Context Some prospective studies have shown an inverse association between fish
intake and risk of stroke, but none has examined the relationship of fish
and omega-3 polyunsaturated fatty acid intake with risk of specific stroke
subtypes.
Objective To examine the association between fish and omega-3 polyunsaturated
fatty acid intake and risk of stroke subtypes in women.
Design, Setting, and Subjects Prospective cohort study of women in the Nurses' Health Study cohort,
aged 34 to 59 years in 1980, who were free from prior diagnosed cardiovascular
disease, cancer, and history of diabetes and hypercholesterolemia and who
completed a food frequency questionnaire including consumption of fish and
other frequently eaten foods. The 79 839 women who met our eligibility
criteria were followed up for 14 years.
Main Outcome Measure Relative risk of stroke in 1980-1994 compared by category of fish intake
and quintile of omega-3 polyunsaturated fatty acid intake.
Results After 1 086 261 person-years of follow-up, 574 incident strokes
were documented, including 119 subarachnoid hemorrhages, 62 intraparenchymal
hemorrhages, 303 ischemic strokes (264 thrombotic and 39 embolic infarctions),
and 90 strokes of undetermined type. Among thrombotic infarctions, 90 large-artery
occlusive infarctions and 142 lacunar infarctions were identified. Compared
with women who ate fish less than once per month, those with higher intake
of fish had a lower risk of total stroke: the multivariate relative risks
(RRs), adjusted for age, smoking, and other cardiovascular risk factors, were
0.93 (95% confidence interval [CI], 0.65-1.34) for fish consumption 1 to 3
times per month, 0.78 (95% CI, 0.55-1.12) for once per week, 0.73 (95% CI,
0.47-1.14) for 2 to 4 times per week, and 0.48 (95% CI, 0.21-1.06) for 5 or
more times per week (P for trend = .06). Among stroke
subtypes, a significantly reduced risk of thrombotic infarction was found
among women who ate fish 2 or more times per week (multivariate RR, 0.49;
95% CI, 0.26-0.93). Women in the highest quintile of intake of long-chain
omega-3 polyunsaturated fatty acids had reduced risk of total stroke and thrombotic
infarction, with multivariate RRs of 0.72 (95% CI, 0.53-0.99) and 0.67 (95%
CI, 0.42-1.07), respectively. When stratified by aspirin use, fish and omega-3
polyunsaturated fatty acid intakes were inversely associated with risk of
thrombotic infarction, primarily among women who did not regularly take aspirin.
There was no association between fish or omega-3 polyunsaturated fatty acid
intake and risk of hemorrhagic stroke.
Conclusions Our data indicate that higher consumption of fish and omega-3 polyunsaturated
fatty acids is associated with a reduced risk of thrombotic infarction, primarily
among women who do not take aspirin regularly, but is not related to risk
of hemorrhagic stroke.
An inverse relationship between fish intake and risk of stroke has been
reported in several,1,2 but not
all,3,4 prospective studies. Mechanisms
for protection against stroke by fish intake may include inhibition of platelet
aggregation5,6; lowered blood
viscosity6; suppressed formation of leukotrienes
(lipid mediators for neutrophil and macrophage aggregation)7;
and reduction of plasma fibrinogen8 blood pressure
levels9 and insulin resistance.10
The possibility that fish consumption may increase the risk of hemorrhagic
stroke was suggested by ecologic studies in which Greenland Eskimos with very
high intake of omega-3 polyunsaturated fatty acids (omega-3 fatty acids) had
an excess risk of mortality from hemorrhagic stroke compared with Danish whites.11,12 However, the average food supply
per capita for omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic
acid) among persons living in the United States is about 0.1 to 0.2 g/d,13 much lower than that of Danish whites (0.8 g/d) and
Greenland Eskimos (10.5 g/d).14 Thus, the potential
for any increased risk of hemorrhagic stroke may be minimal at the average
intake level of US residents. To our knowledge, no prospective study has examined
previously the relationship between intake of fish and omega-3 fatty acids
and risk of stroke by stroke subtype. We investigated this relationship prospectively
during 14 years of follow-up. Our a priori hypothesis was that intake of fish
and omega-3 fatty acids would be associated with reduced risk of ischemic
stroke and would not be associated with increased risk of hemorrhagic stroke
among middle-aged US women.
