The NHLBI Workshop on Sodium and Blood Pressure:
A Critical Review of Current Scientific Evidence
Aram V. Chobanian, M.D., Workshop Co-Chair
Professor, Department of Medicine
Dean, Boston University School of Medicine
Boston, Massachusetts
Martha Hill, R.N. Ph.D., Workshop Co-Chair
Professor
Johns Hopkins University School of Nursing
Baltimore, Maryland
The Workshop on Sodium and Blood Pressure was convened by
the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda,
Maryland, on January 28-29; 1999. The purpose of the workshop
was to examine recent evidence concerning the effects of sodium
on blood pressure, updating earlier efforts.1-3
More than 55 invited speakers and other attendees from the
United States and abroad reviewed and discussed the scientific
information. The categorical topics reviewed were as follows:
an overview of the relationship between sodium and blood pressure;
individual differences in blood pressure responsiveness to
sodium intake and other nutrients; sodium and blood pressure
in the young; clinical trials and clinical studies; observational
studies in populations; sodium intake in relationship to other
cardiovascular disease (CVD) and non-CVD conditions; physiological
effects of sodium intake; research needs; and public policy
considerations. This paper synthesizes the presentations and
discussions.
Many factors affect the development of high blood pressure.
Genetic predisposition, male gender, and increasing age are
presently nonmodifiable risk factors for hypertension. Diet
composition, alcohol intake, obesity, and physical activity
are modifiable risk factors for hypertension. Animal experimental
studies, clinical research, and epidemiologic and actuarial
studies conducted over the past 50 years have shown a clear
curvilinear relationship of higher adult blood pressure levels
to higher rates of coronary heart disease (CHD), stroke, heart
failure, and kidney failure. The higher the pressure, the
greater the risk. A continuous relationship is apparent from
below the 120/80 mm Hg level. Thus, a significant portion
of CVD occurs in persons whose blood pressure is above the
optimal level (120/80 mm Hg) but who have not reached the
arbitrary 140/90 mm Hg level defining hypertension, when many
clinicians begin treatment for most patients. For this subset,
a population-wide approach to lowering blood pressure--based
on lifestyle modifications that have been shown to prevent
or delay increases in blood pressure--could affect the total
CVD burden as much as or more than that of treating only those
with established hypertension.
For these reasons, two strategies have been adopted by the
National High Blood Pressure Education Program (NHBPEP): a
high risk strategy, which aims to reach those with hypertensive
blood pressure levels, and a population-based strategy, which
seeks to reach all people. The population approach aims to
prevent the rise of blood pressure with age and reduce the
average blood pressure levels for a population.
Research provides evidence that CVD morbidity can be reduced
by these complementary approaches. First, studies show unequivocally
that lowering high blood pressure can reduce the likelihood
of developing or dying from CVD, including CHD and stroke.
Second, dietary factors in individuals and in the population
at large have important effects on blood pressure levels,
which are generally assumed to translate to CVD risk; genetic
background, expressed in part as a higher level of blood pressure,
also has an important influence as family studies have shown.
There are many effective strategies for helping the population
develop more healthful eating patterns and lifestyles.
Workshop Presentations and Discussions
Overview of the Relationship Between Sodium and Blood Pressure
An abundance of scientific evidence indicates that higher
sodium consumption is associated with higher levels of blood
pressure. This evidence is found in animal studies, observational
epidemiologic studies, and clinical studies and trials.
Studies in laboratory animals, including salt-sensitive
models, have clearly shown that high blood pressure can be
induced by diet.4 Nonhuman primates (chimpanzees)
have recently been used to demonstrate the clear association
between salt intake and a rise in blood pressure. In a randomized
trial, 26 chimpanzees were initially given a low salt/high
potassium diet (pretreatment period). Subsequently, one-half
of the group continued this diet and the remainder received
increasing amounts of additional dietary salt (5 g/d for 19
weeks; 10 g/d for 3 weeks; 15 g/d for 67 weeks). Both groups
were then followed for a 20-week post-treatment period while
receiving the pretreatment diet. Blood pressure increased
progressively during the treatment phase in the active treatment
group but not in the controls; at the end of the treatment
period, blood pressure averaged 33/10 mm Hg higher in the
active treatment compared with control groups. During the
post-treatment period, the blood pressure fell quickly to
pretreatment levels in the active treatment group. This study
in a species that is genetically similar to humans provides
strong evidence of a causal relationship between salt intake
and level of blood pressure.5 A positive relationship
between dietary sodium and blood pressure has been shown from
observational research in humans, including migration studies.
