disease (15% fatal cases) those in which coronary disease was the underlying
cause on the death certificate but for which no records were available.
For each woman, person-months of follow-up were calculated from the
date of return of the 1980 questionnaire to the first end point, death, or
June 1, 1996, whichever came first. Women who reported having cardiovascular
disease or cancer on previous questionnaires were excluded from subsequent
Because of the long follow-up period, dietary variables were updated
to better represent long-term dietary patterns, using the information from
1980, 1984, 1986, 1990, and 1994 dietary questionnaires. We calculated intake
of fish and omega-3 fatty acids as a cumulative average of intake from all
available dietary questionnaires up to the start of each 2-year follow-up
interval in which events were reported.20 Because
changes in diet after the development of intermediate end points such as angina,
hypercholesterolemia, and diabetes may confound information on diet and disease,
we stopped updating information on diet at the beginning of the interval during
which these intermediate end points developed in an individual subject.21 The other nutrient variables (fiber, trans-fat, and the ratio of polyunsaturated to saturated fats) and
intake of fruits and vegetables and red meat (beef, pork, or lamb as the main
dish or mixed dish) were also calculated as a cumulative average of intake.
We divided women into 5 categories according to frequency of fish consumption
(<1 per month, 1-3 times per month, 1 per week, 2-4 times per week, and ≥5
times per week) or quintiles of omega-3 fatty acids (as the percentage of
total energy) and calculated incidence rates by dividing the number of events
by person-time of follow-up in each category. The relative risk (RR) was computed
as the rate in a specific category of fish or omega-3 fatty acid consumption
divided by that in the lowest category, with adjustment for age in 5-year
We used Cox proportional hazards modeling (PROC PHREG) for all multivariable
analyses (SAS Institute Inc, Cary, NC). The Anderson-Gill data structure was
used to handle time-varying covariates efficiently,22
where a new data record was created for every questionnaire cycle at which
a participant was at risk, with covariates set to their values when the questionnaire
was returned. To control as finely as possible for confounding by age, calendar
time, and any possible 2-way interactions between these 2 time scales, we
stratified the analysis jointly by age in months at the start of follow-up
and calendar year of the current questionnaire cycle. The time scale for the
analysis was measured as months since the start of the current questionnaire
cycle, which is equivalent to age in months. In the multivariable models,
we simultaneously included total energy intake; cigarette smoking; body mass
index; menopausal status and postmenopausal hormone use; alcohol use; history
of hypertension, high cholesterol, and diabetes; multivitamin use; vitamin
E supplement use; family history of MI; physical activity (number of hours
spent on moderate vigorous exercise per week); and aspirin use (Table 1). In a second multivariate model, we also adjusted for intake
of trans-fat, fiber, and the ratio of polyunsaturated
to saturated fats. Because further adjustment for intake of fruits and vegetables
(5 categories), red meat (quintiles), or α-linolenic acid did not appreciably
alter the results, we did not include them in the final model.
We conducted analyses stratified by aspirin use and the ratio of omega-6
polyunsaturated fat (linoleic acid) to omega-3 fatty acids (the sum of α-linolenic
acid, eicosapentaenoic acid, and docosahexaenoic acid) to assess possible
effect modification by these variables. We tested the significance of the
interaction with a likelihood ratio test by comparing a model with the main
effects of omega-3 fatty acids and the stratifying variable and the interaction
terms with a reduced model with only the main effects.
In a supplemental analysis, we performed a propensity analysis23 in which we used logistic regression modeling to
describe the likelihood of being a woman who consumes fish frequently as opposed
to rarely. Demographic, clinical, and nonfish dietary variables were included
in the propensity model. We used the resulting propensity scores to match
women from the 2 groups.
During 16 years of follow-up (1 307 157 person-years), we
documented 1513 incident cases of CHD (484 CHD deaths and 1029 nonfatal MIs).
As described in detail elsewhere,15 compared
with women who seldom ate fish, women with a higher fish consumption were
slightly older, had a lower prevalence of current smoking, and had a higher
prevalence of being overweight and of hypertension, vigorous activity, regular
aspirin use, and mutivitamin use. Fish consumption was positively associated
with intake of chicken, fruits and vegetables, and dairy foods and was inversely
associated with intake of red meat.
Table 1 presents relative
risk of CHD according to fish intake. We observed significant inverse associations
between fish intake and incidence of CHD after adjustment for age alone and
age plus standard cardiovascular risk factors (P
for trend <.001). After further adjustment for other cardiovascular risk
factors, the association was still significant (P
for trend = .001). Further adjustment for dietary factors did not appreciably
alter the results. The inverse association was somewhat stronger for fatal
CHD (multivariate RR comparing extreme categories of fish consumption was
0.55 [95% CI, 0.33-0.90]) than for nonfatal MI (corresponding RR was 0.73
[95% CI, 0.51-1.04]).
Intake of dietary omega-3 fatty acids was significantly inversely associated
with a lower risk of CHD (Table 2)
(P for trend <.001). Further adjustment for dietary
factors did not materially change these RRs. Again, this inverse association
appeared to be stronger for fatal CHD than for nonfatal MI (Table 2).
