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Serum Potassium and Risk of Cardiovascular Disease
The Framingham Heart Study
Craig R. Walsh, MD;
Martin G. Larson, ScD;
Eric P. Leip, MS;
Ramachandran S. Vasan, MD, DM;
Daniel Levy, MD
Arch Intern Med. 2002;162:1007-1012.
ABSTRACT
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Background Published studies of the association between serum potassium concentration
and risk for cardiovascular disease in community-based populations have reported
conflicting results. We sought to determine the association between serum
potassium concentration and cardiovascular disease risk in the Framingham
Heart Study.
Methods A total of 3151 participants (mean age, 43 years; 48% men) in the Framingham
Heart Study who were free of cardiovascular disease and not taking medications
affecting potassium homeostasis had serum potassium levels measured (1979-1983).
Proportional hazards models were used to determine the association of serum
potassium concentration at baseline with the incidence of cardiovascular disease
at follow-up.
Results During mean follow-up of 16 years, 313 cardiovascular disease events
occurred, including 46 cardiovascular disease–related deaths. After
adjustment for age, serum potassium level was marginally associated with risk
of cardiovascular disease (hazard ratio [HR] per 1 mg/dL increment, 1.03;
95% confidence interval [CI], 1.00-1.05; P = .02).
However, after further adjustment for multiple confounders, serum potassium
level was not significantly associated with cardiovascular disease risk (HR,
1.00; 95% CI, 0.98-1.03). There were no significant associations between serum
potassium level and cardiovascular disease–related death in either age-
and sex-adjusted models (HR, 1.06; 95% CI, 0.99-1.12) or multivariable-adjusted
models (HR, 1.04; 95% CI, 0.97-1.11).
Conclusion In our community-based sample of individuals free of cardiovascular
disease and not taking medications that affect potassium homeostasis, serum
potassium level was not associated with risk of cardiovascular disease.
INTRODUCTION
ALTHOUGH SEVERAL observational studies1-6
have reported an inverse association between dietary potassium intake and
risk of cardiovascular disease, less is known about the association of serum
potassium levels and cardiovascular risk. Low serum potassium levels may identify
individuals at increased risk for cardiovascular events because of insufficient
dietary potassium intake1-6
or activation of the renin-angiotensin-aldosterone system.7
In addition, low serum potassium concentration is associated with ventricular
ectopy and may identify individuals at risk for death due to ventricular arrhythmias.8
Previous community-based observational cohort studies that examined
the association between serum potassium levels and cardiovascular disease
have reported conflicting results. One study9
reported an increased risk of cardiovascular disease associated with high
serum potassium levels, whereas another study10
reported no association between serum potassium levels and cardiovascular
disease risk. To clarify the association between serum potassium levels and
cardiovascular disease, we determined the association between serum potassium
levels and risk of incident cardiovascular disease among participants in the
Framingham Offspring Study.
PARTICIPANTS AND METHODS
STUDY POPULATION
The Framingham Heart Study is a prospective, epidemiological cohort
study established in 1948 to evaluate potential risk factors for coronary
heart disease. The original cohort consisted of 5209 residents of Framingham,
Mass, aged 28 to 62 years at study entry. In 1971, an additional 5124 individuals
(offspring of original cohort members and their spouses) were enrolled into
the Framingham Offspring Study. The study design and entry criteria for both
cohorts have been detailed elsewhere.11-14
Participants in the present study were members of the offspring cohort
who had blood samples taken for the measurement of serum potassium levels
at their second examination (1979-1983). Individuals were excluded if they
met any of the following criteria: (1) history of cardiovascular disease,
(2) treatment with medications that alter potassium homeostasis (eg,  -adrenergic
blocking agents, diuretics, and potassium supplements), (3) creatinine concentration
of 2.0 mg/dL or greater ( 180 µmol/L), (4) hemolyzed or missing blood
specimens, or (5) extreme elevation of serum potassium level (>6.2 mEq/L).