The Yi People Study in China compared Yi farmers in remote
areas with a group of Yi farmers who migrated to the county
seat during the 1950s and a group of other residents of the
county seat, the Han people. Blood pressure rose very little
with age after puberty in the stationary Yi farmers, but there
was a trend of increasing blood pressure with age in Yi migrants
and Han people. In a sample of 417 men, the data showed a
positive relationship between sodium intake and higher blood
pressure and demonstrated the importance of other factors,
such as body mass index (BMI). These findings suggest that
changes in lifestyle, including dietary changes, contribute
to the higher blood pressure among Yi migrants.6
Several large, long-term randomized clinical trials have
shown in free-living populations that a moderate reduction
in sodium intake reduces blood pressure levels. The Trials
of Hypertension Prevention (TOHP), Phase II evaluated the
benefits of weight reduction and sodium reduction, alone and
in combination, for individuals who were slightly to moderately
overweight and had high normal blood pressure readings. Both
weight loss of 2 to 4.5 kg and sodium reduction of 40 to 50
mmol reduced blood pressure at 6 and 36 months. Blood pressure
decreased 2.9/1.6 mm Hg in the sodium reduction group at 6
months and 1.2/0.7 mm Hg at 36 months. In the weight loss
group, the blood pressure decreased 3.7/2.7 mm Hg and 1.3/0.9
mm Hg at 6 and 36 months respectively. In the combined group,
blood pressure decreased 4.0/2.8 mm Hg and 1.1/0.6 mm Hg at
6 and 36 months, respectively. For the longer followup, differences
were statistically significant for systolic and diastolic
blood pressure in the weight loss group and for systolic blood
pressure in the sodium reduction group. Each of the interventions
significantly lowered the incidence of hypertension by about
20 percent over the 3 to 4 year duration of the trial.7
The Trial of Nonpharmacologic Interventions in the Elderly
(TONE) showed that in hypertensive men and women ages 60 to
80 who were in good health and taking one antihypertensive
medication, salt reduction or weight loss alone lowered blood
pressure and reduced the need for medication. Weight loss
coupled with salt reduction was even more effective. Compared
with usual care, mean weight loss was about 10 pounds and
mean sodium reduction was 40 mmol per day. In the group that
lost weight and reduced salt intake as well, about half were
able to stop and remain off medication, whereas this was the
case for about one-third of those who received single interventions.8
In summary, there is conclusive evidence that dietary salt
is positively associated with blood pressure level. In addition,
blood pressure can be lowered with reductions in sodium intake
of 40 to 50 mmol in both hypertensive and non-hypertensive
persons.
Differences in Blood Pressure Responsiveness to Sodium
Intake and Other Nutrients
Sodium
Typically, studies to determine individual differences in
blood pressure response to sodium intake have used a very
low level of sodium chloride (10 to 20 meq/d) for several
days followed by a very high sodium intake, provided either
as a saline intravenous infusion or a high sodium chloride
dietary intake over several days. As reviewed by Weinberger9
in one study of 19 hypertensive individuals, 9 were
categorized as salt sensitive (SS), that is, a decrease then
an increase of >=10 mm Hg when a very low sodium diet was
followed by a saline infusion. In a study of 82 normotensive
individuals following a diet moderately reduced in sodium,
42 percent were considered to be SS, that is, a blood pressure
change >=3 mm Hg; 18 percent were salt-resistant (SR);
and the remaining 40 percent were considered to be indeterminate.
Investigators have also found that some individuals appear
to change classification from SS to SR or vice-versa.10
In a study of 28 individuals, blood pressure response to change
from a 10 meq sodium chloride intake compared with a high
sodium chloride infusion was observed twice within a 12-month
period. Reproducibility was reflected by a moderate correlation
(R=0.56). On restudy, 18 of 28 were consistent in their responses,
4 changed salt responsivity classification, and 6 were classified
as indeterminate (69 mm Hg); 3 were initially classified
as resistant (<=5 mm Hg).11
Also, age appears to influence SS. In a study of 660 adults,
a progressive increase in SS was seen in hypertensive persons
with increasing age. In normotensive individuals, increased
SS was seen among those 60 and older. After age 60, there
was no significant difference between the SS responses of
normal and hypertensive persons.11
The workshop discussion emphasized that individuals' response
to sodium is variable for any nutrient. In addition to age,
race, and genetic background, response to sodium also may
be influenced by medications, the intake of other nutrients,
and the duration of the exposure.
Potassium
Population studies have often shown an inverse relationship
between potassium intake and blood pressure and (less consistently)
between calcium intake and blood pressure. Since the intake
of these and other nutrients tends to be correlated and there
are limitations to statistical adjustment of these correlations,
the effects are best examined in controlled clinical trials.
Pooling of results has been undertaken because most of the
trials are small. A recent meta-analysis included 33 randomized
controlled trials (2,609 participants) of the effect of potassium
supplementation on blood pressure. This pooled analysis showed
a 3/2 mm Hg decrease in blood pressure for about a 50 mmol
higher median potassium excretion for intervention versus
control, with a greater decrease in trials with >=80 percent
African Americans. Another subgroup analysis suggested that
the effect of potassium supplements was enhanced in those
consuming a high intake of sodium.12
Calcium
Two meta-analyses have suggested that diastolic blood pressure
is unaffected by dietary calcium supplementation. In one study,
data from 22 clinical trials were pooled with a total of 1,231
persons. The calcium supplements ranged from 400 to 2,160
mg (median 1,000 mg). Sixteen of these trials enrolled hypertensive
persons. Pooled estimates showed a decrease in systolic blood
pressure of 0.53 mm Hg for trials of normotensive persons
and 1.68 mm Hg for trials of hypertensive persons.13
The second meta-analysis included 33 trials with 2,412 participants
who had supplementation of 1,000 mg to 2,000 mg of calcium;
the pooled estimates showed a reduction in systolic blood
pressure of 1.27 mm Hg in normotensive participants.14
Included in the subgroup analysis of normotensive participants
were six studies that defined the participants as hypertensive.15
Also included among the 33 trials of calcium supplementation
was one study of guava fruit, a food with a high content of
potassium, as well as calcium.16 Thus, the meta-analyses
show that dietary calcium supplementation has a small effect
on systolic blood pressure level in hypertensive persons,
with less effect in normotensive persons. During the discussion,
it was noted that a more recent meta-analysis17
shows that calcium supplementation results in a greater reduction
in blood pressure than previously appreciated, and this observation
is attributable to inclusion of dietary trials and the greater
effect of foods rich in calcium compared with calcium compounds
in pill form.
