From the Departments of Nutrition (A.A., E.B.R., E.L.G., M.J.S., W.C.W.),
Epidemiology (A.A., E.B.R., M.A.H., M.J.S., W.C.W.), and Health and Social
Behavior (I.K.), Harvard School of Public Health, and the Channing Laboratory,
Department of Medicine, Harvard Medical School and Brigham and Women's
Hospital (E.B.R., E.L.G., M.J.S., W.C.W., I.K.), Boston, Mass.
Methods and Results—We examined the association of potassium and
related nutrients with risk of stroke among 43 738 US men, 40 to 75
years old, without diagnosed cardiovascular diseases or
diabetes, who completed a semiquantitative food frequency questionnaire
in 1986. During 8 years of follow-up, 328 strokes (210
ischemic, 70 hemorrhagic, 48 unspecified) were documented. The
multivariate relative risk of stroke of any type for
men in the top fifth of potassium intake (median intake, 4.3 g/d)
versus those in the bottom (median, 2.4 g/d) was 0.62 (95% CI, 0.43,
0.88; P for trend=0.007). Results for ischemic
stroke alone were similar. Intakes of cereal fiber and magnesium, but
not of calcium, were also inversely associated with risk of total
stroke. These inverse associations were all stronger in hypertensive
than normotensive men and were not materially altered by adjustment for
blood pressure levels. Use of potassium supplements was also inversely
related to risk of stroke, particularly among men taking
diuretics (relative risk, 0.36; 95% CI, 0.18, 0.72).
Conclusions—Although these data do not prove a causal
relationship, they are consistent with the hypothesis that
diets rich in potassium, magnesium, and cereal fiber reduce the risk of
stroke, particularly among hypertensive men. Potassium supplements may
also be beneficial, but because of potential risks, use should be
carefully monitored and restricted to men taking potassium-losing
diuretics.
However, the overall evidence is unconvincing. Small size and
inadequate dietary assessment are among the limitations of the previous
epidemiological studies, because diet based on a single 24-hour recall
was used to predict stroke incidence over a 12-,1
16-,2 or 20-year period.4
This dietary assessment reduces the ability to adjust for consumption
of other foods or nutrients that may explain the inverse associations
reported.11 To overcome this limitation, we
addressed the hypothesis that high potassium intake reduces the risk of
stroke in a large cohort of men who completed a detailed and validated
semiquantitative food frequency questionnaire at baseline and were
followed up for 8 years. In addition, we examined the associations
between risk of stroke and intakes of dietary fiber, magnesium, and
calcium, which are correlated with intake of potassium and may be
related to risk of stroke.
Assessment of Diet and Other Exposure Variables
Cases
Deaths were reported by next of kin, coworkers, postal authorities, or
the National Death Index. Fatal strokes were confirmed by medical
records or autopsy reports or were considered probable if these
were not obtainable and stroke was listed as the underlying cause on
the death certificate.
Statistical Analysis
Intakes of dietary fiber and magnesium were both inversely associated
with risk of total stroke in age-adjusted analyses (Table 2
Neither calcium nor sodium intake (data not shown) was significantly
associated with risk of total, ischemic, or hemorrhagic stroke.
Sodium intake was also unrelated to intake of potassium (Pearson
correlation = -0.02) and was not analyzed further.