All examinations and procedures were approved by the institutional review
board of Boston University School of Medicine, and all participants gave informed
consent.
BASELINE MEASUREMENTS
Medical histories were taken and physical examinations were performed
for each participant at the baseline examination. Systolic and diastolic blood
pressures were measured twice in the left arm of each participant. The average
of the 2 readings was used for each blood pressure variable. Body mass index
was calculated as weight in kilograms divided by the square of height in meters.
Diabetes mellitus was defined on the basis of a nonfasting blood glucose level
of 200 mg/dL or greater (11.1 mmol/L), a fasting blood glucose level of
140 mg/dL or greater (7.8 mmol/L), or the use of insulin or an oral hypoglycemic
agent.15 Self-reported smoking history was
used to classify participants as nonsmokers or current smokers. Participants
who reported smoking at least 1 cigarette daily during the year before the
examination were classified as current smokers. Self-reported alcohol intake
was used to quantify the number of alcoholic drinks (12 oz of beer, 4 oz of
wine, or 1 oz of liquor) consumed weekly.16
Self-reported consumption of caffeinated beverages was used to quantify the
number of caffeinated drinks (8 oz of coffee or 23.2 oz of tea) consumed daily.16 Serum potassium level was measured using flame-emission
spectrophotometry.17 Serum creatinine values
were determined using an autoanalyzer18-19
on blood specimens drawn at the baseline examination.
OUTCOME MEASUREMENTS
The principal outcomes of interest were incident cardiovascular disease,
death from cardiovascular disease, and death from all causes. Cardiovascular
disease events included the following: angina pectoris, coronary insufficiency,
myocardial infarction, stroke, intermittent claudication, and death due to
coronary heart disease or stroke. Criteria for these outcomes have been described
previously.14 Cardiovascular disease events
without a clearly identifiable time of onset (eg, angina pectoris or intermittent
claudication) were considered to have occurred midway between consecutive
examinations. A panel of 3 physicians determined the outcome events after
reviewing Framingham Heart Study and outside hospital and physician records.
STATISTICAL ANALYSIS
Serum potassium concentration was considered to be a continuous and
a categorical variable. Participants were categorized into sex-specific quartiles
of serum potassium. For the primary analysis, sex-specific potassium quartiles
were pooled, and baseline characteristics were computed for each pooled quartile.
Cox proportional hazards models20 were used
to calculate age- and sex-adjusted and multivariable-adjusted hazards ratios
(HRs) for cardiovascular disease, death due to cardiovascular disease, and
death due to all causes. The following variables were included in the multivariable
model: age, sex, systolic and diastolic blood pressure, hypertension treatment,
diabetes mellitus, cigarette smoking (cigarettes smoked daily), alcohol consumption
(drinks per week), caffeine consumption (drinks per day), serum creatinine
level, body mass index, and total and high-density lipoprotein (HDL) cholesterol
levels. Variables included in the multivariable model were chosen a priori
either because they were well-recognized risk factors for cardiovascular disease
(eg, diabetes mellitus) or because they were potential determinants of serum
potassium levels (eg, cigarette smoking). The highest quartile of serum potassium
served as the reference group. Results of the regression models were displayed
as HRs and their 95% confidence intervals (CIs). The analyses were repeated
after stratifying by sex.
Increased risk of cardiovascular disease or death may be confined to
individuals with high or low serum potassium values. In a secondary analysis,
participants were classified into those with low ( 4.0 mEq/L), normal (4.1-5.1
mEq/L), and high (5.2 mEq/L) serum potassium levels. Age- and sex-adjusted
and multivariable-adjusted HRs of cardiovascular disease, death from cardiovascular
disease, and death from all causes were calculated in participants with low
and high potassium levels compared with those with normal potassium levels
(reference group).