Magnesium
The evidence associating magnesium with blood pressure level
is inconsistent. In the data from the cross-sectional analyses
of 15,248 participants in the Atherosclerosis Risk in Communities
study, hypertensive participants had lower serum magnesium
levels than did normotensive persons.18 A recent
review of 29 observational studies concluded that the evidence
was suggestive of an inverse association between magnesium
intake and blood pressure level.19 However, the
authors concluded that the interpretation was complicated
because few studies appeared to be specifically designed to
examine the association of magnesium with blood pressure.
Recent controlled clinical studies have shown no significant
effect of magnesium on blood pressure. In TOHP Phase I, supplementation
of 15 mmol or 360 mg of magnesium for 6 months had no effect
on blood pressure in 461 persons with high normal blood pressure.20
In a trial of 300 female non-hypertensive nurses with a low
dietary intake of magnesium, supplementation of 336 mg magnesium
daily for 6 months had no significant effect on blood pressure.21
Multiple Nutrients
The Dietary Approaches to Stop Hypertension (DASH) trial
was based on observational data that suggest that in addition
to calorie balance and intakes of sodium and alcohol, multiple
nutrients influence blood pressure.22 In the 8-week
feeding study, a "combination" diet high in fruits, vegetables,
and low-fat dairy products, which included whole grains, poultry,
fish, and nuts and was reduced in fats, red meat, sweets,
and sugar-containing beverages, produced greater reductions
in blood pressures than a diet high in fruits and vegetables,
each compared with an average American diet.23
Sodium was controlled and held constant across diets. The
degree of reduction in blood pressure was remarkable, averaging
11.4/5.5 mm Hg among those with hypertension and 3.5/2.1 mm
Hg among those without hypertension. The combination diet
produced the greatest reduction in blood pressure in black
hypertensive persons.24
In the DASH trial, the blood pressure results are almost
certainly not attributable to a single nutrient's influence.
Some interest has been focused on the calcium content of the
DASH combination diet. However, in addition to a high calcium
content, the DASH diet had a lower than average sodium content--3,000
mg/day, and compared with the control diet, it contained 173
percent higher magnesium, 150 percent higher potassium, 240
percent higher fiber, and 30 percent higher protein, as well
as reduced total fat, saturated fat, and cholesterol content.
Sodium and Blood Pressure in the Young
Blood pressure is considerably lower in children than adults
and increases steadily throughout the first 2 decades of life,
corresponding with growth. Children with blood pressure in
the upper portions of the blood pressure distribution curve
tend to remain in that segment of the distribution as they
grow into adulthood.25 A relationship between sodium
intake and blood pressure has been found in certain groups
of adolescents and appears to be linked with other risks for
hypertension, that is, family history of hypertension, obesity,
and African American ethnicity.25 In addition,
a review of more than two dozen observational and intervention
studies in children found that sodium was positively associated
with blood pressure.26 Conversely, in some clinical
studies, significant correlations have not been shown for
sodium intake and blood pressure in children and adolescents
overall.
In 1980, a randomized trial was initiated among Dutch newborn
infants to study the effect of a diet reduced by two-thirds
versus a usual level of sodium on blood pressure during the
first 6 months of life. At the end of the trial, systolic
blood pressure in the low sodium group (n = 231) was 2.1 mm
Hg lower than in the control group (n = 245). Subsequently,
blood pressure was measured in 167 children from the original
cohort (group of 476) after 15 years of followup. The adjusted
blood pressure was 3.6/2.2 mm Hg lower in adolescents who
as infants had been assigned to the low sodium group (n =
71) compared with the control group (n = 96). The study investigators
stated that these findings suggest sodium intake in infancy
may be important in relation to blood pressure later in life.27
During the discussion, concerns were expressed about the study
design, appropriateness, and completeness of followup of the
cohort.
Clinical Trials and Clinical Studies
Meta-analyses for the effect of dietary sodium on blood
pressure
Four meta-analyses of randomized clinical trials are available
for estimating the effect of dietary sodium on blood pressure:
the analysis by Midgley and colleagues,28 which
included 56 trials; the two analyses by Cutler and colleagues,29,30
the most recent of which included 32 trials; and an analysis
by Graudal.31 Graudal examined 58 studies of 3,000
hypertensive participants with a median age of 49 years and
found that the difference in mean 24-hour urinary sodium between
randomized groups was 129 mmol. Systolic blood pressure decreased
by a mean of 4.5 mm Hg, and diastolic blood pressure decreased
by a mean of 2.3 mm Hg. In 56 studies of more than 2,000 normotensive
participants with a median age of 27 years, the mean difference
in urinary sodium was 165 mmol, and this produced a mean reduction
in systolic blood pressure of 1.6 mm Hg.
The discussion emphasized the consistent findings from the
four meta-analysis, for example, that sodium reduction has
been found to have a small but significant effect on blood
pressure. As expected, the effect is smallest in normotensive
persons. Issues were raised regarding statistical and operational
heterogeneity, that is, adherence to diet and to the collection
and measurement of urine. Some discussion was devoted to the
possibility of publication bias, reported by some but not
other authors. A general theme was that scientists must be
more discriminating in their interpretation of sodium reduction
studies, taking into account data quality and completeness,
duration, and efficacy versus effectiveness trials.