Because in a previous investigation an inverse association was reported
between calcium from dairy sources and risk of
stroke,20 we examined this relationship in our
cohort. The multivariate risk for the top compared with
the bottom quintile of dairy calcium intake was 0.83 (95% CI, 0.59,
1.17) for total (Table 2
When intakes of dietary fiber from different sources were considered
separately, only cereal fiber was inversely associated with risk of
stroke. This association remained after adjustment for potassium,
magnesium, and fiber from other sources; both potassium and cereal
fiber intake appeared to be independently inversely associated with
risk of total stroke (Figure 1
We further examined separately the associations of potassium and
magnesium from supplements with risk of stroke. Neither use of
potassium supplements (RR=0.78; 95% CI, 0.69 to 1.22) nor use of
magnesium supplements (RR=0.85; 95% CI, 0.55 to 1.32) was associated
with risk of total or ischemic stroke in analyses
adjusted for age only, but use of potassium supplements became strongly
inversely associated after adjustment for history of hypertension
(RR=0.55; 95% CI, 0.35 to 0.86). History of hypertension was a strong
independent risk factor for stroke (RR=2.8; 95% CI, 2.1, 3.7) and was
associated with use of potassium supplements (46% of the 1248
supplement users were hypertensives, compared with 19% of
nonusers). The inverse association between use of potassium
supplements and risk of stroke in multivariate
analyses was independent of dietary intakes of nutrients,
including potassium, magnesium, and fiber, and was stronger among men
with low dietary intake of potassium, magnesium, and cereal fiber. The
RR comparing the top with the bottom quintile of potassium intake was
0.39 in the lowest tertile of a dietary score, including the 3
nutrients, 0.57 in the middle, and 0.86 in the highest tertile. To
further test the hypothesis that use of potassium supplements reduces
the risk of stroke, we compared men who reported using supplements both
in 1986 and 1988 with men who never used supplements. During the 6
remaining years of follow-up, the multivariate RR of
total stroke among supplement users was 0.31 (95% CI, 0.12, 0.85;
P=0.02); the risk of stroke was also reduced among men who
reported using potassium supplements only in 1986 (0.46; 95% CI, 0.22,
0.98; P=0.05) but not among men who started taking
supplements in 1988 (1.07; 95% CI, 0.55, 2.11).
Because of the importance of hypertension as a risk factor for stroke,
we conducted analyses stratified by history of hypertension at
baseline. Inverse associations between nutrient intakes and risk of
stroke were observed only among hypertensive men (Figures 2
A protective effect of potassium intake on risk of stroke would be
consistent with the reduced risk that we observed among
hypertensive men taking potassium supplements in the present study
and with the findings of a previous epidemiological
investigation1 and experiments with hypertensive
rats.5 21 In a separate cohort among Japanese men
in Hawaii, potassium intake was inversely related to risk of fatal
thromboembolic stroke (RR for the top versus the bottom quintile of
intake=0.3, P for trend=0.002) but not with risk of nonfatal
thromboembolic stroke (RR=0.87, P for
trend=0.12).2 The weak association with nonfatal
events is not inconsistent with a protective effect, which may
have been diluted by error in the single 24-hour recall– based dietary
assessment. In randomized trials, high potassium intake has caused
modest reduction in blood pressure, especially among hypertensive
subjects.6 7 This effect, however, is small and
could only partially explain the strong inverse association observed in
this study. In addition, adjustment for baseline blood pressure levels
had little effect on the estimated RRs relating potassium intake to
stroke incidence, and potassium intake was not a significant predictor
of risk of hypertension within this cohort.14
Alternative mechanisms proposed include the inhibition of free radical
formation, vascular smooth muscle proliferation, and
arterial thrombosis.22 However, these
effects were produced by experimental increases in serum potassium
concentrations in animals, and their relevance to humans is uncertain.
High potassium intake may increase serum concentrations, particularly
when intake is low or sodium intake is high,22
and could therefore reduce the risk of hypokalemia among men at high
risk because of diuretic treatment. Diuretic-induced
hypokalemia may increase the risk of ventricular
dysrhythmia.23 24 Although no increased mortality
from cardiovascular disease or other causes was found
among men with low serum potassium in 2 previous
studies,25 26 neither was large enough to detect
a specific association between serum potassium and risk of stroke.
Intakes of magnesium and fiber were also inversely associated with risk
of stroke, but their correlation with intake of potassium and
measurement errors reduced the ability of multivariate
analyses to discriminate between them. This difficulty is
compounded by the fact that some previous epidemiological evidence and
biological plausibility can be invoked for a beneficial effect of any
of these nutrients, although only potassium has been shown to directly
reduce risk of stroke in animal models. In a cross-sectional study,
magnesium intake has been found to be inversely associated with carotid
artery thickness in women but not in men.27 Also,
there are reports that magnesium deficiency increases susceptibility of
lipoproteins to peroxidation in rats.28
Conversely, magnesium supplementation failed to reduce blood pressure
in randomized trials among normotensive
subjects,7 29 and high-magnesium diets have been
reported to increase rather than decrease the risk of stroke in
hypertensive rats.30 In a randomized trial in
China, a multiple vitamin/mineral supplement containing 200 mg of
magnesium reduced the risk of stroke among men, but this effect may
have been due to 1 of the several other micronutrients included in the
supplement.31 Intake of fiber, particularly
cereal fiber, has been shown to be inversely related to risk of
coronary heart disease in most prospective
investigations.32 33 34 These results strongly
suggest that high fiber intake inhibits the development of
atherosclerosis or thrombosis and indirectly support a
preventive effect of fiber on risk of ischemic stroke.
