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Evidence Relating Dietary Sodium to Cardiovascular Disease

Albert Einstein College of Medicine, Dept. of Epidemiology & Population Health, Bronx, New York

Address reprint requests to: Michael H. Alderman, M.D., Albert Einstein College of Medicine, Dept. of Epidemiology & Population Health, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: alderman{at}aecom.yu.edu

	ABSTRACT

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
The expectation that dietary sodium intake might influence cardiovascular disease occurrence has been based upon its impact on blood pressure (BP). Solid experimental data confirms the ability of large (75–100 mmols/24 hours) changes in dietary sodium to reduce pressure by, on average, mid-low single digits. However, there is substantial inter-individual variation in BP response. In addition, sodium restriction generates other, sometimes undesirable effects, including increased insulin resistance, activation of the renin-angiotensin system, and increased sympathetic nerve activity. The health effects of salt restriction are, therefore, the sum of these recognized, and probably other unrecognized, intermediate effects. Ideally, salt restriction would be tested in a randomized clinical trial. In its absence, there are 9 observational studies linking baseline sodium intake, estimated by either 24 hour urine or dietary intake, to morbidity and mortality. The results have been inconsistent. The only study in hypertensive patients, there was an inverse relation of sodium to cardiovascular outcome. In a Japanese study, stroke incidence was increased among males with the highest salt intake. Two studies found a direct relation of sodium intake to cardiovascular mortality in an obese minority of the group studied. Taken together, these results suggest, not surprisingly given the genetic, behavioral, and environmental variety of humankind, that heterogeneity best describes the relation of sodium intake to cardiovascular morbidity and mortality. In short, the available data provides no support for any universal recommendation of a particular level of dietary sodium.

Key words: sodium, blood pressure, cardiovascular events

	Introduction

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
The link of sodium intake to cardiovascular outcomes was first addressed in a long-term prospective cohort study of Japanese descendents resident in Hawaii. There was no association of dietary sodium intake to subsequent stroke was found [1].

Nevertheless, even before that study report, there was widespread calls to restrain what was often described as excess salt intake, despite the absence of any evidence that such a dietary modification would favorably effect the quality or duration of life. The purpose of this article is review the evidence that has subsequently accumulated relating sodium intake to cardiovascular health outcomes.

	Usual Sodium Intake

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
Worldwide, in a variety of socioeconomic and cultural circumstances, sodium intake for the population is remarkably consistent—centering about 150 mmols/24 hour [2]. This aggregate homogeneity, however, masks substantial inter-individual variation [3], which, probably, reflects the rich genetic [4], behavioral [5], and environmental variety [6] that characterizes humankind’s milieu.

	The BP Rationale for a Salt to Cardiovascular Disease Relationship

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
The relationship of sodium intake to blood pressure is the basis for the belief that restriction of dietary sodium consumption will prevent blood pressure related cardiovascular events. There is, however, a less well developed and supported contention that there are non-hemodynamic effects of sodium restriction that may contribute independently to adverse cardiovascular events. Some contend that the increased cardiac output and blood flow associated with high sodium intake may ultimately lead to remodeling, arterial stiffening, and systolic hypertension [7]. However, others have found just the opposite [8]. There is also evidence that left ventricular mass is increased by a high sodium diet independent of BP [9]. Finally, there is some evidence that increasing sodium intake increases serum and interstitial sodium concentration. This, in turn, may alter vascular reactivity and response to angiotensin II. These non-hemodynamic effects are neither well established in humans, nor firmly placed in a causal pathway that links salt intake to adverse morbid or mortal results [10].

Greater confidence supports the salt to blood pressure relationship. The importance of blood volume in maintaining blood pressure and hemodynamic integrity has been known for centuries. Sodium is a central determinant of blood volume. Since the association of blood pressure and cardiovascular—particularly stroke—morbidity and mortality is clear, it is reasonable to hypothesize that since salt might raise blood pressure, increased salt intake might increase cardiovascular risk. This notion gained early support from cross cultural studies.

