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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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