The Nurses' Health Study began in 1976, when 121 700 female registered
nurses (98% white) living in 11 states who were then aged 30 to 55 years completed
questionnaires about their lifestyle and medical history, including previous
cardiovascular disease, cancer, diabetes, hypertension, and high serum cholesterol
concentration.15 Every 2 years, follow-up questionnaires
have been sent to update information and identify new major illnesses. A total
of 98 759 women returned the 1980 dietary questionnaire. For these analyses,
we excluded women who left 10 or more items blank (n = 4056), those with reported
total food intakes judged to be implausible (n = 2235), and those who had
a history of cancer (except nonmelanoma skin cancer), angina, myocardial infarction,
coronary revascularization, stroke, or other cardiovascular diseases prior
to 1980 (n = 6739). Women who reported a history of physician-diagnosed diabetes
or high serum cholesterol levels (n = 5890) were also excluded because these
disorders might have caused a change in diet, particularly with regard to
intake of fish and fatty acids. After these exclusions, 79 839 women
remained for these analyses.
The semiquantitative food frequency questionnaire used in 1980 included
a survey of 61 foods, including a single question assessing fish intake.16 A common unit or portion size for each food (eg,
6-8 oz [168-224 g] 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 "six or more
times per day." In 1984, 1986, and 1990, the dietary questionnaire was expanded
to include 4 fish and seafood items: (1) dark-meat fish such as mackerel,
salmon, sardines, bluefish, or swordfish (3-5 oz [84-140 g]);(2) canned tuna
(3-4 oz [84-112 g]); (3) other fish (3-5 oz [84-140 g]); and (4) shrimp, lobster,
or scallops as main dish (3.5 oz [98 g]). 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.
For calculating intake of long chain omega-3 fatty acids (eicosapentaenoic
acid and docosahexaenoic acid), we assigned grams per serving as follows:
1.51 g for dark-meat fish, 0.42 g for canned tuna fish, 0.48 g for other fish,
and 0.32 g for shrimp, lobster, or scallops. These omega-3 fatty acids values
were derived by weighting the mean values of omega-3 fatty acids17
for the most common types of fish based on US landing data in 1984 (US Department
of Commerce). For dark-meat fish with landings of 10 million pounds or more,
the percentage of the total landing weight was 70% for salmon, 18% for Atlantic
herring, 7% for canned sardines, 3% for mixed mackerel, and 1% for bluefish
and swordfish. For canned tuna, these values were 75% for light tuna, and
25% for white tuna. For other fish, these values were 43% for flounder, 19%
for Atlantic cod, 16% for whiting (Hake), 9% for halibut, 8% for Atlantic
pollock, and 5% for haddock. For shrimp, lobster, and scallop, the value of
omega-3 fatty acids in moist shrimp was used. The reason for the relatively
high omega-3 fatty acids grams per serving for the "other fish" category (0.48
g) was due to the inclusion of flounder and whiting, which contain 0.57 to
0.59 g of omega-3 fatty acids per serving (4 oz [112 g]) even though they
are regarded as light-meat fish.
Nutrient intakes were adjusted for total energy intake by the residual
approach.16 To make the intake of marine omega-3
fatty acids from the 1980 questionnaire be as comparable as possible with
the later, more detailed questionnaires, we assigned 1.16 g of long chain
omega-3 fatty acids per portion (6-8 oz [168-224 g]) on the 1980 questionnaire.
This number was calculated as a weighted average of long chain omega-3 fatty
acids composition from dark-meat fish, canned tuna, and other fish, 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 through 70 years living in
the Boston, Mass, area by comparing the data from the questionnaire with the
data from two 1-week dietary records, collected approximately 6 to 8 months
apart and with the fatty acid composition of adipose tissue. Spearman 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.18
The mean total fish intake was 3.7 servings per week according to the questionnaire
and 3.6 servings per week according to two 1-week dietary records (Spearman
correlation coefficient, 0.61; P<.001).18 The energy-adjusted intake of eicosopentaenoic acid
from fish also was correlated with percentage of eicosopentaenoic acid in
adipose tissue (Spearman correlation coefficient, 0.49; P<.001).19 Information on fish oil
supplement was not requested until 1990 in the Nurses' Health Study. At that
point the prevalence of consumption of this supplement was only 1.6%.