RESULTS
STUDY SAMPLE AND BASELINE CHARACTERISTICS
A total of 3854 adults attended the second offspring examination. Of
these, we excluded 167 with prevalent cardiovascular disease, 371 reporting
use of medications that alter serum potassium levels, 5 with serum creatinine
levels of 2.0 mg/dL or greater (180 µmol/L), 149 with hemolyzed
or missing blood specimens, and 11 with extreme elevations of serum potassium
concentration (>6.2 mEq/L). Thus, 3151 individuals (1515 men [age, mean ±
SD, 44 ± 10 years] and 1636 women [age, mean ± SD, 43 ±
10 years]; 82% of attendees) were eligible for the analysis. The mean ±
SD serum potassium level among eligible individuals was 4.7 ± 0.5 mEq/L
(men, 4.8 ± 0.4 mEq/L; women, 4.6 ± 0.4 mEq/L). In individuals
excluded because of use of medications that alter serum potassium levels,
the mean ± SD serum potassium level was 4.4 ± 0.5 mEq/L (men,
4.5 ± 0.5 mEq/L; women, 4.3 ± 0.5 mEq/L).
Participant characteristics at the baseline examination are given in Table 1. Serum potassium concentration
was positively associated with age, smoking, caffeine consumption, and total
and HDL cholesterol levels. There were no significant associations of serum
potassium level with blood pressure, diabetes mellitus, alcohol consumption,
body mass index, and serum creatinine level. Serum potassium concentration
was negatively associated with hypertension treatment.
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Table 1. Baseline Characteristics of 3151 Individuals Free of Cardiovascular
Disease According to Quartile of Serum Potassium
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SERUM POTASSIUM AND CARDIOVASCULAR DISEASE
During 16 years of follow-up, 313 cardiovascular disease events occurred
(217 in men and 96 in women). Of these, 214 were coronary heart disease events.
The age- and sex-adjusted cumulative incidence of cardiovascular disease stratified
by serum potassium quartile is displayed in Figure 1. Of 50 cardiovascular disease events occurring between
1.5 and 2.5 years of follow-up, 39 did not have a clearly identifiable time
of onset (24 angina pectoris, 10 intermittent claudication, and 5 unrecognized
myocardial infarction) and were considered to have occurred midway between
the baseline examination and the first follow-up examination, accounting for
the sudden increase in the incidence of cardiovascular disease at 2 years
of follow-up (Figure 1). The results
of proportional hazards models comparing serum potassium quartile and cardiovascular
disease risk are given in Table 2
(top). After adjusting for age and sex, there was no significant association
between serum potassium quartile and risk of cardiovascular disease. Further
adjustment for multiple confounders did not materially alter the results.
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Figure 1. Age- and sex-adjusted cumulative
incidence of cardiovascular disease according to quartile of serum potassium
in 3151 individuals free of cardiovascular disease at baseline.
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Table 2. Age-, Sex-, and Multivariable-Adjusted Risk of Cardiovascular
Disease, Death Due to Cardiovascular Disease, and Death Due to All Causes
According to Quartile of Serum Potassium
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Considered to be a continuous variable, potassium concentration was
marginally associated with risk of cardiovascular disease after adjustment
for age (HR, 1.03; 95% CI, 1.00-1.05). However, this association was no longer
statistically significant after further adjustment for systolic and diastolic
blood pressure, hypertension treatment, diabetes mellitus, cigarette smoking,
alcohol intake, caffeine consumption, serum creatinine level, body mass index,
and total and HDL cholesterol levels (HR, 1.00; 95% CI, 0.98-1.03).
SERUM POTASSIUM LEVEL AND DEATH DUE TO CARDIOVASCULAR DISEASE
During follow-up, there were 46 cardiovascular disease–related
deaths (34 in men and 12 in women). The age- and sex-adjusted cumulative incidence
of death due to cardiovascular disease stratified by serum potassium quartile
is displayed in Figure 2. The results
of proportional hazards models testing the association between serum potassium
quartile and death due to cardiovascular disease are given in Table 2 (middle). After adjusting for age and sex, there was no
significant association between serum potassium quartile and risk of death
due to cardiovascular disease. Further adjustment for multiple potential confounders
did not materially alter the results.