Sodium and Blood Pressure in Subpopulations
The data pertaining to high blood pressure in subpopulations
make clear several distinctions. The prevalence of hypertension
in African Americans is among the highest in the world. Compared
with whites, hypertension develops earlier in life and average
blood pressures are much higher in African Americans. Baseline
data from the Treatment of Mild Hypertension Study (TOMHS)
used to assess differences among subgroups of participants
showed that education and income levels were inversely correlated
with sodium excretion and with systolic blood pressure in
African Americans, but not in whites. This finding may indicate
a lower level of awareness of lower sodium food selections
among the African American participants.32 The
results from the intervention show that although TOMHS participants
with low education had a higher sodium intake, they also experienced
the largest decrease in sodium excretion with intervention.33
The TOHP I found a 40 percent increase in sodium excretion
after 18 months of a "sodium light lifestyle." There were
no significant differences in the effect of the sodium intervention
in blacks versus whites for either systolic or diastolic blood
pressure. However, women had a greater decrease in systolic
blood pressure.34
The Study of Sodium and Blood Pressure (SnaP) II study,
which examined 130 normotensive young black participants,
found that a reduction of 40 mmol in urinary sodium was accompanied
by reductions in blood pressure of 1 to 2 mm Hg.35
The prevalence of salt sensitivity (SS) was investigated in
one study of 200 healthy white and African American post menopausal
women, half of whom were hypertensive. When a 200 meq sodium
intake followed a low sodium intake, the prevalence of SS
was similar in whites versus the African American women. Preliminary
data suggest that the mechanism of SS, however, may differ
in whites versus African American postmenopausal women (Janice
Douglas, unpublished, 1999).
Quality of Life
Quality of life has been defined as the ability to function
well in daily living, maintain psychological and physical
well-being, pursue social and leisure activity, and obtain
reasonable satisfaction with life.36
In the TOMHS, there was an assessment of the relationship
of lifestyle factors and their changes to quality of life.
All participants were advised to reduce weight, reduce dietary
sodium and alcohol intake, and increase physical activity.
There was also a comparison of the effect of five antihypertensive
drugs. Reducing dietary sodium by 20 to 30 percent did not
impair quality of life.36 Success with lifestyle
changes affecting weight loss and increase in physical activity
related to greater improvements in quality of life. These
interventions contributed to blood pressure control and had
positive effects on the general well-being of individuals.37
The effect of a moderate level of sodium intake on quality
of life has also been explored through an examination of the
proposition that a moderate sodium intake would negatively
affect the palatability, enjoyment, convenience, or cost of
food choices.38,39 Anticipating the
need to assure acceptability of diet and enhance compliance
for clinical trials, a pilot study for the Hypertension Prevention
Trial addressed this issue. The results showed that 59 to
97 percent of participants gave high ratings to food with
a lower content of sodium.40In addition to influences
on the enjoyment of food, some have suggested that possible
physical effects could occur with substantial sodium reduction.
These effects included possible fatigue, cramps, or dizziness,
possible problems in physical functioning, or impaired sexual
functioning. However, quality-of-life measures obtained in
the TOHP and TONE clinical trials showed that sodium reduction
can lead to improvement in quality of life, perhaps due to
blood pressure lowering and cessation of medication.39
Observational Studies in Populations
INTERSALT
The INTERSALT Study (INTERnational study of SALT and blood
pressure), a cross-sectional epidemiologic study, involved
more than 10,000 individuals, ages 20 to 59 years, in 52 population
samples from 32 countries.41-43 Across the 52 populations,
24-hour sodium excretion was significantly related to median
systolic and diastolic blood pressure, the upward slope of
systolic and diastolic blood pressure with age, and the prevalence
of hypertension. Further analyses based on individuals showed
that the relationship between sodium excretion and blood pressure
was similar for non-hypertensive and all participants, indicating
that salt responsiveness in normotensive and hypertensive
people occurs throughout the range of blood pressures. Among
individuals overall, a difference of 100 mmol per day in sodium
excretion was associated on average with a difference of 3
to 6 mm Hg in systolic blood pressure, and across the populations,
100 mmol/day was associated with a 10 mm Hg lesser rise in
systolic blood pressure with age comparing individuals age
25 with those age 55 years. Forty-eight populations were grouped
for post hoc subgroup analysis because of similarities in
lifestyles. An additional four population samples were found
to have very low sodium excretion, low blood pressure levels,
and little or no rise in blood pressure over age. The INTERSALT
findings support similar studies that show a relationship
between sodium intake and blood pressure. INTERSALT also found
that other factors such as high alcohol intake, high body
mass index (BMI), and low potassium intake are additional
risk factors for hypertension. The study found that persons
with higher education levels tended to have lower blood pressure
and persons with lower education levels tended to eat more
sodium, drink more alcohol, consume less potassium, and be
overweight.44
The discussion relative to INTERSALT emphasized that its
strengths are its large sample size and sophisticated statistical
analyses. Issues raised about the study relate to concerns
such as the adjustments for BMI and prior specification of
hypotheses. Several reasons were offered to suggest that the
relationship between sodium consumption and blood pressure
in individuals in the INTERSALT Study was underestimated.
These include incomplete urine collections and the effect
of antihypertensive medications. The study investigators stated
that INTERSALT's set of a priori hypotheses included examining
increased blood pressure with age. During the subsequent extensive
discussion, it was noted that difficult statistical issues
are involved in the interpretation of the INTERSALT data.