Mechanisms for these beneficial effects, however, remain largely
elusive.33
The lack of association between sodium intake and risk of stroke in our
study may be due to the difficulty in measuring sodium intake
accurately and to the scarcity of men with low or very high intake and
does not in itself contradict the hypothesis that substantial
reductions in intake decrease risk.35 36 37 38
Although measurement error also may have affected the results on
calcium, our data do not support the previously reported inverse
association between calcium consumption and risk of
stroke.20 In hypertensive rats, high calcium
intake provided partial protection against salt-induced stroke,
decreasing lesion size but increasing lesion
number,39 whereas in rabbits it prolonged
clotting time and reduced the severity of
atherosclerosis.40 The relevance
of these observations to humans, however, remains to be
established.
In conclusion, although these data do not prove a causal relationship,
they provide strong support for a preventive effect of diets rich in
potassium, magnesium, and cereal fiber on stroke, particularly among
men with high blood pressure. Increased intake of potassium alone may
decrease the risk of stroke, and perhaps potassium supplements for
hypertensives should be more broadly considered. However, evidence is
inadequate to support an indiscriminate use of potassium supplements,
which can be harmful.41 Rather, potassium intake
should be increased by substituting fruits, vegetables, and their
natural juices for low-potassium processed foods and sodas.
Received November 18, 1997;
revision received May 19, 1998;
accepted May 20, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Intake of Potassium, Magnesium, Calcium, and Fiber and Risk of Stroke Among US Men
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Animal experiments and
epidemiological studies have suggested that high potassium intake may
reduce the risk of stroke, but the evidence is inconclusive, and the
role of other nutrients in potassium-rich foods remains unknown.
Key Words: stroke • potassium • magnesium • epidemiology • diet
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
A role for potassium
in determining risk of stroke is suggested by epidemiological
studies1 2 3 4 and animal
experiments.5 A beneficial effect of potassium
intake could be due to its hypotensive effect,6 7
but this is small, and neither in rats5 nor in
humans1 4 could it explain the reduced risk of
stroke. Other mechanisms that have been suggested include inhibition of
free radical formation,8 vascular smooth muscle
proliferation,9 and arterial
thrombosis.10
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Population
The Health Professionals Follow-up Study began in 1986, when
51 529 health professionals 40 to 75 years old12
completed a 131-item food-frequency questionnaire and provided
information about medical history and lifestyle. Follow-up
questionnaires were sent every 2 years to update information on
potential risk factors and to identify newly diagnosed cases of stroke
and other diseases. We excluded from analysis 1595 men who did
not satisfy the a priori criteria of daily caloric intake between
800 and 4200 kcal and <70 blanks out of 131 total listed food items.
In addition, we excluded men with prior diagnosis of myocardial
infarction, angina, coronary artery surgery, stroke, transient
ischemic attack, peripheral arterial
disease, or diabetes. We followed up the 43 738 eligible men for
stroke incidence during the subsequent 8 years. The average response
rate for the 2-year follow-up cycles was >94%. Nonresponding
participants not matched to the National Death Index were assumed to
be alive.
The 1986 questionnaire asked about average frequency of intake
during the previous year of specified portions of 131 foods and use of
vitamin and mineral supplements. Nutrient calculations took into
account the specific brand of breakfast cereal and multivitamins
reported by each subject. We also asked about use of specific
supplements of potassium and magnesium (apart from multivitamins). We
assumed the amount of potassium in these specific supplements to be 1
g/d and that of magnesium 0.3 g/d, because details on doses were not
asked in the questionnaire. We assessed the validity of the
questionnaire in a random sample of 127 men who completed two 1-week
diet records.13 The correlations between the
2 assessments of intake, energy-adjusted and corrected for
within-person variation in the diet records, were 0.65 for
potassium, 0.64 for dietary fiber, 0.66 for magnesium, and 0.53 for
calcium. In addition to diet, in 1986, participants were asked to
report their usual systolic and diastolic blood
pressure and whether or not they had physician-diagnosed hypertension.
