(Circulation. 2001;103:856.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Prospective Study of Fat and Protein Intake and Risk of Intraparenchymal Hemorrhage in Women
From Channing Laboratory (H.I., M.J.S., J.E.M., K.R., G.A.C., F.E.S., W.C.W.) and the Division of Preventive Medicine (J.E.M., K.R.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; Departments of Epidemiology (M.J.S., G.A.C., W.C.W.) and Nutrition (M.J.S., F.B.H., W.C.W.), Harvard School of Public Health, Boston, Mass; and University of Miami (C.H.H.), Miami, Fla.
Correspondence to Meir J. Stampfer, MD, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115.
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Abstract |
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Background—Dietary animal fat and protein have been inversely associated with a risk of intraparenchymal hemorrhage in ecological studies.
Methods and Results—In 1980, 85 764 women in the Nurses’ Health Study cohort, who were 34 to 59 years old and free of diagnosed cardiovascular disease and cancer, completed dietary questionnaires. From these questionnaires, we calculated fat and protein intake. By 1994, after 1.16 million person-years of follow-up, 690 incident strokes, including 74 intraparenchymal hemorrhages, had been documented. Multivariate-adjusted risk of intraparenchymal hemorrhage was higher among women in the lowest quintile of energy-adjusted saturated fat intake than at all higher levels of intake (relative risk [RR], 2.36; 95% CI, 1.10 to 5.09; P=0.03). For trans unsaturated fat, the corresponding RR was 2.50 (95% CI, 1.35 to 4.65; P=0.004). Animal protein intake was inversely associated with risk (RR in the highest versus lowest quintiles, 0.32; 95% CI, 0.10 to 1.00; P=0.04). The excess risk associated with low saturated fat intake was observed primarily among women with a history of hypertension (RR, 3.66; 95% CI, 1.09 to 12.3; P=0.04), but such an interaction was not seen for trans unsaturated fat or animal protein. These nutrients were not related to risk of other stroke subtypes. Dietary cholesterol and monounsaturated and polyunsaturated fat were not related to risk of any stroke subtype.
Conclusions—Low intake of saturated fat and animal protein was associated with an increased risk of intraparenchymal hemorrhage, which may help to explain the high rate of this stroke subtype in Asian countries. The increased risk with low intake of saturated fat and trans unsaturated fat is compatible with the reported association between low serum total cholesterol and risk.
Key Words: dietary fats • proteins • stroke • hemorrhage
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Introduction |
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Ecological studies among populations suggest that a low intake of saturated fat (mostly animal fat) and animal protein is associated with an increased risk of intraparenchymal hemorrhagic stroke, specifically intraparenchymal hemorrhage.1 2 Rural Japanese with a very low mean intake of animal fat (15 g/d) and animal protein (44 g/d) had twice the incidence of intraparenchymal hemorrhage as urban Japanese, but the incidence of subarachnoid hemorrhage did not vary among populations.1 2 Japanese persons living in Japan, who had an average intake of 16 g/d of saturated fat and 40 g/d animal protein, had a 3-fold higher incidence of hemorrhagic stroke3 than Japanese persons living in Honolulu, who consumed a mean of 40 g/d saturated fat and 71 g/d animal protein.4 The groups had similar blood pressure levels.4
An association between a low intake of saturated fat and risk of intraparenchymal hemorrhage has also been suggested by a higher risk for intraparenchymal hemorrhage among individuals with very low serum total cholesterol levels (<4.14 mol/L) in studies of Japanese,5 6 7 Japanese-American,8 and white US men.9 In the white men, the increased risk associated with low serum cholesterol levels was confined to those with hypertension.9 However, no prospective study has examined the relationship between the dietary intake of animal fat and protein and the risk of intraparenchymal hemorrhage. An inverse association between animal protein intake and risk of hemorrhagic stroke was reported in a small study (n=34 cases) of Japanese men living in Honolulu, but intraparenchymal and subarachnoid hemorrhages were grouped together.3 Fourteen years of prospective data from the Nurses’ Health Study allowed us to investigate the relationship between animal fat and protein intake and the incidence of stroke. Our a priori hypothesis was that a low intake of animal fat and protein increase the risk of intraparenchymal hemorrhage and that this relationship is most pronounced in hypertensive women.