A Worksite Cohort, the Scottish Heart Health Study, and
NHANES I
A workplace cohort of 2,937 drug-treated hypertensive patients
ages 42 to 63 years was examined to determine whether a very
low sodium diet over a 3- to 4-week period might be associated
with myocardial infarction (MI). Sodium intake was measured
by one urine collection in patients who had been counseled
to limit their sodium intake for measurement of plasma renin
activity. The primary finding from this study was that in
men but not in women, sodium excretion was inversely associated
with cardiovascular events, particularly MI.45The
discussion of the findings noted several concerns that had
been raised previously.46 No information was published
as to doses of treatment or multidrug regimens; thus, the
influence of drug therapy on sodium excretion is unknown.
In addition, the lack of detailed information on smoking and
alcohol use allows the possibility that differences in risk
factors may be associated with greater mortality in men with
the lowest quartile of sodium excretion, who also had higher
blood pressures. It may be that those with the highest risk
are more apt to reduce their sodium intake.
The Scottish Heart Health study examined persons ages 40
to 59 years in eight 5-year age-bands. In contrast with the
Worksite Cohort Study, average followup time was 7.6 years.
Baseline urinary sodium excretion and the subsequent incidence
of MI were directly and significantly associated in women.
No association was observed in men.47
A 20-year followup of NHANES I (the National Health and
Nutrition Examination Survey) that measured the nutritional
status and health of a national sample of U.S. residents up
to 74 years old showed an inverse association between reported
sodium intake at baseline and all-cause and CVD mortality
20 years later. However, there was a positive association
of mortality at 20-year followup with sodium per 1,000 calories.48
During the discussion, concerns were raised about the analysis
and conclusions from the NHANES I followup study. The reservations
pertained to undermeasurement of calorie intake and sodium
(no measures of discretionary salt), calorie and weight discrepancies,
collinearity between sodium and calories, and the absence
of data on urinary sodium excretion. In addition, the analysis
did not include information on smoking or on comorbidities.
Without such information, it is difficult to attribute mortality
to level of sodium intake. It was noted that followup data
from NHANES II failed to show a relationship between the baseline
sodium intake and mortality at followup.
MRFIT Follow-up
A recent analysis from the Multiple Risk Factor Intervention
Trial (MRFIT) followup was conducted to test the hypothesis
that sodium intake influences mortality risk. A total of 11,696
men who were between 42 and 64 years of age at the sixth annual
MRFIT visit had multiple 24-hour dietary recalls during the
trial to assess nutrient intake, including sodium in foods.
The low and high quintiles of sodium intake at baseline had
means of about 1,600 mg and 4,300 mg respectively for both
the intervention and usual care groups. There were no measures
of urinary sodium excretion. The baseline intake data were
compared with post-trial followup (1982-1996) for risk of
mortality from all causes, acute myocardial infarction, CHD,
and CVD using multiple regression analyses. The results, adjusted
for baseline age, race, education level, average energy and
alcohol intake, ECG abnormalities, incidence of nonfatal CVD,
and antihypertensive drug treatment, showed no significant
differences across the quintiles. The findings were similar
in the subgroup of 6,193 hypertensive men included in the
trial. These and other results from MRFIT do not support the
hypothesis that differences in sodium intake influence risks
for CVD or for total mortality (Jerome D. Cohen, unpublished
data, 1999). During the discussion, the probability of confounding
was acknowledged, for example, that the men at greatest risk
of CVD might have made the greatest reduction in sodium intake
over time because they were aware of their risk.
Sodium Intake and Other Cardiovascular and Noncardiovascular
Conditions
A number of studies have shown an association between sodium
intake and non-CVD conditions. A high sodium intake is positively
associated with calcium excretion, urinary stones, risk of
osteoporosis, indicators of asthma, insulin concentrations,
and gastric carcinoma. Several epidemiologic studies have
reported a positive association between a high sodium intake
and increased calcium excretion. A study of 3,625 Italian
adults reported that urinary sodium/potassium and sodium/calcium
ratios were positively associated with urinary stones.49
Sodium intake estimated from multiple food frequency questionnaires
has been positively associated with 12-year risk of urinary
stones in 91,731 nurses.50Other studies have investigated
the implications of the relationship between urinary sodium
and calcium and its influence on indicators of osteoporosis.
