Salt, blood pressure and health: a cautionary tale

Michael H Alderman

Albert Einstein College of Medicine, Department of Epidemiology & Social Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. E-mail: alderman{at}aecom.yu.edu

By virtue of its central role in maintaining intravascular and extracellular volume, sodium is essential to human survival. Taste, habit, environment, genes, and behaviour probably all influence sodium intake. In view of the heterogeneity that characterizes humankind, it is remarkable that the vast majority of the world's citizens, everywhere, given free access to salt, consume between 100 and 200 mmol of sodium per 24 hours.1 Despite this uniformity of sodium intake across all dietary, cultural, environmental, and hereditary circumstances, and the fact that life spans that are steadily increasing worldwide, many authorities now contend that current salt intake is too high by half.

Advocates of universal restriction of sodium intake to <100 mmol/24-h base their case on the belief that this will produce a population-wide reduction of blood pressure which, in turn, will reduce cardiovascular morbidity and mortality. There is even stronger enthusiasm for strict control of sodium intake for hypertensive people. Indeed, these dogma are often preached with a fervour usually associated with religious zealotry. I will argue here that the available data provides insufficient evidence to justify any universal target for sodium intake for either the whole population or for its hypertensive subset.

The Link of Salt to Blood Pressure

Recognition of the strong, continuous, independent, and significant relationship of blood pressure to the occurrence of cerebral, cardiac, and renal disease, provided the reasonable stimulus for seeking safe, simple, and effective means for reducing blood pressure on a population-wide basis. Dietary intake of sodium, or salt, both because of its ubiquity in the human diet, and its centrality in determining blood volume, presented an obvious opportunity to intervene on blood pressure. The first indication that differences in dietary sodium might explain variation in blood pressure came from cross-cultural studies. In unacculturated societies, blood pressures tended to be lower, and did not appear to rise with age. This contrasted sharply with the age-related rise in pressure and high levels of ‘hypertension’ common in most industrialized nations. Sodium intake, among many other factors, was found to differ between ‘developed’ and ‘undeveloped’ communities. In fact, people confined to an economy of hunting and gathering, with little access to salt, had daily intakes of sodium often limited to 20–40 mmol sodium.2

This ecological association of salt intake to blood pressure led to the suspicion that changes in sodium intake could alter pressure. Investigation of migrant experience produced the first test of that hypothesis. As it turned out, those who exchanged an unacculturated environment for an urban setting generally increased their blood pressure. Among the multiple changes inherent in such an environmental transformation, sodium intake generally rose to the intake of the host cosmopolitan population, thus supporting the view that an increase in sodium intake produced a rise in blood pressure.

Recent findings among the Kuna Indians, initially residents of the San Blas Islands off the coast of Panama, cast doubt upon the notion that salt is responsible for the change in blood pressure associated with migration.3 As long as the San Blas island people had minimal access to sodium, both sodium intake and pressures were low throughout life. Over the past 50 years, as the Kuna established trade relations with the mainland, sodium availability increased to the level consumed by mainland Panamanians. Remarkably, however, these island people, still maintaining their traditional cultural patterns, except for a dietary sodium intake which now is about 140 mmol/24-h, still have low blood pressures, without any age-related rise. In short, salt is only one of many factors that change with migration. There is no shortage of other possible explanations for the observed change in blood pressure.

For example, in a 30-year observational study comparing 144 nuns living in seclusion to 138 lay women in the same region of Italy, although sodium intake was similar, an age-related increase in blood pressure was limited to the community group.4 The community group also experienced a significant increase in cardiovascular mortality and morbidity. The point, of course, is that factors other than sodium intake may be more powerful environmental and behavioural determinants of blood pressure. This study highlights the potential effect of difficult to measure sociocultural circumstances and reinforces the view that ecological analysis is simply too blunt an instrument through which to link a single factor, like dietary sodium, to the blood pressure of individuals.

Observational Studies of Sodium and Blood Pressure

More precise exploration of the relationship between sodium intake and blood pressure has been possible in epidemiological studies. The most ambitious of these has been the Intersalt Study, a cross-sectional assessment of more than 10 000 subjects in 52 locations around the world.1 Its most important finding was that, in those 48 of 52 sites where salt was freely accessible, intakes were invariably between 100 and 200 mmol sodium/ 24-h. Analysis limited to those 48 cosmopolitan centres revealed no association between sodium intake and blood pressure. However, after age stratification, in societies with greater sodium excretion as opposed to those consuming less, blood pressure rose with increasing age. Because Intersalt was cross-sectional, and not a prospective longitudinal study, the notion that pressure rises with age represents one possible extrapolation from the available data. Overall, the results of cross-sectional studies have been inconsistent and inconclusive.