The validity of these variables has been documented
previously.14
End points were fatal and nonfatal strokes occurring between the
return of the baseline questionnaire and January 31, 1994. Participants
reporting an incident stroke on a follow-up questionnaire were asked
for permission to review medical records. Strokes were confirmed if
characterized by a typical neurological defect of sudden or rapid
onset, lasting 
24 hours and attributable to a cerebrovascular event.
Strokes caused by infection or neoplasia were excluded. Reviews were
conducted by physicians with no knowledge of the subjects' risk factor
status. Strokes were subclassified according to the criteria of the
National Survey of Stroke as due to ischemia (embolism or
thrombosis), subarachnoid hemorrhage,
intracerebral hemorrhage, or unknown
cause.15 If no records could be obtained,
strokes were considered probable if they required hospitalization and
were corroborated by additional information provided by letter or
interview.
Participants contributed follow-up time from the return of the
1986 questionnaire up to the occurrence of a confirmed stroke, death,
or January 31, 1994. The occurrence of nonfatal
cardiovascular events, such as myocardial infarction or
coronary surgery, was not a reason for censoring. Intakes of
potassium and other nutrients were energy-adjusted to 2000
kcal/d.16 Relative risks (RR) were calculated by
dividing the incidence of stroke among men in each fifth of
energy-adjusted potassium intake at baseline by the incidence among men
in the lowest fifth of intake. Similar calculations were done for the
other nutrients. We adjusted RRs for age (5-year
categories)17 and used the Mantel extension
test18 to test for linear trends. To adjust for
other risk factors, we used pooled logistic regression with 2-year
intervals. When the probability of an event within an interval is
small, this method is equivalent to a Cox proportional-hazards
analysis.19 Multivariate
models included as covariates calendar time (2-year intervals), total
energy intake (continuous variable), smoking (current, past, and 1
to 14, 15 to 24, and 25 cigarettes/d), alcohol consumption (<5, 5 to
9, 10 to 14, 15 to 29, and 30 g/d), history of hypertension, history
of hypercholesterolemia, parental history of
myocardial infarction before age 65 years, profession, and quintiles of
body mass index and physical activity. In these models, we evaluated
monotonic trends by using the median value of each category and
modeling this as a continuous variable. All P values are
2-sided. Covariates were not updated during the follow-up.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
During 323 394 person-years of follow-up, we documented 328 cases
of cerebrovascular accidents (50 fatal), including 210
ischemic, 70 hemorrhagic, and 48 unclassified strokes. Men in
the top fifth of potassium intake (including potassium from
supplements) were less likely to smoke, were more physically active,
and consumed less alcohol, less fat, more protein, and more
micronutrients than men in the bottom fifth (Table 1
). Similar relations were found for
magnesium, fiber, and calcium (data not shown). The age-adjusted RR of
total stroke for men in the top fifth of potassium intake compared with
those in the bottom fifth was 0.59 (Table 2). This RR was slightly attenuated by
adjustment for nondietary risk factors (RR=0.62) and by further
adjustment for intakes of magnesium and dietary fiber (RR=0.69). The
corresponding associations with ischemic stroke were similar,
whereas no significant associations were observed for hemorrhagic
stroke (data not shown). Further adjustment for intakes of total fat,
protein, saturated fat, vitamin C, vitamin E, carotene, or folic acid
did not materially change the association between potassium intake and
risk of total stroke, nor did adjustment for baseline systolic
and diastolic blood pressure or addition to the model of an
interaction term between age and hypertension.
View this table:
[in a new window]
Table 1. Age-Standardized Relation of Intake of Potassium to
Selected Variables at Baseline
View this table:
[in a new window]
Table 2. RR of Stroke According to Intake of Potassium, Total
Fiber, Magnesium, and Calcium Adjusted by
Energy 
).