In young adults, sodium-dependent loss of calcium in the urine
seems to be met by increased calcium absorption; it appears
that this does not happen in postmenopausal women.51
In postmenopausal but not premenopausal women, urinary hydroxyproline--an
indicator of increased bone reabsorption--is related to obligatory
sodium and calcium input, and reduction of salt intake lowers
not only urinary sodium but also calcium and hydroxyproline.51,52
In a 2-year longitudinal study of 124 postmenopausal women,
sodium intake measured as urinary sodium excretion was associated
with bone loss at the hip, independent of calcium intake,
physical activity, and weight.53 The proposed mechanism
for this relationship is that increased sodium intake increases
the filtered sodium load and reduces the tubular reabsorption
of calcium. In turn, there are increased urinary calcium excretion,
increased bone reabsorption, and decreased bone density. There
are also supporting data from studies with animals that a
high dietary salt intake lowers bone mineral density.54
The evidence to support a positive association between dietary
sodium and asthma includes data showing an association between
salt sales and asthma deaths in men and children in Great
Britain.55 In addition, a positive association
has been reported between 24-hour urinary sodium excretion
and the response to a histamine challenge test in men with
asthma.56 The purported mechanisms by which sodium
might adversely affect asthma are that a high dietary sodium
may increase the reactivity of airway smooth muscle and/or
may decrease circulating catecholamine concentrations leading
to increased airway reactivity. One randomized controlled
study of the effect of a high sodium diet (regular diet plus
200 meq/day of slow sodium) found an increase in asthma symptoms,
medication use, and timed forced expiratory volume.57
However, another randomized crossover clinical trial of 2-week
periods of either a low (84 meq), normal (147 meq), or high
(201 meq) sodium intake did not show an effect on peak expiratory
flow in 17 patients with mild asthma.58The prevalence
of gastric carcinoma has also been reported to be related
to a high salt intake. The INTERSALT data showed that countries
with the highest sodium excretion had the highest mortality
rates for gastric carcinoma.59 In addition, stomach
cancer is lower in most countries with a lower sodium intake,
and gastric carcinoma rates decline in most countries as dietary
sodium decreases (similar to stroke).
Association of a High Sodium Intake with Left Ventricular
Mass
In the last decade, left ventricular mass (LVM) as estimated
by echocardiography has been reported to be positively related
to the risk for developing subsequent hypertension.60
A high salt intake has been described as a potential stimulus
to LV hypertrophy and in an animal model appears to influence
the magnitude of LVM independent of and more consistently
than the level of blood pressure.61
The TOMHS study reported that in men and women with mild
hypertension, changes in systolic blood pressure, body weight,
and urinary sodium excretion were directly associated with
changes in LVM. During the first 12 months of treatment, antihypertensive
drug monotherapy, especially with the diuretic chlorthalidone,
added to lifestyle intervention that emphasized weight loss
and reduction of dietary sodium, reduced LVM more than placebo.
However, averaged over 4 years, the reduction in LVM was as
great in the group assigned to lifestyle intervention alone
(with addition of drug therapy if blood pressure rose above
specified levels) as it was in the groups assigned to combined
lifestyle and pharmacologic therapy.62
In the discussion, participants noted that blood pressure
level is related to pulse wave velocity and LVM. Pulse wave
velocity decreases with sodium reduction and is highly correlated
with age and BMI. Further study is needed to learn more about
the influence of excessive sodium intake on pulse wave velocity.
Physiological Effects of Sodium Intake
One of the governing hypotheses dealing with the regulation
of blood pressure was developed by Arthur Guyton.63
Guyton proposed that the primary mechanism for initiating
high blood pressure is excessive retention of sodium chloride.
In Guyton's model, a primary lesion resulting in excessive
sodium retention within the kidney may be an important initiating
factor in hypertension by causing an expansion of extracellular
fluid volume, increased venous return, increased cardiac output,
a temporary elevation in blood pressure, and an increase in
tissue perfusion. By the Guyton theory, excessive perfusion
of tissues other than the kidney can result in "autoregulation,"
which is a reduction in blood flow to specific tissues caused
by an increase in total peripheral resistance. Over time,
vascular remodeling may occur as a result of the increased
blood pressure and other hormonal and neuronal events, and
at a certain stage the vascular remodeling may be irreversible,
leading to elevation in total peripheral resistance and hypertension.
Plasma Insulin, Cholesterol, and Coagulation Factors
There is little information on the association between sodium
intake and coagulation factors. Studies on the effect of sodium
intake on plasma insulin and cholesterol have been of short
duration and have been limited to relatively small numbers
of individuals.64 Two studies involving a cross-over
study between dietary intake of 20 meq and 200 to 300 meq
each for 7 days showed that the very low sodium diet was associated
with significantly higher total and low density lipoprotein
(LDL)-cholesterol than the high sodium diet.65,66Egan
and colleagues have studied associations between sodium intake
and plasma insulin levels. They suggest that most people have
greater insulin levels during a very low salt intake (20 mmol)
compared with a high salt intake (200 mmol). These investigators
also note that the evidence is based largely on short-term
studies. There is less concern about a moderate sodium reduction,
and longer term interventions with sodium reduction in individuals
at high risk for adverse effects could be useful.64
In the discussion period, it was emphasized that short-term
and long-term physiological responses to very low dietary
sodium almost certainly differ. The immediate and dramatic
metabolic and hormonal responses that occur soon after marked
salt depletion are not sustained. Therefore, the effects of
extreme levels of sodium probably have limited relevance to
dietary guidance policy for moderate sodium intakes. Nevertheless,
the interrelationships between the multiple mechanisms that
influence sodium and fluid homeostasis should continue to
be investigated.
Research Needs
Several basic research needs were identified. These involved
continued support of studies into the role of salt in normal
and pathophysiologic functions, the identification of those
genes that confer salt sensitivity, and the identification
of individuals who carry these genetic mutations. Notwithstanding
the excellent findings to date, the numerous steps in many
organs that result in hypertension remain to be defined. Clinical/epidemiologic
research opportunities include the need for the use of accurate
and consistent population-based measurements to assess trends;
improved strategies to assess salt intake in individuals;
study of the effects of modifiers, both genotypic and phenotypic,
that influence the effect of salt on blood pressure and clinical
outcomes; continued investigation of the effects of a moderate
sodium reduction on both non-CVD and CVD outcomes; study designs
that help to overcome bias (observational studies) and noncompliance
(trials); collection of additional survey information on the
public's knowledge and attitudes regarding sodium/salt and
skills related to the establishment of food patterns that
are reduced in sodium intake; development of practical strategies
to reduce sodium intake; and, finally, further analysis and
followup of existing cohort data to look at the issues raised
by the observational studies such as those reviewed during
the workshop.