Experimental Studies of Sodium and Blood Pressure

Because association does not prove causality, the salt to blood pressure relationship needed experimental validation. Animal studies have shown that sodium reduction can lower pressure, and, conversely, that sodium addition, as was the case in a study involving a dozen chimpanzees, could elevate arterial pressure.5 In humans, the issue has been more complicated. There is enormous variation between individuals on the effect of salt on pressure (Figure 1Go). This has given rise to the notion that the population includes salt ‘sensitive’ and ‘insensitive’ individuals. This may be associated with genetic variation.6 The fraction of people classified as sodium sensitive is unknown. A recent study of 269 male medical students revealed that roughly half had no response to changing sodium intake from 20 to 270 mmol/24-h, while 1/4 had a rise in response to moving from low to high salt intake, and an almost exactly (66 versus 67) equal fraction had a similar fall in blood pressure in response to this 12-fold increase in sodium intake.7 It is this inter-individual variation that may explain the inconsistency of human experimental results.



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Figure 1 Change in mean arterial blood pressure following dietary salt restriction in normotensive adults. The change is determined by subtracking initial blood pressure from that obtained during diet. Muntzel MS; Drueke T: ‘A Comprehensive Review of the Salt and Blood Pressure Relationship’ American Journal of Hypertension 1992;5(4):2S

 
Perhaps the best estimate of the effect of sodium intake on blood pressure can be gained from meta-analyses of randomized trials. Meta-analyses can only reflect the studies included. Unfortunately, well-designed and conducted studies involved considerable variation in sodium consumption, and many were of short duration. Nevertheless, the most rigorous meta-analyses are in general agreement.8,9 They indicate that, among hypertensive and older subjects, a 75–100 mmol/day reduction in salt intake generates a change of 3–5 mmHg systolic, and about 1–2 mmHg difference in diastolic pressure. The effect on younger and normotensive subjects is less—about 2–3 mmHg for systolic, and <1 mmHg diastolic. It would appear that the largest decline is achieved when small groups of subjects were studied for short periods of time. It has been difficult to sustain, beyond a year, either the blood pressure reduction, or the sodium restriction in free-living subjects. It should be noted, however, that a sustained decrease of even a few mmHg could, assuming the method in its achievement produced no harm, reduce morbidity and mortality more than is currently achieved by restricting treatment to patients with high blood pressure. It is that possibility that energizes advocates of sodium restriction.

In sum, these data indicate that a large (50–75%) reduction in sodium intake by a population can produce, on average, but with wide individual variation, at least for periods of months, a modest, but detectable decline in mean blood pressure. The multiple studies supporting these conclusions are sufficiently robust to make it unlikely that further study will alter their essential findings.

Other Effects of Sodium Reduction

Attempts to alter one aspect of the interior milieu may produce other effects. It is not surprising that so profound and pervasive an intervention as dietary manipulation designed to alter sodium intake by half would also produce non-blood pressure effects. Moreover, just as individuals vary in the way that sodium modulation effects blood pressure, it is to be expected that other physiological responses may also vary.

Blood pressure is not even the only haemodynamic effect of variation in dietary sodium. Increasing attention is being paid to arterial compliance as a measure of vascular health. New, non-invasive techniques now make it possible to assess compliance in the clinical setting. It has been shown that in hypertensive and normal subjects, arterial compliance is positively related to urinary sodium excretion.10 This finding is, of course, consistent with the positive relation of blood volume to compliance previously reported.11

The renin/angiotensin/aldosterone/sodium mechanism for the regulation of haemodynamic integrity is well understood.12 An inverse relation of sodium/volume to renin release is part of the normal mechanism for control of blood pressure and flow. But, in addition, an activated renin/angiotensin system, particularly in the face of elevated blood pressure, adversely affects the vascular endothelium, smooth muscle cells, and inflammation associated with atherosclerotic lesions.13 Reduction of sodium intake by 100 mmol/24-h increases plasma renin activity by threefold, and the relation of sodium intake to plasma renin is continuous across the usual range of dietary sodium. Increased aldosterone activity, also stimulated by reduced sodium intake, has similar unwanted cardiovascular effects.9,14 It has also been shown that sodium restriction stimulates the sympathetic nervous system and increases insulin resistance.15

The complexity of the effects of changes in sodium intake has recently been demonstrated in an exploration of the relation of salt to heart rate.16 Folkow had previously demonstrated the importance of increases in heart rate on cardiac work and cardiovascular morbidity. It has now been shown that, in people whose blood pressure increases with sodium restriction, a higher sodium intake actually decreased left ventricular workload, and this was in contrast to the salt sensitive subjects. In this regard, the recent report by Weinberger,17 revealing greater cardiovascular mortality in salt sensitive than insensitive subjects, suggests that these phylogenic characteristics may have real clinical relevance. Since the Weinberger observational study included no data on actual sodium intake, it is not possible to draw any inferences about whether sodium intake might have influenced outcomes of either group.