The inverse association between intake of fish and omega-3 fatty acids
and risk of CHD was stronger for women who did not use aspirin regularly (<1/week)
than for regular aspirin users (Table 3), but tests for interaction did not reach statistical significance
(P for interaction between fish consumption and aspirin
use = .14; P for interaction between omega-3 fatty
acids and aspirin use = .27). Intake of omega-3 fatty acids was significantly
associated with a lower risk of CHD death among regular aspirin users and
nonusers. In contrast, the inverse association between omega-3 fatty acids
and nonfatal MI was significant only among women who did not use aspirin regularly
(RR comparing extreme quintiles = 0.68; 95% CI, 0.42-1.09; P for trend = .008), not among regular aspirin users (RR comparing
extreme quintiles = 0.83; 95% CI, 0.59-1.16; P for
trend = .15).
We conducted a stratified analysis according to the ratio of omega-6
(linoleic) to omega-3 (the sum of α-linolenic acid and fish oil) fatty
acid intake. In this analysis, we used the mean of the omega-6/omega-3 ratio
(7.6) as a cutoff point to define low and high ratio groups. As shown in Table 4, omega-3 fatty acids were associated
with a significantly lower risk of CHD in both low- and high-ratio omega-6/omega-3
groups. The inverse association appeared to be somewhat stronger in the high-ratio
group than in the low-ratio group, but test for interaction was not statistically
significant (P = .38).
During the 16 years of follow-up, we documented 4121 deaths from all
causes in the cohort. Both fish and omega-3 fatty acid consumption were associated
with a lower risk of all-cause mortality. The multivariate RR of all-cause
mortality comparing women consuming fish at least 5 times weekly with those
consuming fish less than once a month was 0.68 (95% CI, 0.57-0.82; P for trend <.001). The multivariate RR of all-cause mortality comparing
extreme quintiles of omega-3 fatty acid intake was 0.75 (95% CI, 0.67-0.85; P for trend <.001).
In the supplementary analysis of propensity-matched women, those who
consumed fish frequently still had a reduced risk of CHD compared with those
who ate fish rarely (adjusted RR, 0.62; 95% CI, 0.41-0.92).
In this prospective cohort study, we observed a significant inverse
association between fish and omega-3 fatty acid consumption and incidence
of major CHD events, CHD deaths in particular, throughout a 16-year follow-up.
This inverse association was independent of established cardiovascular risk
factors and dietary predictors of CHD such as fiber, trans-fatty acids, and the ratio of polyunsaturated to saturated fats. It
was also not explained by differences in intake of red meat or fruits and
Several prospective cohort studies examined associations between fish
consumption and risk of CHD in men. In the Dutch component of the Seven Countries
Study, with 20 years of follow-up, Kromhout et al7
found that men who consumed 30 g of fish daily had a 50% lower CHD mortality
than men who rarely ate fish. In the Western Electric Study, Daviglus et al8 found that men who consumed at least 35 g of fish
daily had a 40% lower risk of fatal CHD. In the US Physicians' Health Study,
Albert et al9 found that weekly fish consumption
was associated with a lower risk of sudden cardiac death (RR, 0.48; 95% CI,
0.24-0.96) but was not related to risks of nonfatal MI or other cardiovascular
end points.10 In the Health Professionals Follow-up
Study, Ascherio et al11 found no overall association
between dietary intake of omega-3 fatty acids or fish intake and the risk
of coronary disease, but there was a nonsignificant trend for a lower risk
of fatal CHD with increasing fish consumption. Our study is broadly consistent
with previous studies, suggesting that fish consumption is probably more protective
against fatal CHD than nonfatal MI. Notably, previous studies were conducted
in men, none used repeated measures of fish intake in the analysis, and few
adjusted for potential confounding dietary variables.
Two secondary prevention trials, the Diet and Reinfarction Trial (DART)12 and the GISSI-Prevenzione trial,13
showed that fish consumption or fish oil supplementation also reduces coronary
mortality among patients after MI. In the DART, which included 2033 men allocated
to 3 dietary interventions, subjects who received advice to eat more fish
had a significantly lower (29%) total mortality during 2 years of follow-up.
There was also a nonsignificant trend toward a reduction in recurrent ischemic
heart disease events with increased fatty fish consumption. In the more recent
GISSI-Prevenzione trial, which included 11 324 MI patients (primarily
men), daily supplementation (1 g/d) of omega-3 fatty acids for 2 years reduced
occurrence of the main cardiovascular end points (cardiovascular death, nonfatal
MI, and stroke) by 20%, cardiovascular death (including coronary or cardiac
deaths and sudden deaths) by 30%, and all fatal events by 20%. In a secondary
prevention trial, post-MI patients receiving an experimental diet that included
greater intake of α-linolenic acid (a shorter-chain omega-3 fatty acid)
experienced a significant reduction in sudden cardiac death and all-cause
mortality.24,25 Our findings that
fish and omega-3 fatty acid consumption was associated with a lower risk of
overall mortality were consistent with those in other trials.