These associations were only moderately attenuated by adjustment for
nondietary risk factors, but they were substantially weakened in
regression models that simultaneously included potassium,
magnesium, and dietary fiber because of the positive correlations
between intakes of these nutrients (Pearson correlation coefficients
were 0.65 for magnesium and potassium, 0.62 for magnesium and fiber,
and 0.58 for potassium and fiber). ), 0.90 (95% CI, 0.59, 1.37) for
ischemic, and 0.73 (95% CI, 0.36, 1.51) for hemorrhagic
stroke; the lowest incidence of each outcome was observed in the middle
quintile of intake. Also, we examined whether the risk of stroke was
lower among men who reported using calcium supplements at baseline. The
RR for men who took 400 mg/d of supplemental calcium compared with
nonusers was 0.88 for total stroke (95% CI, 0.60, 1.27) and
0.83 for ischemic stroke (95% CI, 0.52, 1.34). ). Intakes
of fruits, vegetables, and cereal products were each inversely
associated with risk of total stroke, but none of these associations
were significant. The multivariate RR for an increase
of 1 serving per day was 0.96 (95% CI, 0.89, 1.03; P for
trend=0.26) for fruits, 0.96 (95% CI, 0.91, 1.02; P for
trend=0.18) for vegetables, and 0.94 (95% CI, 0.87, 1.02; P
for trend=0.11) for cereal. Results for ischemic stroke were
similar.
View larger version (82K):
[in a new window]
Figure 1. RR of stroke by intake of potassium and cereal
fiber. and 3).
In analyses restricted to men taking diuretics at
baseline, alone or in combination with other antihypertensive drugs,
the RR of stroke for users of potassium supplements compared with
nonusers was 0.36 (95% CI, 0.18, 0.72; P=0.004).
Both fiber and cereal fiber were significantly inversely associated
with risk of stroke among hypertensive (RRs for a 10-g increase in
intake were 0.59 and 0.33, respectively) but not among normotensive
(RRs were 0.88 for both) men.
View larger version (66K):
[in a new window]
Figure 2. Multivariate RR of total stroke
according to intake of dietary potassium and magnesium. Top, Men
without history of hypertension; bottom, men with history of
hypertension.
View larger version (69K):
[in a new window]
Figure 3. Multivariate RR of total stroke
according to intake of potassium and magnesium supplements. Top, Men
without history of hypertension; bottom, men with history of
hypertension.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In this large prospective study, we found that men with diets
higher in potassium, cereal fiber, and magnesium had a substantially
reduced risk of stroke. These inverse associations were only partly
explained by nondietary risk factors but were strong and significant
only among men with diagnosed hypertension. No significant associations
were found between intakes of sodium and calcium and risk of
stroke.
Acknowledgments
This study was supported by research grants HL-35464 and
CA-55075 from the National Institutes of Health. Dr Ichiro
Kawachi is supported by a Career Development Award from the NHLBI. We
are indebted to the participants of the Health Professionals Follow-up
Study; to Al Wing, Mira Kaufman, Karen Corsano, and Steve Stuart for
computer assistance; to Jill Arnold, Betsy Frost-Hawes, Kerry Demers,
and Mitzi Wolff for their assistance in the compilation of data and the
preparation of the manuscript; and to Laura Sampson and Helaine Rockett
for maintaining our food composition tables.
Footnotes
Reprint requests to Alberto Ascherio, MD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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D. M. Green, A. H. Ropper, R. A. Kronmal, B. M. Psaty, and G. L. Burke Serum potassium level and dietary potassium intake as risk factors for stroke Neurology, August 13, 2002; 59(3): 314 - 320. [Abstract] [Full Text] [PDF]
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 A. A. McDonough, C. B. Thompson, and J. H. Youn Skeletal muscle regulates extracellular potassium Am J Physiol Renal Physiol, June 1, 2002; 282(6): F967 - F974. [Abstract] [Full Text] [PDF]
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C. R. Walsh, M. G. Larson, E. P. Leip, R. S. Vasan, and D. Levy Serum Potassium and Risk of Cardiovascular Disease: The Framingham Heart Study Arch Intern Med, May 13, 2002; 162(9): 1007 - 1012. [Abstract] [Full Text] [PDF]
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S. Fukui, N. Otani, N. Tsuzuki, H. Nawashiro, K. Shima, L. Bazzano, and J. He Race and Sex Differences in the Effects of Dietary Potassium Intake on the Risk of Stroke Stroke, May 1, 2002; 33(5): 1178 - 1179. [Full Text] [PDF]
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M. A. Pereira, D. R. Jacobs Jr, L. Van Horn, M. L. Slattery, A. I. Kartashov, and D. S. Ludwig Dairy Consumption, Obesity, and the Insulin Resistance Syndrome in Young Adults: The CARDIA Study JAMA, April 24, 2002; 287(16): 2081 - 2089. [Abstract] [Full Text] [PDF]
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