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Methods |
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The Nurses’ Health Study began in 1976, when 121 700 female registered nurses (98% white) living in 11 states completed questionnaires about their lifestyle and medical history, including previous cardiovascular disease, cancer, diabetes, hypertension, and high serum cholesterol concentration. Every 2 years, follow-up questionnaires are sent to these women to update their exposure variables and to identify any newly diagnosed major illnesses.
Ascertainment of Diet
In 1980, we collected information on usual dietary
intake using a semiquantitative food-frequency
questionnaire.10 For each of
61 food items, a commonly used unit or portion size was specified, and
each woman was asked how often, on average, during the previous year
she had consumed that amount of the item. Nine responses were possible,
ranging from "almost never" to "six or more times per day." The
average daily intake of nutrients was calculated by multiplying the
frequency of the consumption of each item by the nutrient content and
totaling the nutrient intake for all food items. Nutrient intakes were
adjusted for total energy
intake.10 The correlations
between nutrient intakes assessed from four 1-week diet records and
from a subsequent questionnaire were 0.59 for saturated fat, 0.56 for
monounsaturated fat, 0.48 for polyunsaturated fat, 0.61 for
cholesterol, and 0.47 for total
protein.10 A total of
98 462 women returned the 1980 dietary questionnaire. We excluded
women who left 
10 items blank or who had implausible total food
intakes and those who had a history of cancer, angina, myocardial
infarction, coronary revascularization, stroke, or other cardiovascular
diseases in 1980; 85 764 women remained for the
analyses.
Ascertainment of Stroke
Women who reported a nonfatal stroke on a follow-up
questionnaire were asked for permission to review their medical
records. The 18.4% of nonfatal strokes for which confirmatory
information was obtained by telephone or letter but for which no
medical records were available were regarded as probable. Fatal strokes
were initially ascertained from reports from relatives or postal
authorities and a search of the National Death
Index.11 They were then
documented by medical records and/or death certificates. Mortality
follow-up was >98%
complete.11 The 22.3% of
fatal strokes confirmed by telephone, letter, or death certificate, but
for which no medical records were available, were regarded as probable.
Medical records were reviewed by physicians blinded to dietary and
other risk factors.
Strokes were confirmed from medical records according to the
criteria of the National Survey of
Stroke,12 which require a
constellation of neurological deficits of sudden or rapid onset lasting
24 hours or until death; events were further subclassified as
subarachnoid hemorrhages, intraparenchymal hemorrhages, ischemic
strokes (thrombotic or embolic), or strokes of undetermined type.
Results from CT scans, MRIs, or autopsy were available for 88% of
intraparenchymal hemorrhages, 81% of subarachnoid hemorrhages, and
94% of ischemic strokes. Furthermore, complete inter-rater concordance
was achieved when tested in a systematic sample of 100
strokes.13 Strokes were
regarded as incident if they occurred after the date of return of the
1980 questionnaires but before June 1, 1994. Only confirmed and
probable strokes were considered in the analyses of total stroke. For
analyses of intraparenchymal hemorrhage and other specific types of
stroke, only confirmed cases were included. For the end point of
intraparenchymal hemorrhage, we also conducted analyses excluding women
with subcortical hematoma, which is commonly caused by arteriovenous
malformation, and those with concurrent subdural hematoma and cerebral
infarction, because these end points have different pathogenetic
mechanisms.