Strokes were included in these analyses if they occurred after the date
of return of the 1980 questionnaire and before June 1, 1994. Women who reported
a nonfatal stroke on a follow-up questionnaire were asked for permission to
review their medical records. Medical records were available for review for
81% of stroke cases and were confirmed by physicians blinded to the data on
diet and other risk factors. Nonfatal strokes for which confirmatory information
was obtained by telephone or letter but for which no medical records were
available were regarded as probable (19% of nonfatal strokes). Deaths were
ascertained by reports of relatives or postal authorities and a search of
the National Death Index. Mortality follow-up was more than 98% complete.20 For fatal strokes, confirmatory information was obtained
by telephone interview, letter, medical records, or death certificate. When
no medical records were available (death certificate information only), fatal
strokes were regarded as probable (21.8% of fatal strokes). For the analyses
of total stroke, both confirmed and probable strokes were used.
Strokes were confirmed by medical records according to the criteria
of the National Survey of Stroke,21 which requires
a constellation of neurologic deficits of sudden or rapid onset lasting at
least 24 hours or until death. Events were classified as subarachnoid hemorrhages,
intraparenchymal hemorrhages, ischemic strokes (thrombotic or embolic), or
stroke of undetermined type. Subarachnoid hemorrhage
was defined as hemorrhage in the subarachnoid space, usually caused by the
rupture of a saccular aneurysm of the cerebral arteries, less commonly by
arteriovenous malformations or other causes. Intraparenchymal
hemorrhage was defined as hemorrhage in intraparenchymal regions of
the brain not due to an aneurysm or arteriovenous malformation. Ischemic stroke includes cerebral infarction caused by thrombi (thrombotic
stroke) or by emboli from extracranial sources (embolic stroke). For each
subtype of stroke, a definite diagnosis was made when computed tomographic
(CT) scan, magnetic resonance imaging (MRI), angiography, surgery, or autopsy
confirmed the lesion. If such confirmation was lacking, a probable diagnosis
was made.
All confirmed thrombotic strokes were further classified as large-artery
occlusive infarction, lacunar infarction, or unclassified thrombotic infarction
based on the results of CT scan, MRI, or autopsy according to the criteria
of Perth Community Stroke Study.22 Large-artery
occlusive infarction was defined as infarction involving the cerebral artery
regions in the cerebrum and cerebellum, presumably caused by thrombosis of
large or medium-sized cerebral arteries. A definite diagnosis was made when
CT scan, MRI, or autopsy showed confirmatory findings. If imaging studies
lacked positive findings, but the patient had cerebral signs, a diagnosis
of probable large-artery occlusive infarction was made. Lacunar infarction, which is caused by occlusion of small penetrating
arteries, was defined as infarction of a focal, small, and deep area such
as internal capsule, corona radiata, basal ganglia, or brainstem without involvement
of cortex. A definite diagnosis was made when CT scan, MRI, or autopsy showed
confirmatory findings. If imaging studies were negative, but the patient had
a lacunar syndrome (pure motor stroke, pure sensory stroke, ataxic hemiparesis,
dysarthria-clumsy hand syndrome, or sensorimotor stroke), a diagnosis of probable
lacunar infarction was made. Other thrombotic strokes were regarded as unclassified
thrombotic infarction. Additional details and validation of the stroke subclassification
system have been published elsewhere.23 When
we combined the data for definite and probable cases of large-artery occlusive
infarction and lacunar infarction, results were similar (70 and 20 for definite
and probable large-artery occlusive infarction; and 63 for definite and probable
lacunar infarction, respectively).
Analyses were based on incidence rates of stroke during 14 years of
follow-up (1980-1994). 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, 1994, whichever came first. Women who reported having cardiovascular
disease or cancer on previous questionnaires were excluded from subsequent
follow-up.