In our cohort, omega-3 fatty acid intake and fish consumption were associated
with a significantly lower risk of CHD. This finding is consistent with the
hypothesis that omega-3 fatty acids are the active agent primarily responsible
for the apparent protective effect of fish. Omega-3 fatty acids may reduce
CHD incidence and mortality through multiple mechanisms, including reduction
of serum triglycerides,26 platelet aggregability,27 and antiarrhythmic effects.28
Animal studies have established that fish oil intake effectively reduces the
incidence and duration of cardiac arrhythmia.29
In a case-control study, Siscovick et al30
found that dietary intake and cell membrane levels of long-chain omega-3 fatty
acids were associated with a significantly lower risk of primary sudden cardiac
arrest. Multiple mechanisms have been proposed to explain the antiarrhythmic
effect of fish oil, including modification of the eicosanoid system (eg, reducing
the production of thromboxane A2), alteration of the fatty acid
composition of membrane phospholipids, effects on various enzymes and receptors,31 inhibition of the voltage-gated sodium channels,
and changes in heart rate variability.32
There is growing evidence to support the hypothesis that fish oil improves
endothelial dysfunction, which is considered an early marker of atherosclerosis.33,34 In vitro studies have consistently
shown that omega-3 fatty acids decrease expression of adhesion molecules on
the endothelium and also decrease leukocyte-endothelium interactions.33 Additionally, clinical experimental studies have
shown that omega-3 fatty acid supplementation improves endothelial-dependent
vasomotor function.34,35 The beneficial
effects of omega-3 fatty acids on endothelial function may in part explain
the inverse association we observed for nonfatal MI.
Aspirin decreases the risk of CHD in part by blocking the cyclooxygenase
enzyme that converts arachidonic acid to thromboxane, inhibiting platelet
aggregation.36 Long-chain omega-3 fatty acids
also interact with cyclooxygenase enzymes; however, these fatty acids act
as a substrate for the enzymes, leading to the production of an inactive thromboxane
moiety in platelets and an active prostaglandin molecule in endothelial cells.37 The result is reduced platelet aggregation and increased
dilation of blood vessels. Since aspirin is a more potent inhibitor of cyclooxygenase
enzymes than fish oil, it is possible that aspirin use could mask the effect
of small amounts of fish intake. Consistent with our a priori hypothesis,
the inverse association between omega-3 fatty acids and MI was stronger among
women who did not use aspirin regularly than among regular users, which is
consistent with our previous analyses of fish consumption and ischemic stroke.15 However, even among regular aspirin users, a higher
omega-3 fatty acid intake was associated with a significant reduction in CHD
death, suggesting that mechanisms other than those related to prostaglandin
metabolism were involved.
Because omega-6 and omega-3 fatty acids compete for delta-6 desaturase
enzyme in the desaturation and chain elongation pathway and a higher intake
of omega-6 fatty acid may lead to an increase in the production of thromboxane
A2, a proaggregatory vasoconstrictor,31,38
a higher ratio of omega-6 to omega-3 fatty acid intake may attenuate the benefit
of omega-3 fatty acid. In our study, however, the inverse association between
omega-3 fatty acid and CHD persisted in women with a low or high ratio of
omega-6/omega-3 fatty acid intake. Clearly, reducing thrombotic tendency is
only one of several biological mechanisms through which long-chain omega-3
fatty acids may lower the risk of CHD. Because a higher intake of linoleic
acid20 and α-linolenic acid39
was associated with a lower risk of CHD in our cohort, the ratio of omega-6
to omega-3 fatty acids was not appreciably associated with CHD risk.
Our large sample size and long follow-up provided adequate power to
look at CHD deaths and nonfatal MIs separately and conduct planned subgroup
analyses. A unique advantage of this study is that fish consumption was assessed
multiple times, and our analyses using cumulative averages not only took into
account changes in eating behaviors, but also reduced measurement errors caused
by intrasubject variation.21 Finally, we were
able to adjust for important nondietary and dietary covariates, which were
also updated over time.
These observational data cannot prove that fish consumption causes a
reduction in CHD risk. In our cohort, women who consumed more fish had a somewhat
healthier diet and lifestyle. However, careful adjustment for potential dietary
and lifestyle confounding variables did not appreciably alter the results,
suggesting an independent effect of fish and omega-3 fatty acids on CHD risk.
Still, the possibility of unmeasured or incompletely controlled confounding
cannot be excluded. Nevertheless, the biological plausibility of a causal
relationship between fish consumption and reduction in CHD risk through antiarrhythmic
and antithrombotic effects of fish oil, as well as the consistency of the
present findings with those from other prospective cohort studies and secondary
prevention trials, supports the likelihood of a causal association.
In conclusion, this prospective study provides strong evidence for an
inverse association between fish and omega-3 fatty acid consumption and risk
of CHD in women, particularly CHD death. These findings lend further support
to current dietary guidelines recommending fish consumption twice weekly for
the prevention of CHD.40
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