Recently, a major effort has been placed on the mapping
and identification of genes that could be involved in the
control of blood pressure and the development of hypertension.67
In addition, the development of biomarkers for hypertension
risk eventually may allow clinicians to tailor preventive
or treatment strategies for given individuals or sub-populations.
One session of the workshop was set aside for a discussion
of the question "Should there be a randomized clinical trial
on sodium reduction and blood pressure with morbidity/mortality
as an outcome?" There was no support for a randomized clinical
trial to answer the question of whether to use dietary sodium
reduction as a preventive health measure across the entire
population. It was noted that the cost would be prohibitive.
In addition, there would also be confounding of data that
would make it difficult to isolate the effect of dietary sodium
reduction in free-living participants from other environmental
factors that influence blood pressure, that is, other dietary
changes, exercise habits, and weight changes. It was emphasized
that such a randomized clinical trial is not needed because
evidence shows that a moderate sodium intake, as one component
of an overall strategy to reduce all CVD risk factors of the
general population, can have a positive effect on health outcomes.
There was one suggestion for a randomized clinical trial that
would test a reduced sodium diet in older hypertensive individuals
to determine its effect on mortality. Two counterpoints were
offered. First, there would be ethical concerns in not offering
pharmaceutical treatment for individuals with hypertension.
Second, a reduced sodium intake has not been proposed as the
monotherapy for persons with hypertension.
There was discussion of the merits of a cohort study of
older individuals with high normal blood pressure and a high
sodium intake with outcomes based on mortality and morbidity,
as well as changes in blood pressure. If conducted with existing
cohorts with baseline data (including sodium excretion), this
could be an inexpensive and informative study. Other participants
noted that results from this type of cohort study are likely
to be confounded by associations of environmental factors
other than sodium, such as alcohol intake, body weight, and
physical activity.
Public Policy Considerations
A review of the history of dietary guidance policy regarding
sodium intake showed the consistency of the recommendation
for a moderate sodium intake (1,800-2,400 mg), from the first
U.S. policy statement--the 1970 Senate Goals--to the most
recent--the 1995 Dietary Guidelines for Americans.68
The latter is the policy document currently used by all Federal
agencies. Historically, several guiding principles have been
useful in developing dietary guidance policy: scientific
evidence is central, with policy based on the totality
of the evidence, not the outliers; individual people matter,
thus, distinctions between groups should be recognized; numbers
are useful, for example, quantitative indicators can help
guide consumers in the marketplace and guide the food industry
to develop and offer more food product choices that are consistent
with the recommendation on public health; food products
count, discuss foods not just nutrients; consider cultural
factors, understand and recognize diverse dietary habits;
maintain consistency in recommendations whenever possible,
both over time and among expert groups; and do no harm
to people. It was also suggested that, in addition to
salt and sodium intake, associated factors such as iodine
intake should continue to be monitored. The recommended allowance
for iodine for adults is 150 ug/day.69 Iodized
salt is the major dietary source of iodine with one-fourth
teaspoon of salt (1.25g) furnishing about 95 ug iodine. Salt
used in the processing of food and bulk salt for institutional
use are not likely to be iodized, and levels of iodine in
the diet have been declining since 1982.70,71
The discussion emphasized different viewpoints about the
principles that for three decades have guided the development
of dietary guidance public policy. A recurring theme was to
use the information from the workshop to focus on reducing
sodium at the food processing level as a means to improve
the health of the public. Evidence suggests that the sharp
increase in low-fat and nonfat products in the marketplace
during the 1990s resulted from information dissemination that
stressed the health benefit of a lower fat intake, especially
saturated fat. Thus information on diet and health relationships
can influence consumer demand and in turn change the types
of foods available in the marketplace.
Conclusion
The workshop provided an occasion to review evidence from
the last decade about the relationship between sodium intake
and blood pressure. The discussion provided an opportunity
to emphasize that the NHBPEP offers a set of recommendations
designed to help healthy people lower their blood pressure
through changes in eating patterns--including a reduced sodium
intake--and, thus, to reduce their likelihood of developing
CVD. Recognizing that the population's food consumption is
influenced by many factors, the workshop discussions suggested
that recommendations be directed to many components of the
food industry and that relevant government agencies and public
and private education systems work together to provide consistent
coordinated nutrition education and policies and take steps
to improve the consumers' comprehension necessary to achieve
healthful eating patterns. The workshop speakers also recommended
that research and surveillance must be ongoing to develop
new information concerning diet, blood pressure, and CVD.
Adopting a healthful eating pattern will help most Americans
lower their levels of blood pressure. The result will lead
to a reduction in CVD and consequently to significant improvement
in the health and quality of life of the people.
Acknowledgments
The Workshop on Sodium and Blood Pressure was held in Bethesda,
Md, January 28-29, 1999, and was supported by the National
Heart, Lung, and Blood Institute.
Appendix
Participants in the Sodium and Blood Pressure Workshop
Co-Chairs: Aram V. Chobanian, Boston,
MA; Martha Hill, Baltimore, Md.