Because of the long follow-up period, dietary exposures and variables
were updated to better represent long-term dietary patterns, using the 1980,
1984, 1986, and 1990 dietary questionnaires. We calculated intakes 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. For example, the incidence of stroke from 1980
through 1984 was related to fish and omega-3 fatty acids intake reported on
the 1980 questionnaire, and the incidence from 1984 through 1986 was related
to the average intake reported on the 1980 and 1984 questionnaires. 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. The
other nutrient variables (saturated fat, trans-unsaturated
fat, animal protein, linoleic acid, and calcium) and intake of fruits and
vegetables were also calculated as a cumulative average of intake.
Height was ascertained in 1976. Information on regular exercise was
ascertained on the 1980 questionnaire. Usual aspirin use was updated in 1982,
1984, and 1988, and usual alcohol intake was updated in 1984, 1986, and 1990.
All other exposure variables (ie, smoking, body mass index, menopausal status,
postmenopausal hormone use, and use of multivitamins) were updated on each
follow-up questionnaire.
The relative risk (RR) of stroke was defined as the incidence rate of
stroke among women in various categories of fish intake and in quintiles of
omega-3 fatty acids intake divided by the corresponding rate among women in
the lowest category of intake. Relative risks with 95% confidence intervals
(CIs) were adjusted for age in 5-year categories, and Mantel-Haenszel tests
for trend across the dietary categories were conducted by assigning median
values for each category.
We also conducted analyses stratified by aspirin use to assess possible
effect modification by this variable. Because aspirin reduces platelet aggregation
by inhibiting synthesis of thromboxane A2 in platelets, intakes
of fish and omega-3 fatty acids might be expected to have a smaller effect
in the prevention of stroke among regular aspirin users.24
To adjust simultaneously for other cardiovascular risk factors and selected
nutrient variables associated with risk of all stroke or stroke subtypes,
we used pooled logistic regression with seven 2-year follow-up intervals.25
Among 79 839 women followed up for 14 years, 574 incident cases
of stroke occurred during 1086 261 person-years of follow-up. These strokes
included 119 subarachnoid hemorrhages, 62 intraparenchymal hemorrhages, 303
ischemic strokes (264 thrombotic and 39 embolic), and 90 strokes of undetermined
type. Among the thrombotic infarctions, there were 90 large-artery occlusive
infarctions and 142 lacunar infarctions.
Table 1 shows selected cardiovascular
risk factors, as well as intakes of selected nutrients and foods, by categories
of fish and omega-3 fatty acids intake. Compared with women who ate fish less
than once per month, women who ate fish 2 or more times per week were slightly
older, had a lower prevalence of current smoking, and had a higher prevalence
of overweight, hypertension, vigorous activity, and regular aspirin use and
mutivitamin use. Fish intake was positively associated with total energy intake
and intakes of chicken, egg, fruits and vegetables, and dairy foods, and it
was inversely associated with intake of red meat. Moreover, fish intake was
positively associated with dietary intakes of animal protein, calcium, and
was inversely associated with intake of saturated fat, trans-unsaturated fat, and linoleic acid. Similar but weaker associations
were observed between omega-3 fatty acids quintiles because the 2 highest
categories of fish intake (ie, 2-4 and ≥5 times per week) mostly corresponded
to the highest quintile of omega-3 fatty acids intake.
Table 2 presents RRs of
total stroke and stroke subtypes according to fish intake. There were significant
inverse associations between fish intake and age- and smoking-adjusted risk
of total stroke, ischemic stroke, and thrombotic infarction, specifically
lacunar infarction. After further adjustment for other cardiovascular and
selected dietary variables, the inverse remained significant for thrombotic
infarction and lacunar infarction, with a reduced risk of these stroke subtypes
among women who ate fish 2 or more times per week. The multivariate RRs were
0.49 (95% CI, 0.26-0.93; P = .03), and 0.28 (95%
CI, 0.12-0.67; P = .004), respectively. We found
no excess risk of hemorrhagic stroke, either intraparenchymal or subarachnoid
hemorrhage, among women who ate fish frequently.