The point of these examples is, of course, that intervention on sodium, like virtually all other medical interventions, will have multiple effects. The only way to determine the total or health effects of these interventions is to determine their effect on the quality and duration of life. We commonly recognize this need in regard to pharmacological interventions, but have been less vigilant in assessment of so-called ‘natural’ interventions.18 This has not always been wise. For example, pregnant women were once advised to contain weight gain during pregnancy to <20 lbs to reduce the risk of rising blood pressure and eclampsia. In fact, limiting weight gain did produce those desired outcomes. Unfortunately, at the same time, this intervention unexpectedly increased fetal morbidity and mortality. Women are no longer advised to avoid weight gain in pregnancy.19–21

The Overall Health Effects of Sodium Restriction

Unfortunately, very little data currently exist linking salt intake to the duration or quality of life. It has been shown in rodents that a restricted sodium intake, while reducing blood pressure, also stunts growth and shortens life.22 Members of non-acculturated societies with minimal sodium intake also have short life spans. By contrast, in developed societies, with strikingly uniform sodium intakes between 100–200 mmol/24-h, life expectancy is nearly twice as long. In Japan, where sodium intakes tend to be high, life expectancy is among the highest in the world. Thus, ecological data, albeit weak evidence, provides no suggestion that a reduced sodium intake will extend life, nor that a high sodium intake is inconsistent with a prolonged life expectancy.

Epidemiological data, in which individual sodium intake and health outcomes are linked, is the next level of evidence through which to determine whether dietary sodium might influence the length or quality of life. Unfortunately, despite intense interest in this issue, regrettably little solid data are available. The Scottish Heart Study, a population-based longitudinal study of 10 000 people designed to assess the association of a variety of individual characteristics, measured at baseline, to subsequent morbidity and mortality, did include an estimate of sodium intake obtained by measuring 24-h urinary sodium excretion.23 In this study there was no consistent association between sodium intake and cardiovascular or all-cause mortality.

A subsequent study of 3000 treated hypertensive patients, in whom pretreatment 24-h sodium intake (measured after advice to refrain from excess salt intake for 5 days) and baseline plasma renin activity (PRA) were measured, showed there was a stepwise, significant, and independent inverse relationship between level of sodium measured in a 24-h urine, and subsequent strokes and heart attacks.24 Although this relationship held for the group as a whole, after stratification, it was significant only for men—who accounted for 75% of events. Among men, this relationship persisted after stratification by age, ventricular mass, and race (Figure 2Go). Not unexpectedly, in view of the inverse association of sodium intake and PRA, a good deal of the association of sodium to events was accounted for by level of PRA. Nevertheless, even after accounting for PRA in multivariable analysis, sodium intake retained an independent and inverse association with cardiovascular disease (CVD) events.



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Figure 2 Urinary sodium excretion levels shown for age, race, and left ventricular hypertrophy (LVH). Alderman MH: ‘Salt, Blood Pressure, and Human Health’. Hypertension 2000;36:890–93

 
Our group also analysed the NHANES I epidemiological follow-up data to further explore the relationship of sodium intake to CVD and all-cause mortality.25 In this study of 14 000 adults selected randomly to represent the entire US population, sodium intake was estimated on the basis of a 24-h dietary recall. Again, sodium intake proved to be inversely related to CVD mortality. Those in the lowest quartile of sodium intake were 20% more likely to die of a cardiovascular cause than were those in the highest quartile of sodium consumers.

He and colleagues re-analysed the same NHANES I epidemiological follow-up data.26 Presumably, although not stated, conclusions drawn from their analysis of the entire data set did not differ from that already published. Consistent with the expected heterogeneity of response to sodium restriction, and the possibility that effects in the obese might be greater, the focus of this analysis was on the salt to CVD relationship in the normal sized majority and those 28% who were classified as obese. After eliminating participants with prior evidence of CVD, and removing a large fraction of cardiovascular end points from consideration, they found that the obese subjects in the remaining subgroup, expressed a direct and positive relation of sodium intake to morbid and mortal outcomes. For the 72% of this subset who were not obese, no association of sodium intake to the restricted definition of CVD morbidity and mortality was found. These data are consistent with the expectation that there would be heterogeneity in the relation of sodium intake to health outcomes.