Ecologic study is, however, a notoriously weak basis from which to draw causal inferences, since a myriad of other changes might confound an apparent ecological association. The example of experience among the Kuna Indians of Central America is a case in point [11]. These island dwellers, believed to be both salt deprived, and normotensive in the 1940s, were revisited 50 years later. Then, with free access to salt, these islanders consumed amounts relatively equal to those found in the routine western diet. Surprisingly, these now salt replete, but otherwise relatively unchanged natives still had low pressures that did not rise with age. By contrast, other Kuna, who had migrated to urban Panama, ate about the same amount of salt, but these relative cosmopolites had blood pressure patterns indistinguishable from their western neighbors.

The BP to salt relationship rests, happily, on firmer ground. Experimental studies have convincingly confirmed that reduction of sodium intake by about half (75–100 mmols/24 hours) can reduce both systolic and diastolic pressures, in the aggregate, by several mmHgs [12–14]. Genetic studies [4] now add another dimension to existing evidence that behavioral and environmental heterogeneity routinely influence both variation of salt intake and its relation to blood pressure.

	Variability in BP Response to Sodium

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
The heterogeneity of blood pressure response to variation in sodium intake is best described as following a normal or Gaussian distribution [3]. Nevertheless, the concept of "salt sensitivity" has considerable currency and is based upon the arbitrary classification of persons characterized by BP response to large (20–220 mmol/day) variation in sodium intake. The prevalence of "salt sensitivity" is unknown, but probably well less than half of the general population. It is reputed to be more common in older, black, and obese subjects. Salt sensitive subjects have been reported to have a higher level of other CVD risk factors including hyperlipidemia, increased serum creatinine, and increased urinary albumin. The later appears to be accentuated by a high sodium diet, which may account for blood pressure elevation [15]. Finally, Weinberger has found that salt sensitive patients are at greater risk of cardiovascular events than non-sensitive subjects even after controlling for other cardiovascular risk factors [16]. Because sodium intakes were unavailable, this study provides no insight into the relation of sodium intake to morbidity and mortality. It does, however, provide further evidence of the physiological heterogeneity that characterizes response to sodium.

	Other Intermediate Effects of Sodium Restriction

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
All medical interventions have multiple effects. Sodium restriction is no exception. Thus, there is experimental evidence that, among other things, sodium restriction increases sympathetic nerve activity [17], increases insulin resistance [18] and activates the renin-angiotensin system [19]. Perhaps more closely linked to cardiovascular outcomes may be the correlation between sodium intake and left ventricular mass and hypertrophy [20]. These, and perhaps other unrecognized effects associated with alterations in sodium intake, are both positive and negative. The health consequences of sharp sodium restriction are the sum total of all these effects. That extrapolation from the effects on intermediate variables to health outcomes is not an ideal basis for medical intervention has led to recent clinical trials to compare antihypertensive drugs [21]. Medical interventions are best judged, not on the basis of their impact on a single intermediate variable of interest, but on their health effect—assessed by morbidity and mortality. The gold standard of modern evidence based medical practice is the randomized clinical trial whose end points are morbidity and mortality.

	Dietary Salt and Cardiovascular Outcomes: Ecological Data

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
Regrettably, no clinical trial has assessed the health effect of a low sodium diet. The short term randomized trials of sodium restriction, even when taken together, do not provide evidence of either safety or efficacy [14]. Instead, the case for sodium restriction must be based on animal and ecologic data, as well as extrapolation from observational human data. There is strong experimental evidence from animals that salt restriction reduces blood pressure. Moreover, in a variety of species, including rodents, caloric restriction, presumably associated with reduced sodium intake, extends life [22]. Because of the substantial effect of behavior and environment on dietary intake, extrapolation from animal experiments to the human condition must be made with caution. Ecological data regarding the sodium to health link is inconclusive. The Yamamono Indians have very low sodium intake and rather short life expectancy, while the Japanese, with much higher sodium intakes, are among the most long lived of all national groups. Assembling data from a variety of sources, Sasaki and colleagues [23] found, in 17 industrialized countries, a strong correlation between average sodium intake—which ranged narrowly from 127.2 to 186.0 mEq/24 hours—and national stroke mortality.