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Figure 2. Age- and sex-adjusted cumulative
incidence of death due to cardiovascular disease according to quartile of
serum potassium in 3151 individuals free of cardiovascular disease at baseline.
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Considered to be a continuous variable, potassium concentration was
not significantly associated with risk of death due to cardiovascular disease
after adjustment for age and sex (HR, 1.06; 95% CI, 0.99-1.12) or after further
adjustment for systolic and diastolic blood pressure, hypertension treatment,
diabetes mellitus, cigarette smoking, alcohol intake, caffeine consumption,
serum creatinine level, body mass index, and total and HDL cholesterol levels
(HR, 1.04; 95% CI, 0.97-1.11).
SERUM POTASSIUM LEVEL AND DEATH DUE TO ALL CAUSES
During follow-up there were 214 deaths from all causes (131 in men and
83 in women). The age- and sex-adjusted cumulative incidence of death from
all causes stratified by serum potassium quartile is displayed in Figure 3. The results of proportional hazards
models testing the association between serum potassium quartile and death
due to all causes are given in Table 2
(bottom). After adjusting for age and sex, there was no significant association
between serum potassium quartile and all-cause mortality. Further adjustment
for multiple potential confounders did not materially alter the results.
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Figure 3. Age- and sex-adjusted cumulative
incidence of death due to all causes according to quartile of serum potassium
in 3151 individuals free of cardiovascular disease at baseline.
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Considered to be a continuous variable, potassium concentration was
not significantly associated with all-cause mortality after adjustment for
age and sex (HR, 1.01; 95% CI, 0.98-1.04) or after further adjustment for
systolic and diastolic blood pressure, hypertension treatment, diabetes mellitus,
cigarette smoking, alcohol intake, caffeine consumption, serum creatinine
level, body mass index, and total and HDL cholesterol levels (HR, 0.99; 95%
CI, 0.96-1.02).
LOW AND HIGH SERUM POTASSIUM LEVELS
Of 3151 participants, 175 had serum potassium levels of 4.0 mEq/L or
less (low potassium concentration) and 540 had serum potassium levels of 5.2
mEq/L or greater (high potassium concentration). Neither low nor high potassium
levels were significantly associated with risk of cardiovascular disease,
death due to cardiovascular disease, or death due to all causes compared with
individuals with normal potassium levels after adjustment for potential confounders
(Table 3).
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Table 3. Age-, Sex-, and Multivariable-Adjusted Risk of Cardiovascular
Disease, Death Due to Cardiovascular Disease, and Death Due to All Causes
in Patients With Low, Normal, and High Serum Potassium Levels
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COMMENT
In our community-based sample of 3151 individuals free of cardiovascular
disease, serum potassium concentration was not associated with risk of cardiovascular
disease, death due to cardiovascular disease, or death from all causes.
Although it is well recognized that extremely high and extremely low
serum potassium levels can be lethal,21 less
is known about the prognostic value of serum potassium at the ranges commonly
encountered in individuals in the community. Serum potassium level is inversely
related to risk of ventricular arrhythmias8
and may therefore be related to risk of sudden cardiac death. Also, serum
potassium level is inversely related to activation of the renin-angiotensin-aldosterone
system.7 Hypertensive individuals with high
renin profiles and low serum potassium levels may be at increased risk for
acute myocardial infarction.7
Published studies that have examined the association between serum potassium
level and risk of cardiovascular disease in community-based samples have reported
conflicting results. In 7262 men enrolled in the British Regional Heart Study
followed for 11.5 years, Wannamethee et al10
reported no association between serum potassium level and risk of death due
to cardiovascular disease. However, in 2836 men and women enrolled in the
first National Health and Nutrition Examination Survey Epidemiological Follow-up
Survey followed for 15.9 years, Fang et al9
reported that risk of death due to cardiovascular disease was increased in
individuals with high serum potassium levels (4.5 mEq/L) compared with
those with normal serum potassium levels (3.8-4.4 mEq/L) after adjustment
for multiple confounders (HR, 1.54; 95% CI, 1.03-2.31).