Intake of omega-3 fatty acids was inversely associated with age- and
smoking-adjusted risks of total stroke, hemorrhagic stroke, and subarachnoid
hemorrhage (Table 3). Women in
the highest quintile of omega-3 fatty acids intake had reduced risk of ischemic
stroke, thrombotic infarction, and lacunar infarction although the trends
did not reach statistical significance. There was no association between omega-3
fatty acids intake and risk of intraparenchymal hemorrhage. After further
adjustment for other cardiovascular risk factors and selected dietary variables,
women in the highest quintile of omega-3 fatty acids intake had significantly
reduced risks of total stroke and lacunar infarction and a borderline reduction
in risk of thrombotic infarction. The multivariate RRs in the highest vs the
lowest quintiles of omega-3 fatty acids intake were 0.72 (95% CI, 0.53-0.99; P for trend = .12) for total stroke, 0.37 (95% CI, 0.19-0.73; P for trend = .004) for lacunar infarction, and 0.67 (95%
CI, 0.42-1.07; P for trend = .19) for thrombotic
infarction. The inverse associations of omega-3 fatty acids intake with risks
of ischemic stroke and subarachnoid hemorrhage were no longer of statistical
significance. We also conducted analyses using omega-3 fatty acids intake
categories that corresponded to the same percentages as the fish intake categories
(9%, <1 time per month; 34%, 1-3 times per month; 39%, 1 time per week;
15%, 2-4 times per week; and 3%, ≥5 times per week); using these categories
the multivariate RRs of thrombotic infarction were 0.84 (95% CI, 0.48-1.47)
for the second category, 0.63 (95% CI, 0.36-1.10) for the third category,
0.57 (95% CI, 0.29-1.13) for the fourth category, and 0.23 (95% CI, 0.05-1.08)
for the highest category, P for trend = .04.
When we stratified our results by aspirin consumption, the inverse association
between fish intake and risk of thrombotic infarction was more evident among
women without regular aspirin use (Table
4). Women who did not use aspirin and were in the highest quintile
of omega-3 fatty acids intake had a significantly reduced risk of thrombotic
infarction whereas the trend among aspirin users was nonsignificant. Further
classification of thrombotic infarction subtypes (large-artery occlusive infarction
and lacunar infarction) was not possible due to the small number of cases
in these strata. When we conducted the analysis according to omega-3 fatty
acids intake categories using the same percentages as fish categories, the
interaction between aspirin, omega-3 fatty acids, and risk of thrombotic infarction
became more evident. Among women who did not use aspirin, the multivariate
RRs of thrombotic infarction were 0.77 (95% CI, 0.39-1.50) for the second
category, 0.56 (95% CI, 0.29-1.10) for the third category, and 0.34 (95% CI,
0.14-1.83) for the fourth category with no cases in the highest category (P for trend = .01). The respective RRs among regular aspirin
users were 0.98 (95% CI, 0.34-2.85), 0.77 (95% CI, 0.27-2.21), 0.96 (95% CI,
0.29-3.17), and 0.75 (95% CI, 0.12-4.63) (P for trend
= .94).
We observed a significant inverse association between fish intake and
risk of stroke, primarily thrombotic stroke, after adjustment for cardiovascular
risk factors and selected dietary variables. Risk of thrombotic infarction
was significantly reduced by 48% among women who ate fish 2 to 4 times per
week. The observed reduction in stroke risk associated with a relatively low
frequency of fish intake is consistent with several previous prospective studies.1,2 In a Dutch study,1
men who consumed more than 0.7 oz (20 g) of fish per day were at half the
risk of total stroke as men who consumed less fish. The First National Health
and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study2 indicated that women who ate fish more than once a
week were at about half the risk of total stroke as women who never ate fish.
Women who ate fish once a week or less had a 22% to 23% lower risk than those
who never ate fish; however, the trend did not reach statistical significance.2 Two prospective studies among white men showed no
significant relationship between fish intake and risk of total stroke.3,4 The Physicians' Health Study3 found an RR of 0.6 (95% CI, 0.3-1.6) for total stroke
among men who ate fish 5 or more times per week compared with men who ate
fish less than once a week. Of note, half of the men in the Physicians' Health
Study were also taking aspirin, so the effect of fish intake would have been
attenuated. The Chicago Western Electric study4
found an RR of 1.3 (95% CI, 0.7-2.2) among men who ate 1.2 oz (35 g) or more
fish per day compared with men who ate no fish. This study relied only on
death certificates and information from the Health Care Financing Administration
for stroke ascertainment. In our study, the hypothesized inverse association
with fish intake was seen primarily for ischemic stroke, specifically thrombotic
infarction. Furthermore, we found a reduced risk associated with fish intake
for lacunar infarction but not for large-artery occlusive infarction. We found
no excess risk of hemorrhagic stroke, either subarachnoid hemorrhage or intraparenchymal
hemorrhage, with fish intake.