Statistical Analyses
The analyses were based on incidence rates of stroke
during 14 years of follow-up (1980 to 1994). For each woman,
person-months of follow-up were allocated according to 1980 exposure
variables and were updated according to information on biennial
follow-up questionnaires until death or an end point (stroke) was
reached or until May 31, 1994. From the 1980 questionnaire, we used
information on the intake of fat, protein, and selected foods; the
consumption of n3 polyunsaturated fatty acids; and regular exercise. We
present findings based on the 1980 dietary variables without updating
because we were most interested in the long-term effects of the intake
of fat and protein on risk of stroke. Updating the intakes of these
nutrients using the 1984, 1986, and 1990 questionnaires yielded
generally similar associations with risk of stroke. Height was
ascertained in 1976. Information on usual aspirin use was updated in
1982, 1984, and 1988, and data on alcohol intake were updated in 1984,
1986, and 1990. All other exposure variables (ie, body mass index,
menopausal status, postmenopausal hormone use, and histories of
hypertension, diabetes, high cholesterol levels, and the use of
multivitamin and vitamin E supplements) were updated on each follow-up
questionnaire.
The relative risk of stroke was defined as the incidence of stroke among women in various categories for intake of nutrients and foods, divided by the corresponding rate among women in the lowest category of intake. Relative risks with 95% confidence intervals (95% CI) were adjusted for age in 5-year categories and for smoking status in 5 categories (never, former, current 1 to 14 cigarettes/d, current 15 to 24/d, and current 25+/d), and tests for a linear trend across the dietary categories were conducted using median variables of each dietary category. We conducted stratified analyses by history of hypertension to assess effect modification. To adjust simultaneously for other cardiovascular risk factors, we used pooled logistic regression over the seven 2-year intervals.14
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Results |
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Among the 85 764 women followed for 14 years, we documented 690 incident cases of stroke that occurred during 1 164 577 person-years of follow-up; the strokes included 74 intraparenchymal hemorrhages, 129 subarachnoid hemorrhages, 385 ischemic strokes, and 102 unclassified strokes. Saturated fat intake was positively associated with smoking, diabetes, and overweight and inversely associated with vigorous exercise, alcohol intake, use of multivitamin and vitamin E supplements, and intakes of n3 polyunsaturated fat and calcium (Table 1
). Intake of trans unsaturated fat had
similar associations for all of these variables except diabetes, with
which it had no relation. Animal protein intake was positively
associated with hypertension, diabetes, overweight, vigorous exercise,
use of multivitamin and vitamin E supplements, and intakes of n3
polyunsaturated fat and calcium and inversely associated with smoking
and alcohol intake.
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In analyses adjusted for age and smoking, women in the
lowest quintile for saturated fat had a greater risk of
intraparenchymal hemorrhage than those with higher intakes
(Table 2), but the association was nonlinear. A similar
relation was observed for trans unsaturated fat intake. We observed a
modest, nonsignificant trend toward a lower risk of intraparenchymal
hemorrhage with increased intake of monounsaturated fat, probably due
to the high correlation with saturated fat intake
(r=0.81). These relations were
not altered appreciably after adjustment for total energy intake and
other cardiovascular risk factors. Intakes of cholesterol,
polyunsaturated fat, and total fat were not significantly associated
with risk of intraparenchymal hemorrhage. There was no significant
relation between these fat intakes and risk of subarachnoid hemorrhage
or ischemic stroke (Tables I and II, available at
www.circulationaha.org).
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Lower intake of animal protein tended to be associated with
a higher age- and smoking-adjusted risk of intraparenchymal hemorrhage
(Table 2
). When we examined intakes of specific amino acids,
the relative risks in the highest versus the lowest quintile of amino
acid intake, after controlling for age and smoking, were 0.56 (95% CI,
0.27 to 1.14; P=0.09 for trend)
for methionine, 0.59 (95% CI, 0.28 to 1.22;
P=0.04) for tryptophan, 0.69
(95% CI, 0.33 to 1.46; P=0.13
for trend) for aspartate, and 0.41 (95% CI, 0.18 to 0.90;
P=0.02 for trend) for
glutamate. These associations were not appreciably altered after
adjustment for total energy intake and other cardiovascular risk
factors. Intake of vegetable protein was not associated with risk of
intraparenchymal hemorrhage. There was no significant relation between
total protein intake and risk of subarachnoid hemorrhage or ischemic
stroke (Tables I and II).