	Cardiovascular Outcomes: Epidemiological Evidence

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
Perhaps more informative is epidemiological data which links the salt intake of individuals to their health—particularly cardiovascular—outcomes. To date, this is the best available upon which to explore the possibility that, because reducing salt can lower blood pressure, and because lowering blood pressure prevents strokes and heart attacks, it follows that reducing salt intake might reduce the incidence of these cardiovascular events (i.e. because A = B, and B = C, therefore, A = C). The first step to explore this hypothesis is to observe whether and how sodium intake relates to health outcomes. There are now 9 such studies.

As noted above, The Honolulu Heart Study was the earliest cohort study to address this issue [1] (1985). Drs. Yano and colleagues assessed the association of sodium intake (24-hour dietary recall) to stroke in over 7000 men of Japanese ancestry, free of stroke and coronary artery disease and between 45–68 years at entry. During 10 years of follow-up, these were 154 thrombo-embolic, 65 intracranial hemorrhagic, and 19 unclassified strokes. The incidence of stroke in these Japanese migrants was similar to Caucasian residents of Hawaii and the US. Blood pressure, uric acid, cigarettes smoked per day, and alcohol intake were all significant predictors of all types of stroke. Of all the nutrients examined, only fat and protein were associated, both inversely, to stroke incidence in univariate, but not multivariable analysis. Sodium intake was categorized by quintiles ranging from less than 1.78 to greater than 3.87 g/day. Interestingly, the mid-category range was 2.39–3.00 which is roughly the worldwide mean intake of sodium. There was no association of sodium intake and stroke in univariate, or multivariable analysis. The absence of any relation of sodium intake to stroke here should be viewed in the context of finding that risk factors for stroke here were similar to those found in Caucasian populations.

The second relevant report linked pre-study sodium intake (24-hour urine) to cardiovascular morbidity and mortality in 2937 treated mildly hypertensive participants in the NY Worksite Study [24]. Patients were 67% male, had a mean age 53, and a baseline blood pressure of 150/96 mmHg. They were advised to avoid high sodium food for 5 days before a pre-treatment 24-hour urine collection to estimate sodium intake. Mean baseline sodium excretion for men was 115 mmol/24 hours. In treatment pressure averaged 138/83 mmHg over the up to 8 years of study, during which there were 117 cardiovascular events. Because most events occurred in men, they were the primary subjects of study. Unadjusted incidence rates for MI in quartiles of sodium intake revealed a rate ratio of 2.7(95% CI 1.5–4.9) from the lowest to the highest quartile. Based on only 17 strokes, there was no relation of sodium intake to stroke. Subgroup results by age, race, left ventricular mass, and potassium excretion were consistent. Multivariable analysis including other known cardiovascular risk factors, and plasma renin level, revealed a significant independent inverse relation of sodium excretion, as a continuous variable (HR 0.68 [95% CI.46–0.9])—to myocardial infarction. Exclusion of PRA from the multivariable analysis increased the impact of sodium to events. A test for linear trend was significant, supporting the continuous inverse relation of salt intake to cardiac events. The robustness of the inverse relation was sustained in an analysis restricted to those 2/3’s of subjects whose 24-hour urine collection met Cockcroft and Gault criteria for completeness, as well as when analysis was limited to those whose 24-hour urinary sodium was between 35 and 240 mmols. The strengths of this observational study include biological rationality, the estimation of sodium intake by 24-hour urinary output, as well as systematic follow-up and standardized treatment of participants. This study is limited, however, by weaknesses including the availability of but a single 24-hour urine from each patient and, of course, the inability to be certain than unidentified bias may have altered then relationships—a concern in all observational studies. A particular critique has been that the pre-collection recommendation to avoid high salt foods may have altered the relation of salt to outcome. For this to be true, it would require the advice to have altered both the exposure (salt) and the outcome (morbidity). It’s hard to develop a hypothesis that would produce an opposite result—particularly since the inverse relationship of salt to outcome was continuous and consistent, and compatible with the initial hypothesis (salt inversely related to PRA) [19]. No data has yet appeared to confirm or contest these findings in hypertensive patients.

The Multiple Risk Factor Intervention Trial (MRFIT) has been published only in abstract [25] (1997), and presented privately thereafter (1999) [26]. Based on 24 hour dietary recall, in 11,696 men with average sodium intake 121 to 134 mol/day, the authors found no significant association of sodium intake to cardiac mortality either in the group as a whole, or among the 6,103 hypertensive men. Absence of full data limits the usefulness of this study.