We also examined the association between omega-3 fatty acids intake
and risk of stroke and observed a reduced risk of total stroke among women
in the highest quintile. Among stroke subtypes, the risk reduction was of
borderline statistical significance for thrombotic infarction and of statistical
significance for lacunar infarction. When stratified by aspirin use, women
in the highest omega-3 fatty acids intake quintile who did not use aspirin
had a significant 49% reduction in the risk of thrombotic stroke. These results
support the hypothesis that omega-3 fatty acids are the protective component
in fish that reduce the risk of thrombotic infarction. However, we cannot
exclude the possibility that some other ingredients in fish may contribute
to a reduction in risk or that some residual confounding by other risk factors
remains.
Several mechanisms may be involved in the lower stroke risk associated
with omega-3 fatty acids. A high-dose supplementation of these fatty acids
(eg, 15 g/d of eicoapentanenoic acid) reduces the formation of thromboxane
A2 in platelets but does not substantially reduce the synthesis
of prostaglandin I2 in vascular endothelium cells, leading to reduced
platelet aggregation without an adverse effect on vasodilation.5,6,26
Furthermore, eicosapentaenoic acid (in part converted from docosahexaenoic
acid) is transformed into a nonaggregatory agent, thromboxane A3,
which increases the synthesis of a vasodilator, prostaglandin I3,
leading to further reductions in platelet aggregation and increased vasodilation.26 These alterations of prostanoid metabolism are induced
3 to 4 days after the intake of fish oil supplement27
and persist for 8 to 10 weeks after cessation of intake of the supplement.28,29 High-dose supplementation of omega-3
fatty acids (eg, 15 g/d) also lowers blood pressure levels in hypertensive
persons,9 and reduces plasma fibrinogen concentrations
in healthy volunteers.8 These effects may contribute
to the prevention of atherosclerotic development and the thrombotic process.9,30 In in vitro studies, omega-3 fatty
acids decrease product generation by the 5-lipoxygenase pathway (such as leukotriene
B4) of neutrophil and monocytes and attenuate the leukotriene-mediated
chemotaxis and endothelial-cell adherence of neutrophils.7
These fatty acids also reduce production of platelet-derived growth factorlike
protein from vascular endothelial cells,31
which may attenuate proliferation of endothelial cells in the process of atherosclerosis.
In addition to these potential benefits leading to reduced risk of ischemic
stroke, a decrease in whole blood viscosity6,32
and an increase in capillary blood flow33 associated
with omega-3 fatty acids may play a role in the prevention of lacunar infarction,
which involves small cerebral arteries in its pathogenesis.34
Furthermore, dietary omega-3 fatty acids may reduce insulin resistance and
glucose intolerance,10,35 and
this may reduce the risk of lacunar infarction because glucose intolerance
and diabetes are strongly associated with risk of this event.36,37
In our study, the inverse association between estimated intake of omega-3
fatty acids and risk of thrombotic infarction was observed primarily among
women who did not take aspirin regularly. Compared with omega-3 fatty acids,
aspirin has a stronger inhibitory effect on synthesis of thromboxane A2 in platelets; a single dose of aspirin (325 mg) reduces platelet aggregation
for at least 3 days.38 Reduced platelet aggregation
may be one of the major factors in the prevention of thrombotic infarction.
Thus, the strong effect of aspirin on the risk of thrombotic infarction is
likely to obscure a moderate association between omega-3 fatty acids and the
risk among women who take aspirin regularly.
We found no excess risk of either subarachnoid or intraparenchymal hemorrhage
with intake of fish or omega-3 fatty acids in this population, which was not
surprising. While bleeding time is prolonged when the intake of omega-3 fatty
acids exceeds 3 g/d,28,39,40
a level of intake that corresponds approximately to the ingestion of fish
3 times or more per day. In this study of US women, fewer than 0.1% ate fish
3 times or more per day.
