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Sodium Intake and Mortality in the NHANES II Follow-up Study

      Abstract

      Purpose

      US Dietary Guidelines recommend a daily sodium intake <2300 mg, but evidence linking sodium intake to mortality outcomes is scant and inconsistent. To assess the association of sodium intake with cardiovascular disease (CVD) and all-cause mortality and the potential impact of dietary sodium intake <2300 mg, we examined data from the Second National Health and Nutrition Examination Survey (NHANES II).

      Methods

      Observational cohort study linking sodium, estimated by single 24-hour dietary recall and adjusted for calorie intake, in a community sample (n = 7154) representing 78.9 million non-institutionalized US adults (ages 30-74). Hazard ratios (HR) for CVD and all-cause mortality were calculated from multivariable adjusted Cox models accounting for the sampling design.

      Results

      Over mean 13.7 (range: 0.5-16.8) years follow-up, there were 1343 deaths (541 CVD). Sodium (adjusted for calories) and sodium/calorie ratio as continuous variables had independent inverse associations with CVD mortality (P = .03 and P = .008, respectively). Adjusted HR of CVD mortality for sodium <2300 mg was 1.37 (95% confidence interval [CI]: 1.03-1.81, P = .033), and 1.28 (95% CI: 1.10-1.50, P = .003) for all-cause mortality. Alternate sodium thresholds from 1900-2700 mg gave similar results. Results were consistent in the majority of subgroups examined, but no such associations were observed for those <55 years old, non-whites, or the obese.

      Conclusion

      The inverse association of sodium to CVD mortality seen here raises questions regarding the likelihood of a survival advantage accompanying a lower sodium diet. These findings highlight the need for further study of the relation of dietary sodium to mortality outcomes.

      Keywords

      The US Department of Health and Human Services and the Department of Agriculture 2005 nutrition guidelines recommend that adult Americans consume less than 2300 mg of sodium (to convert sodium values to mmol, divide by 23) per day to “…prevent or delay the onset of high blood pressure…” and “…to lower elevated blood pressure.”

      U.S. Department of Health and Human Services, U.S. Department of Agriculture. Dietary guidelines for Americans. Available at: http://www health gov/dietaryguidelines/dga2005/document/pdf/DGA2005 pdf 2005. Accessed March 10, 2005.

      These new guidelines, slightly below the previously recommended 2400 mg per day, also recommend that individuals with hypertension, or who are black, or middle-aged and older, consume no more than 1500 mg of sodium per day.

      U.S. Department of Health and Human Services, U.S. Department of Agriculture. Dietary guidelines for Americans. Available at: http://www health gov/dietaryguidelines/dga2005/document/pdf/DGA2005 pdf 2005. Accessed March 10, 2005.

      The guidelines are largely based on the blood pressure reduction associated with lower sodium in short-term clinical trials.
      • Sacks F.M.
      • Svetkey L.P.
      • Vollmer W.M.
      • et al.
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      • Graudal N.A.
      • Galloe A.M.
      • Garred P.
      Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride a meta-analysis.
      However, these trials could not assess the long-term cardiovascular morbidity and mortality consequences of lower sodium. Of concern is that lower sodium intake can generate increased activity of the renin-angiotensin and sympathetic nervous systems, and possibly increased insulin resistance, and each of these could have adverse cardiovascular effects.
      • Alderman M.H.
      • Madhavan S.
      • Ooi W.L.
      • Cohen H.
      • Sealey J.E.
      • Laragh J.H.
      Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension.
      • Grassi G.
      • Dell’Oro R.
      • Seravalle G.
      • Foglia G.
      • Trevano F.Q.
      • Mancia G.
      Short- and long-term neuroadrenergic effects of moderate dietary sodium restriction in essential hypertension.
      • Petrie J.R.
      • Morris A.D.
      • Minamisawa K.
      • et al.
      Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus.
      Morbidity and mortality outcomes will be influenced by unfavorable and favorable effects, as well as the unknown consequences of a diet altered to achieve lower sodium intake. In the absence of clinical trial data, several observational studies, with contradictory results, are available.
      • Kagen A.
      • Popper J.S.
      • Rhoads G.G.
      • Yano K.
      Dietary and other risk factors for stroke in Hawaiian Japanese men.
      • Alderman M.H.
      • Madhavan S.
      • Cohen H.
      • Sealey J.E.
      • Laragh J.H.
      Low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men.
      • Tunstall-Pedoe H.
      • Woodward M.
      • Tavendale R.
      • A’Brook R.
      • McCluskey M.K.
      Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish heart health study cohort study.
      • Alderman M.H.
      • Cohen H.
      • Madhavan S.
      Dietary sodium intake and mortality the National Health and Nutrition Survey (NHANES I).
      • He J.
      • Ogden L.G.
      • Vupputuri S.
      • Bassano L.A.
      • Loria C.
      • Whelton P.K.
      Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults.
      • Cohen J.D.
      • Grandis G.
      • Cutler J.A.
      • Neaton J.D.
      • Kuller L.H.
      • Stamler J.
      Dietary sodium intake and mortality MRFIT Follow-up Study Results (abstract).
      • Tuomilehto J.
      • Jousilahti P.
      • Rastenyte D.
      • et al.
      Urinary sodium excretion and cardiovascular mortality in Finland a prospective study.
      • Nagata C.
      • Takatsuka N.
      • Shimizu N.
      • Shimizu H.
      Sodium intake and risk of death from stroke in Japanese men and women.
      In this setting, the second National Health and Nutrition Examination Survey

      US Department of Health and Human Services, Centers for Disease Control and Prevention. The Second National Health and Nutrition Examination Survey (1976-1980). Available at: http://www.cdc.gov/nchs/data/series/sr_01/sr01_015.pdf. Accessed March 10, 2005.