The Scottish Heart Health study followed 11,629 representative subjects for 9 years (1997) [27]. A single 24-hour urine collection was obtained at baseline. Some 27 variables related to subsequent coronary artery disease and overall mortality. There were 581 coronary events (206 fatal), and 591 total deaths. Controlling for all other factors, sodium excretion did not predict coronary artery disease events in men (HR 1.05, 95% CI 0.96–1.14), and was "just positive" for women (HR 1.16, 95% CI 1.00–1.33). Of note was the finding of a borderline negative gradient for all deaths. In contrast, potassium was found to be significantly and positively related to reduced coronary events.

In 1999, the 20-year mortality experience of the representative sample of the US population (11,346 adults) in the NHANES 1 Epidemiological Follow-up study was reported [28]. There were 3923 total, and 1970 cardiovascular fatalities. Sodium intake was estimated by a 24-hour dietary recall. This report focused on all participants, but also reported that an analysis limited to those without evidence of prevalent cardiovascular disease at entry yielded identical results. After stratification by quartile of sodium intake, all cause and cardiovascular mortality bore a significant inverse association with sodium. From the highest to the lowest quartile of sodium, CVD mortality rates/1000 patient years were 9.60 and 11.80, (p <0.0019). The sodium/calorie ratio, by contrast, was directly related to CVD mortality, with the highest quartile rate 11.35 versus 9.73 for the lowest, (p = 0.017). In multivariable analysis, (including calories, and sodium, as a continuous variable and other CVD variables), sodium had a significant and independent inverse association with both total and cardiovascular mortality. The association to cardiovascular mortality did not persist in this model when sodium/calorie ratio was also included (HR 0.98, 95% CI 0.77–1.02). The authors concluded that, although there may be an inverse relation of sodium to cardiovascular mortality, it was neither simple nor large.

The Health Professionals Study reported the relation to stroke of baseline sodium, estimated by a food frequency questionnaire, in 43,738 men followed for 8 years [29]. The study sought to determine the stroke protective value of potassium intake. There were 328 fatal and non-fatal strokes (210 ischemic, 70 hemorrhagic, and 48 unclassified). Although the data were not shown, the authors report no relationship of sodium intake to total, ischemic, or hemorrhagic stroke. Thus, in a setting where a significant independent association was found between potassium, magnesium, and cereal fiber and stroke, no link was found between sodium and stroke.

An analysis of the overweight subset of the NHANES Epidemiological Follow-up Study through 1992 was reported in 2000 [30]. The 9485 subjects studied here excluded those with prevalent cardiovascular disease, or who used heart medication (unspecified) in the past 6 months, or who consumed a low sodium (unspecified) diet at baseline. Bifurcating the population at a BMI of 27.8 (men) or 27.3 kg/m² (women) identified 931 men and 1757 women as overweight. Among the 72% who were not overweight, there was no association of dietary sodium to any cardiovascular outcome. During 43,788 person years of follow-up in the overweight group there were 250 strokes (87 fatal) 647 coronary heart disease events (214 fatal), 329 cardiovascular deaths, and 810 deaths from all causes. Among the overweight subset, there was no relation of sodium intake to non-fatal coronary heart disease, but there was a significant direct relation between increasing sodium and stroke, coronary heart disease mortality, as well as cardiovascular and all cause mortality. The authors note this to be the first of 6 published in the 15 years since the first relevant report, to identify a favorable association of lower dietary sodium to any cardiovascular outcome in any subset of any population. Thus, the readily available measure of BMI confirmed the predicted heterogeneity of CVD outcome response to sodium, paralleling the known heterogeneity of individual hemodynamic response to sodium.