The higher risk of intraparenchymal hemorrhage in the lowest
quintile of saturated fat intake was somewhat attenuated but remained
significant after further adjustment for intakes of cholesterol,
specific types of fat, and protein
(Table 3). The multivariate relative risk of the lowest
quintile compared with all higher levels of intakes was 2.36 (95% CI,
1.10 to 5.09; P=0.03). When we
excluded secondary hemorrhages related to use of thrombolytic agents
(n=4) or steroids (n=1) and "atypical cases" with subcortical
hematoma (n=1) or hemorrhage accompanied by subdural hematoma (n=3) or
concurrent cerebral infarction (n=1), the excess risk in the lowest
quintile of saturated fat intake was more pronounced. The multivariate
relative risk of the lowest quintile compared with all higher levels of
intakes was 2.87 (95% CI, 1.23 to 6.47;
P=0.01). We further examined
the risk of primary intraparenchymal hemorrhage in each of the 2 lowest
deciles of saturated fat compared with all higher levels of intake (not
shown in tables). The multivariate relative risk was 3.08 (95% CI,
1.09 to 8.74) for the lowest decile and 2.72 (95% CI, 1.13 to 6.54)
for the second lowest decile
(P=0.02 for trend).
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The significant excess risk of intraparenchymal hemorrhage
in the lowest quintile of trans unsaturated fat intake persisted after
further adjustment for intakes of cholesterol and specific types of fat
and protein
(Table 3); the relative risk of the lowest quintile compared
with all higher levels of intakes was 2.50 (95% CI, 1.35 to 4.65;
P=0.004). The multivariate
relative risk of primary intraparenchymal hemorrhage was 2.73 (95% CI,
1.20 to 6.21) for the lowest decile and 2.53 (95% CI, 1.19 to 5.39)
for the second lowest decile
(P=0.006 for
trend).
An inverse relation between animal protein and risk of
intraparenchymal hemorrhage also remained significant after further
adjustment for intakes of cholesterol, specific types of fat, and
vegetable protein
(Table 3). The association was slightly stronger after
exclusion of secondary or atypical hemorrhage.
The excess risk of intraparenchymal hemorrhage in the lowest
quintile of saturated fat intake was seen primarily among women with a
history of hypertension
(Table 4). The multivariate relative risk in the lowest
quintile compared with all other levels of intake was 3.66 (95% CI,
1.09 to 12.3; P=0.04) among
hypertensives and 1.73 (95% CI, 0.62 to 4.87;
P=0.30) among nonhypertensives.
Such an interaction was not evident for trans unsaturated fat or animal
protein intake.
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We also evaluated foods that contributed importantly to intakes of saturated fat, trans unsaturated fat, or animal protein (data not shown). Women who almost never ate hard cheese were at a significantly higher risk of intraparenchymal hemorrhage than women who ate this food at least once a month, and similar inverse trends were seen for beef, pork, or lamb as a side dish; fish; ice cream; cookies; eggs; cottage cheese; and margarine. Consumption of beef, pork, or lamb as a main dish; chicken; skim or whole milk; hamburger; or white bread was not related to risk of intraparenchymal hemorrhage, and butter intake was positively associated with risk.
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Discussion |
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Intake of Fat and Protein and Stroke Risk
In this large prospective study, women in the lowest quintile of either dietary saturated fat or trans unsaturated fat intake had an
2.5-fold increased risk of intraparenchymal hemorrhage
compared with women in higher quintiles, and animal protein intake was
inversely associated with the risk. As hypothesized a priori, the
excess risk associated with low saturated fat intake was seen primarily
among women with a history of hypertension, but such an interaction was
not evident for trans unsaturated fat or animal protein
intake.
Our findings among American women are consistent with
epidemiological observations comparing Japan and the United States.