In conclusion, consumption of fish and omega-3 fatty acids was associated
with a reduced risk of total stroke and thrombotic infarction primarily among
women who did not take aspirin regularly. Consumption of fish and omega-3
fatty acids was not related to risk of hemorrhagic stroke. These results suggest
that regular intake of fish may be beneficial for the prevention of thrombotic
infarction in middle-aged US women.
1.Keri SO, Feskens EJM, Kromhout D. Fish consumption and risk of stroke: the Zutphen Study.
Stroke.1994;25:328-332.Google Scholar 2.Gillum RF, Mussolino ME, Madans JH. The relationship between fish consumption and stroke incidence: the
NHANES I Epidemiologic Follow-up Study.
Arch Intern Med.1996;156:537-542.Google Scholar 3.Morris MC, Manson JE, Rosner B, Buring JE, Willett WC, Hennekens CH. Fish consumption and cardiovascular disease in the Physicians' Health
Study: a prospective study.
Am J Epidemiol.1995;142:166-175.Google Scholar 4.Orencia AJ, Daviglus ML, Dyer AR, Shekelle RB, Stamler J. Fish consumption and stroke in men: 30-year findings of the Chicago
Western Electric study.
Stroke.1996;27:204-209.Google Scholar 5.Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis.
Lancet.1978;2:117-119.Google Scholar 6.Terano T, Hirai A, Hamazaki T.
et al. Effect of oral administration of highly purified eicosapentaenoic acid
on platelet function, blood viscosity and red cell deformability in healthy
human subjects.
Atherosclerosis.1983;46:321-331.Google Scholar 7.Lee TH, Hoover RL, Williams JD.
et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic
acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil
function.
N Engl J Med.1985;312:1217-1224.Google Scholar 8.Hostmark AT, Bjerkedal T, Kierulf P, Flaten H, Ulshagen K. Fish oil and plasma fibrinogen.
BMJ.1988;297:180-181.Google Scholar 9.Knapp HR, FitzGerald GA. The antihypertensive effects of fish oil: a controlled study of polyunsaturated
fatty acid supplements in essential hypertension.
N Engl J Med.1989;320:1037-1043.Google Scholar 10.Storlien LH, Kraegen EW, Chisholm DJ, Ford GL, Bruce DG, Pascoe WS. Fish oil prevents insulin resistance induced by high-fat feeding in
rats.
Science.1987;237:885-888.Google Scholar 11.Kromann N, Green A. Epidemiological studies in the Upernavik district, Greenland: incidence
of some chronic diseases, 1950-1974.
Acta Med Scand.1980;208:401-406.Google Scholar 12.Kristensen MO. Increased incidence of bleeding intracranial aneurysms in Greenlandic
Eskimos.
Acta Neurochir.1983;67:37-43.Google Scholar 13.Raper NR, Cronin FJ, Exler J. Omega-3 fatty acid content of the US food supply.
J Am Coll Nutr.1992;11:304-308.Google Scholar 14.Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in Greenland.
Am J Clin Nutr.1980;33:2657-2661.Google Scholar 15.Stampfer MJ, Willett WC, Colditz GA, Rosner BA, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary
heart disease.
N Engl J Med.1985;313:1044-1049.Google Scholar 16.Willett WC, Stampfer MJ. Total energy intake: implications for epidemiologic analyses.
Am J Epidemiol.1986;124:17-27.Google Scholar 17.Consumer and Food Economics Institute. Composition of Foods: Handbook 8 Series. Washington, DC: US Dept of Agriculture; 1976-1989.
18.Feskanich D, Rimm EB, Giovannucci El.
et al. Reproducibility and validity of food intake measurements from a semiquantitative
food frequency questionnaire.
J Am Diet Assoc.1993;93:790-796.Google Scholar 19.Hunter DJ, Rimm EB, Sacks FM.
et al. Comparison of measures of fatty acid intake by subcutaneous fat aspirate,
food frequency questionnaire, and diet records in a free-living population
of US men.