In a Finish Study, sodium intake, as estimated by 24-hour urinary excretion, was linked to morbidity and mortality in a a prospective study of some 1173 men (25–64 years) and 1263 women, free of prevalent cardiovascular disease [31]. Follow-up through 1995 revealed 128 coronary heart disease events, and 84 strokes. There was no relationship between sodium intake and stroke. By contrast, for men, and the group as a whole (HR 1.34, 95% CI 1.08–1.67), but not for women, there was a significant direct relationship to coronary heart disease events. However, there was a significant interaction between body mass index (BMI) and sodium for cardiovascular and all cause mortality. After stratification at BMI 27 kg/m^2, in the normal weight majority there was no relation of sodium to cardiovascular or all cause mortality in those with lower BMI. By contrast, among the overweight subjects, increasing sodium intake was significantly associated with both cardiovascular (HR 1.44, 95% CI 1.02–2.04), and all cause mortality (HR 1.56, 95% CI 1.21–2.00). These risks are for a 100 mmol/24 hour difference in sodium excretion, which even in this high sodium consuming population (men = 205 and women = 154 mmol/24 hours) would represent 50–75% of current intake. These results further support the existence of heterogeneity in the relation of salt intake to cardiovascular health outcomes, and suggest a possible adverse effect of high sodium intake in some subjects.

Most recently, Japanese investigators [32] have reported the relation of sodium intake to stroke in a large population based cohort in a single city. A semi-quantitative annual food frequency questionnaire estimated sodium intake in all subjects free of stroke or coronary heart disease on cancer at baseline. A significant increase in total stroke, as well as ischemic and hemorrhagic types, occurred among men in the highest compared to the lowest tertile of sodium intake. Among women, there was no significant association of increased sodium intake with stroke in multivariable analysis. It should be noted that intake averaging 5.6 grams/24 hour (with the upper tertile at nearly 7 grams) was more than twice that consumed in the US. These findings conflict with both the Finish Study where sodium intake was similar and the study of Japanese in Hawaii, where sodium intake was similar to the US population.

	An Overview of Observational Data

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
The available data is drawn from more than 80,000 subjects followed for periods of up to 20 years. Different means of estimating sodium intake, different types of participants, different end points, and, perhaps not surprisingly, different outcomes are the most striking findings of this overview (Table 1). One study identifies a population wide adverse health association of increasing sodium intake—but at salt intake levels well beyond that contained in the American diet. By the same token, two studies found a population wide favorable association of low sodium and cardiovascular mortality. Two studies did, however, find a positive association of increasing coronary disease events in increasing sodium intake. Two of three studies in which stroke was the end-point identified no relation to sodium intake, but one of these two studies that found an adverse relation of high salt to MI, also found that association for stroke. In the most recent stroke study, carried out among high sodium intake Japanese found a positive association of salt to outcome in men. There is only one published study in hypertensive subjects. In this, there was an inverse association of sodium to outcome. The MRFIT abstract, never published in full, reported no association of sodium to outcome in either the full cohort or in its hypertensive subset.

	Implications

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 
The available data on salt and cardiovascular health identifies neither net benefit, nor proof of safety from a low sodium diet, nor harm from a high sodium intake. The appropriate next step may be more rigorous observational study. Perhaps some consistent association of sodium intake will be found in an identifiable sub-group defined by phenotype, genotype, or behavioral characteristics. Mostly likely, there may be a range of sodium intakes which, when violated, can produce harm.

Health related interventions should be based upon solid evidence of both safety and benefit. This dictum is well accepted in personal encounter medicine, but is less stringently applied in public health. This seems surprising, and potentially hazardous, since even a modest adverse effect could be magnified by intervention across a whole population. Policy recommendations should be cautiously made, and then only upon the strongest possible evidence. History (hormone replacement therapy and dietary restriction in pregnancy) is replete [33–35] with examples of the hazard of extrapolation from effects on selected surrogate end points or observational data. Although the most convincing evidence in support of any health intervention comes from randomized clinical trials, that can not be the only basis for policy recommendations. The best example is, of course, the case against cigarette smoking. Instead of a randomized trial, a vast body of consistent observational data has repeatedly demonstrated a strong, graded, and timely link between smoking and adverse health outcomes. The salt data does not meet that test.

Received January 9, 2006.

	REFERENCES

TOP ABSTRACT Introduction Usual Sodium Intake The BP Rationale for... Variability in BP Response... Other Intermediate Effects of... Dietary Salt and Cardiovascular... Cardiovascular Outcomes:... An Overview of Observational... Implications REFERENCES

 

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