Presenters: Lawrence J. Appel, Baltimore,
MD; Gerald S. Berenson, New Orleans, LA; Jerome D. Cohen,
St. Louis, MO; Jay N. Cohn, Minneapolis, MN; Nancy R. Cook,
Boston, MA; Richard S. Cooper, Maywood, IL; Allen W. Cowley,
Jr., Milwaukee, WI; Margo Denke, Dallas, TX; Richard B. Devereaux,
New York, NY; Janice G. Douglas, Cleveland, OH; Johanna Dwyer,
Boston, MA; Brent M. Egan, Charleston, SC; Paul Elliott, London,
UK; Bonita Falkner, Philadelphia, PA; Carlos Ferrario, Winston-Salem,
NC; John M. Flack, Detroit, MI; David Freedman, Berkeley,
Calif; Edward D. Frohlich, New Orleans, LA; Haralambos Gavras,
Boston, MA; David Goff, Winston-Salem, NC; Niels A. Graudal,
Copenhagen, Denmark; Clarence E. Grim, Milwaukee, WI; Richard
Grimm, Jr., Minneapolis, MN; John E. Hall, Jackson, MS; William
R. Harlan, Bethesda, MD; Steven C. Hunt, Salt Lake City, UT;
Julie R. Ingelfinger, Boston, MA; Daniel W. Jones, Jackson,
MS; Hugo Kesteloot, Leuven, Belgium; Theodore Kotchen, Milwaukee,
WI; Lewis H. Kuller, Pittsburgh, PA; Shiriki Kumanyika, Chicago,
IL; Alexander G. Logan, Toronto, Ontario, Canada; Graham MacGregor,
London, UK; Allyn L. Mark, Iowa City, IA; David A. McCarron,
Portland, OR; John C. McGiff, Valhalla, NJ; Michael McGinnis,
Washington, DC; Marion Nestle, New York, NY; Suzanne Oparil,
Birmingham, AL; Diana Petitti, Pasadena, CA; Ronald J. Prineas,
Minneapolis, MN; James M. Robins, Boston, MA; Frank M. Sacks,
Boston, MA; Christopher Sempos, Bethesda MD; Jeremiah Stamler,
Chicago, IL; Meir J. Stampfer, Boston, MA; Michael A. Stoto,
Washington, DC; Laura P. Svetkey, Durham, NC; Louis Tobian,
Minneapolis, MN; Myron Weinberger, Indianapolis, IN; Paul
Whelton, New Orleans, LA; Gordon Williams, Boston, MA.
Attendees: Francois M. Abboud, Iowa
City, IA; Darrell E. Anderson, Washington Grove, MD; Ellen
M. Anderson, Washington, DC; Rhona Applebaum, Washington,
DC; Winnie Barouch, Bethesda, MD; Terry L. Bazzarre, Dallas,
TX; Mary Bender, Washington, DC; Karil Bialostosky, Hyattsville,
MD; Ronette R. Briefel, Hyattsville, MD; Vicki Burt, Hyattsville,
MD; Nancy Boucot Cummings, Bethesda, MD; Jeffrey Cutler, Bethesda,
MD; Patrice Desvigne-Nickens, Bethesda, MD; Karen A. Donato,
Bethesda, MD; Yohannes Endeshaw, Washington, DC; Nancy Ernst,
Bethesda, MD; Abby G. Ershow, Bethesda, MD; Stan Franklin,
Los Angeles, CA; Lawrence M. Friedman, Bethesda, MD; Peter
L. Frommer, Bethesda, MD; Anders Galloe, Copenhagen, Denmark;
John W. Gordon, Washington, DC; Richard L. Hanneman, Alexandria,
VA; Pamela Hartnett, Baltimore, MD; Stephen Havas, Baltimore,
MD; Peter G. Kaufmann, Bethesda, MD; Chor-San Khoo, Camden,
NJ; Kathryn M. Kolasa, Greenville, NC; Jane Kotchen, Milwaukee,
WI; Christine Lewis, Rockville, MD; Michael Lin, Bethesda,
MD; Terry Long, Bethesda, MD; Joan Lyon, Washington, DC; William
Manger, New York, NY; Kathryn McMurry, Washington, DC; Linda
D. Meyers, Washington, DC; Julian Paul Midgley, Alberta, Can;
Gregory J. Morosco, Bethesda, MD; Eileen P. Newman, Bethesda,
MD; Chuke E. Nwachucku, Bethesda, MD; Eva Obarzanek, Bethesda,
MD; Valory Pavlik, Houston, TX; Jean Pennington, Bethesda,
MD; H. Mitchell Perry, Jr., St. Louis, MO; Susan M. Pilch,
Washington, DC; James W. Reed, Atlanta, GA; Sharon Ricks,
Bethesda, MD; Edward J. Roccella, Bethesda, MD; Fred Rohde,
Bethesda, MD; Etta Saltos, Washington, DC; Eleanor Schron,
Bethesda, MD; Sheldon G. Sheps, Rochester, MN; Shlomoh Simchon,
New York, NY; Denise Simons-Morton, Bethesda, MD; Sally Squires,
Washington, DC; Elaine J. Stone, Bethesda, MD; Diane Striar,
Bethesda, MD; James Terris, Bethesda, MD; Harold W. "Pete"
Todd, Englewood, CO; Paul A. Velletri, Bethesda, MD; Louise
Williams, Bethesda, MD; Mary C. Winston, Dallas, TX; Jackson
T. Wright, Jr., Cleveland, OH; Peggy Yen, Baltimore, MD; Elizabeth
Yetley, Washington, DC.
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