Japan has a 2-fold higher stroke mortality rate than the United
States.15 In one
cross-cultural study, Japanese living in Japan had a 3-fold higher
incidence of hemorrhagic stroke than Japanese living in
America.3 In 1965 through
1970, the intake of saturated fat among Japanese living in Japan was
only 20% to 25% that of Japanese living in American and of American
whites; the corresponding proportion for animal protein was
60%.4 The intake of trans
unsaturated fat among Japanese in Japan was only 5% that of American
whites in 1959 through
1964.16 In a rural Japanese
population, the incidence of intraparenchymal hemorrhage declined by
65% between 1964 through 1968 and 1969 through 1973, with a concurrent
increase in dietary meat fat from an average of 3 g/d to 12
g/d.2 ; in this rural Japanese
population, the incidence of subarachnoid hemorrhage was low and did
not change substantially.2
National statistics show that age-adjusted mortality from total stroke
declined by 29% between 1965 and 1975. This period saw a doubling of
the intake of meat and saturated fat and a 36% increase in animal
protein intake.17 In the
present study, the median animal protein intake in the lowest quintile
of 43 g/d corresponded to the current mean consumption among Japanese
living in Japan (40
g/d).18 The mean saturated
fat intake in the lowest decile in the present study (17 g/d) was
similar to the mean intake in Japan (16
g/d).18
The limitations of the present study warrant discussion.
First, it is possible that women who had a low intake of saturated fat,
trans unsaturated fat, and animal protein were at a higher risk for
intraparenchymal hemorrhage due to other health habits and behaviors.
This likelihood was reduced by the multivariate adjustment for a wide
variety of potential confounding variables, including traditional
cardiovascular risk factors, hormone and vitamin use, physical
activity, usual aspirin use, alcohol intake, dietary fat and
cholesterol intake, and total energy intake, which only had a small
effect on the associations observed. In this cohort, <2% drank 45 g
of alcohol per day, and the results were essentially the same when
these heavy drinkers were excluded (data not shown).
Second, the relation of either saturated or trans
unsaturated fat with risk of intraparenchymal hemorrhage was highest in
the lowest quintile of the nutrients and lowest in the second quintile
but then rose again with intake through the third to fifth quintiles.
This shape of the relation may weaken support for a causal
interpretation. However, a rise in the higher quintiles was compatible
with random variation and became smaller when we examined primary
intraparenchymal hemorrhage and then further restricted the analysis to
women with a history of hypertension. Furthermore, the excess risk of
intraparenchymal hemorrhage with the lowest 2 deciles of saturated fat
and trans unsaturated fat intake was graded. Because low intakes of
these 2 types of fat are associated with low serum total cholesterol
levels,19 20 the
present findings are compatible with the reported association between
serum total cholesterol and risk: risk was increased among persons with
very low serum cholesterol levels (
4.14 mmol/L [160 mg/dL]), and
plateaued at higher cholesterol
levels.8 9
Third, measurement errors in assessing nutrient intake are inevitable, but in this prospective study, any errors are likely nondifferential and would have tended to attenuate associations with saturated fat, trans unsaturated fat, and animal protein toward the null.
A previous meta-analysis of randomized clinical trials for cholesterol lowering in individuals at a high risk of coronary disease found an increased risk of fatal stroke (odds ratio for treated versus control, 2.64; 95% CI, 1.42 to 4.92) in 3 trials using clofibrate.21 Because intraparenchymal hemorrhage is more likely to be fatal than ischemic stroke, this excess risk may have been due to intraparenchymal hemorrhage.21 Two recent meta-analyses of statin treatment trials showed a significant reduction of nonfatal stroke, but results for fatal stroke were inconclusive; the overall odds ratios for treatment versus control were 1.17 (95% CI, 0.69 to 1.67)22 and 0.77 (95% CI, 0.57 to 1.04).23 Type of stroke was not distinguished.