Am J Epidemiol.1992;135:418-427.Google Scholar 20.Stampfer MJ, Willett WC, Speizer FE.
et al. Test of the National Death Index.
Am J Epidemiol.1984;119:837-839.Google Scholar 21.Walker AE, Robins M, Weinfeld FD. The National Survey of Stroke: clinical findings.
Stroke.1981;12(2 Pt 2 Suppl 1):I13-I44.Google Scholar 22.Anderson CS, Jamrozik KD, Burvill PW, Chakera TMH, Johnson GA, Stewart-Waynne EG. Determining the incidence of different subtypes of stroke: results
from the Perth Community Stroke Study, 1989-1990.
Med J Aust.1993;158:85-89.Google Scholar 23.Iso H, Rexrode KM, Hennekens CH, Manson JE. Application of computer tomography-oriented criteria for stroke subtype
classification in a prospective study.
Ann Epidemiol.2000;10:81-87.Google Scholar 24.Leaf A, Weber PC. Cardiovascular effects of n-3 fatty acids.
N Engl J Med.1988;318:549-556.Google Scholar 25.D'agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression
analysis: the Framingham Heart Study.
Stat Med.1990;9:1501-1515.Google Scholar 26.von Schacky C, Fischer S, Weber PC. Long term effects of dietary marine n-3 fatty acids upon plasma and
cellular lipids, platelet function and eicosanoid formation in humans.
J Clin Invest.1985;76:1626-1631.Google Scholar 27.Herold P, Kinsella JE. Fish oil consumption and decreased risk of cardiovascular disease:
a comparison of findings from animal and human feeding trials.
Am J Clin Nutr.1986;43:566-598.Google Scholar 28.Thorngren M, Shafi S, Born GV. Delay in primary haemostasis produced by a fish diet without change
in local thromboxane A
2.
Br J Haematol.1984;58:567-578.Google Scholar 29.von Schacky C, Siess W, Fischer S, Weber PC. A comparative study of eicosapetaenoic acid metabolism by human platelets
in vivo and in vitro.
J Lipid Res.1985;26:457-464.Google Scholar 30.Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction.
N Engl J Med.1984;311:501-505.Google Scholar 31.Fox PL, DiCorletto PE. Fish oils inhibit endothelial cell proliferation of platelet derived
growth factor like protein.
Science.1988;241:453-456.Google Scholar 32.Woodcock BE, Smith E, Lambert WH. Beneficial effect of fish oil on blood viscosity in peripheral vascular
disease.
Br Med J (Clin Res Ed).1984;288:592-596.Google Scholar 33.Bruckner G, Webb P, Greenwell L, Chow C, Richardson D. Fish oil increases peripheral capillary blood cell velocity in humans.
Atherosclerosis.1987;66:237-244.Google Scholar 34.Bamford JM, Warlow CP. Evolution and testing of the lacunar hypothesis.
Stroke.1988;19:1074-1082.Google Scholar 35.Feskens EJM, Bowles CH, Kromhout D. Inverse association between fish intake and risk of glucose intolerance
in normoglycemic elderly men and women.
Diabetes Care.1991;14:935-941.Google Scholar 36.Gandolfo C, Caponnetto C, Del Sette M, Santoloci D, Loeb C. Risk factors in lacunar syndromes: a case-control study.
Acta Neurol Scand.1988;77:22-26.Google Scholar 37.Bell DS. Stroke in diabetes patients.
Diabetes Care.1994;17:213-219.Google Scholar 38.Masotti G, Galanti G, Poggesi L, Abbate R, Neri Sernei GG. Differential inhibition of prostacyclin production and platelet aggregation
by aspirin.
Lancet.1979;2:1213-1217.Google Scholar 39.Knapp HR, Reilly IA, Alessandrini P, FitzGerald GA. In vivo indices of platelet and vascular function during fish-oil administration
in patients with atherosclerosis.
N Engl J Med.1986;314:937-942.Google Scholar 40.Lands WEM, Culp BR, Hirag A, Gorman R. Relationship of thromboxane generation to aggregation of platelets
from humans: effects of eicosapentaenoic acid.
Prostaglandins.1985;30:819-823.Google Scholar