An analysis of the available MRFIT data, widely quoted, although still available only in abstract, found no relationship between sodium intake, estimated by an overnight urine collection, and subsequent CVD events or mortality.27 Visual examination of this data in graphic form suggests a tendency for those consuming the least sodium to have the highest coronary heart disease event rates. Full analysis must await publication of the data.

Most recently published have been the results of an observational study of more than 2300 Finnish men and women in whom baseline cardiovascular risk data included measurement of 24-h urinary sodium excretion.28 This group is of particular interest because median sodium intake was 205 (25–552 mmol/ 24-h) in men, and 154 (12–512 mmol/24-h) in women—an average of 216 and 162 mmol/24-h, respectively. Over up to 13 years of follow-up, it was found that increasing sodium excretion bore an independent and significant association with acute coronary events, but not stroke, and only in obese men. Thus, among the 47% of the male participants who were not obese, consuming up to 500 mmol of sodium per day was not associated with any apparent adverse effect. This relationship was not found in women, nor in non-obese men. Interestingly, the Conclusions and Abstract failed to note that the association applied to a minority of the study subjects. Instead, they concluded that ‘These results provide direct evidence of the harmful effects of high salt intake in the adult population’.

The fact, of course, is that these data, somewhat concordant with the findings in the subgroup analysis of NHANES, suggest, not surprisingly, that the impact of sodium intake probably depends upon subject characteristics. No doubt this heterogeneity reflects the varied influence of genetics, environment, and behaviour on the interaction of sodium intake and human health.

Each of these epidemiological studies share the weakness associated with non-experimental techniques. Unrecognized confounders, if they influence both the exposure variable and the outcome, can distort results. All studies attempt to control for recognized confounders. No matter how diligent, however, this may be imperfect. Moreover, all these studies are based upon a single determination of sodium intake. The inevitable intra-individual variation in such measures would tend to diminish any association between an exposure and outcomes. The fact that in four of the six available studies, a significant independent association between salt intake and outcome was found, suggests that the available data may underestimate the true strength of the association of sodium intake to morbidity and mortality—both to the advantage and disadvantage of lower sodium intake depending upon the group studied. In sum, the available data suggests that the association of sodium intake to health outcomes reflected in morbidity and mortality are modest and inconsistent. Therefore, existing evidence provides no support for the highly unlikely proposition that a single dietary sodium intake is an appropriate or desirable goal for the entire population. This is not surprising in view of the genetic, behavioural, and environmental heterogeneity that characterizes human beings.

What Further Data are Needed

The gold standard for assessing the value of any medical or health intervention is the randomized clinical trial. The goal is to have similar subjects, selected without bias, exposed to regimens that differ only in terms of the intervention in question. Somewhat surprisingly, in view of the professed potential value of this approach, no such study has been powered to assess the effect of sodium intake on cardiovascular morbidity and mortality. Several randomized studies have, however, reported some health outcomes. Whelton and others have reported no difference in headaches, hospitalizations,29 etc, between low sodium/weight loss and control subjects within a mildly hypertensive population. Although eight deaths occurred in this study, their distribution was not reported.

Conclusions

Little controversy surrounds much of what is known about the effects of dietary sodium. Substantial variation in intake (75–100 mmol/24-h) can produce measurable, but modest changes in aggregate blood pressure. However, that effect is variable, and subjects have been arbitrarily described as salt sensitive and resistant. The effect seems to be more substantial in older subjects and in those with higher pressures. Any decision to adopt a low sodium diet should be made with awareness that there is no evidence that this reduction is either safe, in terms of ultimate health impact, or that it will produce cardioprotection. Clearly, there is no justification for a population-wide, public health recommendation for radical reduction (30–50%) in sodium intake.

For hypertensive subjects, sodium restriction can be viewed as another technique to lower blood pressure. Neither its efficacy, nor its safety, nor its contribution to cardioprotection has been compared to other antihypertensive therapies—for drugs which, for example, have been shown to be safe, efficacious, and cardioprotective. Adherence to an evidence-based approach to medical care suggests that sodium restriction should be reserved for patients in whom these proven drug therapies are ineffective, unacceptable, or inadequate. Its use should be carefully monitored to assess both efficacy and safety.

Any sound general dietary salt recommendation must await knowledge of the sum of its multiple consequences on the quality and duration of human life. Until then, no universal dietary recommendation can be scientifically justified.

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