Potential Mechanisms for Increased Risk of
Intraparenchymal Hemorrhage
Intraparenchymal hemorrhage is caused by the rupture of
microaneurysms resulting from the arterionecrosis (fibrinoid necrosis
or lipohyalinosis) of small intracerebral penetrating arterioles
(diameter, 100 to 200 µm) from the basal ganglia, thalamus, and brain
stem.24 Hypertension is a
major cause of arterionecrosis. Penetrating arteries are more
vulnerable to arterionecrosis than small arteries in subcortical
regions because they have larger lumens relative to their wall
thickness, sustain higher wall stress, and are liable to injure cell
membranes.25
In hypertensive rats, a diet-induced increase in serum cholesterol from very low to moderate levels was associated with a reduction in arterionecrosis26 and fewer strokes.27 Hypertensive patients with ischemic cerebral infarction and extracerebral atherosclerosis had higher serum cholesterol levels and less arterionecrosis than hypertensive patients without cerebral infarction.25 Also, neonatal rat cardiomyocytes depleted of cholesterol were more prone to anoxia because cholesterol depletion increases permeability and ion fluxes across the membranes of cardiomyocytes, which may lead to cell death.28 In addition to a possible direct effect on vascular walls, low serum cholesterol levels may prevent atherosclerosis in carotid arteries and large cerebral arteries in the circle of Willis, which in turn exposes the distal penetrating arteries to higher wall stress and may enhance arterionecrosis in the presence of systematic hypertension.25 Several observational and experimental studies29 30 31 suggest that low intakes of saturated fat and trans unsaturated fat reduce platelet aggregability, which may enhance the chance of bleeding in the presence of arterionecrosis. These findings suggest that low intakes of saturated fat and trans unsaturated fat, which contribute to low serum total cholesterol concentrations19 20 and/or reduced platelet aggregation, may lead to the development of intraparenchymal hemorrhage.
Stroke-prone spontaneously hypertensive rats fed a diet high in animal protein, specifically sulfur amino acids, had a delayed onset of hypertension and fewer strokes.32 These experiments followed observations33 that stroke-prone hypertensive rats fed a Japanese commercial diet had a 3-fold higher incidence of stroke than those fed an American diet. The main difference between the 2 diets was in the concentrations of methionine; they were not significantly different in fat, fiber, minerals, or vitamins. Those findings were similar to the present findings for specific amino acids. The inverse association of dietary animal protein and urinary sulfur amino acids with blood pressure levels in humans34 also suggest that the apparent protective effect of animal protein on the risk of intraparenchymal hemorrhage might be due, in part, to the attenuation of high blood pressures.
Dietary Patterns and Public Heath
Implications
In the present study, women with a high incidence of
intraparenchymal hemorrhage reported only rare consumption of meat as a
side dish, fish, ice cream, cookies, eggs, cottage cheese, and
margarine, which resulted in low intakes of saturated fat, trans
unsaturated fat, and animal protein. Vegetarians generally consume
little saturated fat,35 but
there are no reports of excess risk of intraparenchymal hemorrhage
among such groups. Low mortality rates from total stroke among
vegetarians36 may limit the
statistical power to assess these associations. Vegetarian diets
consumed by choice, rather than because of poverty, are characterized
by a high intake of fruits and vegetables, which may contribute to
lower blood pressure levels and lower risk of overall
stroke.36
Because lowering serum cholesterol by medication and dietary modification has been effective for the primary prevention of coronary heart disease in the United States and Europe, overall reductions of animal fat intake and trans unsaturated fat are warranted in Western countries.37 38 However, a very low intake of animal fat and protein, as consumed by large populations in Asia and by some persons in Western countries, may not be optimal for the primary prevention of cardiovascular disease.
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Acknowledgments |
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This study was supported by research grants CA40356 and HL34594 from the National Institutes of Health. Dr Iso is the recipient of an overseas research fellowship from the Japan Society for the Promotion of Science. The authors are indebted to the participants in the Nurses’ Health Study for their continuing cooperation and to Al Wing, Mark Shneyder, Karen Corsano, Barbara Egan, and Lisa Dunn for their expert help.
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Footnotes |
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Tables I and II can be found Online Only at www.circulationaha.org
Received June 19, 2000; revision received October 4, 2000; accepted October 16, 2000.
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