Our study was similar to the aforementioned studies with respect to
sample size, time period, and follow-up. In addition, the meticulous assessment
of outcome and risk factors in the Framingham Offspring Study allowed us to
examine the association between serum potassium concentration and multiple
end points (cardiovascular disease, death due to cardiovascular disease, and
death due to all causes) and to account for important confounders in men and
women. In our study, we found no association between serum potassium level
and risk of either cardiovascular disease or death due to cardiovascular disease,
consistent with the study by Wannamethee et al.10
We excluded individuals with serum creatinine levels of 2.0 mg/dL or greater
(180 µmol/L) and those taking diuretics. Although not specifically
excluded, few individuals in the study by Wannamethee et al10
had renal dysfunction or were taking diuretics. Subgroup analysis of the study
by Fang et al9 showed that the increased risk
of death from cardiovascular disease was limited to individuals with abnormal
renal function or those taking diuretics. In individuals with normal renal
function and those not taking diuretics, risk of death from cardiovascular
disease was not significantly associated with serum potassium concentration.
Thus, among individuals with normal renal function who were not taking diuretics,
serum potassium level was not associated with increased risk of cardiovascular
disease.
Although serum potassium concentration is inversely related to risk
of ventricular arrhythmias,8 we found no association
between serum potassium level and cardiovascular mortality. Thus, in patients
without cardiovascular disease, low serum potassium levels may identify individuals
at increased risk for benign ventricular rhythms but not individuals at increased
risk for fatal ventricular rhythms.
Our study was conducted in a largely white population and therefore
may have limited generalizability to other ethnic populations. Also, because
serum potassium concentration was measured at a single point in time, we could
not account for changes in serum potassium levels over time that may modify
the association between serum potassium level and cardiovascular disease.
In addition, relatively few individuals in our study sample died of cardiovascular
disease during follow-up. Therefore, we had limited statistical power to detect
a modest association between serum potassium level and death due to cardiovascular
disease. Further studies in larger sample sizes are warranted to clarify the
association between serum potassium concentration and death due to cardiovascular
disease.
Because of the relatively narrow range of serum potassium values, even
minor errors in sample preparation or measurement of potassium could result
in nondifferential misclassification and would decrease the likelihood of
observing a significant association. We attempted to minimize such errors
by excluding individuals with either hemolyzed specimens or markedly elevated
values of potassium. Furthermore, 2 lines of evidence support the rank-order
validity of the serum potassium categories used for our analysis. First, we
observed statistically significant positive associations between serum potassium
quartile and age, sex, and smoking, consistent with published results.9-10 Second, Tsuji et al8
reported an inverse association between serum potassium level and ventricular
arrhythmias using serum potassium values determined at the second offspring
examination.
In conclusion, in our community-based sample of individuals free of
cardiovascular disease and not taking medications that alter potassium homeostasis,
serum potassium level was not associated with risk of cardiovascular disease.
AUTHOR INFORMATION
Accepted for publication September 13, 2001.
This work was supported in part by grant N01-HC-38038 from the National
Heart, Lung, and Blood Institute's Framingham Heart Study, National Institutes
of Health, and in part by research career award 1K24 HL04334 from the National
Heart, Lung, and Blood Institute (Dr Vasan).
Corresponding author and reprints: Daniel Levy, MD, Framingham Heart
Study, 5 Thurber St, Framingham, MA 01702.
From the National Heart, Lung, and Blood Institute's Framingham Heart
Study, National Institutes of Health, Framingham, Mass (Drs Walsh, Larson,
Vasan, and Levy and Mr Leip); the Cardiology Division, Department of Medicine,
Massachusetts General Hospital (Dr Walsh), and the Department of Medicine,
Beth Israel–Deaconess Medical Center (Dr Levy), Harvard Medical School,
Boston; and the Section of Epidemiology and Preventive Medicine, Evans Department
of Medicine, Boston University School of Medicine (Drs Larson, Vasan, and
Levy and Mr Leip).
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