      (NHANES II) provides a fresh opportunity to assess the relationship between dietary sodium intake and long-term mortality, by examining the experience of a representative sample of the US civilian population.

      Methods

       Study Population

      Detailed methods of NHANES II, conducted by the National Center for Health Statistics, are described elsewhere.

      US Department of Health and Human Services, Centers for Disease Control and Prevention. The Second National Health and Nutrition Examination Survey (1976-1980). Available at: http://www.cdc.gov/nchs/data/series/sr_01/sr01_015.pdf. Accessed March 10, 2005.

      Baseline interview and examination data were collected in 1976-1980 for 20322 NHANES II participants aged 6 months to 74 years. The NHANES II Mortality study assessed vital status for 9250 NHANES II participants aged 30 to 74 years at entry.
      • Loria C.M.
      • Sempos C.T.
      • Vuong C.
      Plan and operation of the NHANES II Mortality Study 1992.
      To avoid confounding due to preexisting disease at entry, we excluded 1483 (16%) with self-reported history of heart disease or stroke, 344 reporting a low salt diet for medical reasons, and 21 who died with ≤6 months follow-up. To limit the influence of extreme, possibly invalid values, we excluded individuals reporting either the highest or lowest 1% of sodium or calories (n = 248). The remaining 7154 constituted the study sample.
      • Dietary guidelines recommend sodium restriction despite absence of clinical trial data.
      • This observational study found significant associations of lower sodium with increased cardiovascular disease mortality.
      • No subgroup observed to experience benefit from lower sodium diet.
      • These data suggest the safety and effectiveness of lower dietary sodium merit further study.

       Baseline Measurements

      Baseline information included medical history, standardized physical examination, laboratory tests, anthropometric measures, and nutrient intakes computed from one 24-hour dietary recall obtained by trained interviewers. Sample mean blood pressure (BP) (127/81 mm Hg) was imputed for 18 individuals (0.25%) with missing values. Individual estimates of sodium added in cooking or at the table were not available. Energy consumption (kilocalories) will be referred to as calories in this report.
      Sociodemographic characteristics included age, sex, race and education. Race was dichotomized as white and nonwhite, and education as less than high school graduate versus else. Body mass index (BMI) was calculated from height and weight (kg/m2) and categorized as normal, overweight and obese (<25, ≥25 and <30, ≥30 kg/m2, respectively) for subgroup analysis. Using 3-level physical activity scales, those reporting the highest “much exercise” for recreational activity or “very active” for nonrecreational activity, were coded as physically active, with all others as reference. Alcohol use was dichotomized as yes/no for regular weekly use of any alcoholic beverage and alternately as a continuous variable (drinks per week). Smoking was dichotomized as yes/no for current smoking.

       Mortality Follow-up

      The NHANES II Mortality Study ascertained vital status through December 31, 1992 from the National Death Index and the Social Security Administration Death Master File.
      • Loria C.M.
      • Sempos C.T.
      • Vuong C.
      Plan and operation of the NHANES II Mortality Study 1992.
      Those not found to be deceased were assumed alive at that date. Death certificates were ordered to resolve indeterminate matches. Underlying cause of death was coded according to the International Classification of Disease 9th revision

      The International Classification of Diseases 9th Revision Clinical Modification (1998 ICD-9-CM), 5th ed. Burr Ridge, IL: Practice Management Information Corp.; 1997.

      (ICD-9): CVD 390-459; coronary heart disease (CHD) 410-414; cerebrovascular 430-438.

       Statistical Analysis

      Sodium and sodium/calorie ratio were analyzed as continuous variables. Sodium was also dichotomized at 2300 mg (100 mmol), the guidelines threshold that was also close to the sample median (2360 mg). Quartiles of sodium were also created (<1645, 1645-2359, 2360-3345, ≥3346 mg). Bivariate associations with dichotomized sodium were assessed with t test and chi-squared for continuous and categorical variables, respectively. Means are reported ± standard errors.
      Age and sex adjusted mortality rates expressed as events per 1000 person-years for coronary heart disease (CHD), cerebrovascular cardiovascular disease (CVD) and all causes were calculated for lower and upper sodium levels.
      Cox proportional hazards regression models
      • Cox D.R.
      Regression models and life tables (with discussion).
      were constructed to predict time to cause-specific and all-cause mortality, simultaneously adjusting for sex, race, treatment for hypertension, smoking, history of diabetes, alcohol use, education and physical activity as indicator variables; and age, BMI, cholesterol, systolic BP, and dietary potassium as continuous variables. Adjustment for energy intake (calories) was done with three alternate methods: the standard multivariate method of adding calories as a continuous covariate to the model, the sodium density method of using sodium/calorie ratio in the model instead of sodium and calories as separate variables, and the residuals method introduced by Willett and Stampfer.
      • Willett W.
      • Stampfer M.J.
      Total energy intake implications for epidemiologic analyses.
      In the Willett and Stampfer method (designed to reduce the correlation of sodium and calories), sodium is regressed on calories, and for each observation the calculated regression residual is added to its modeled expected sodium value. The correlation of this residuals-adjusted sodium with calories was reduced to a negligible r <0.001 (P >.99). The residuals-adjusted sodium value was also dichotomized at its median.
      Interaction product terms of sodium with each covariable were created and separately tested in the full model, including main effects terms. To further assess potential heterogeneity or inadequately adjusted confounding, separate adjusted Cox models were constructed within subgroups defined by each covariable.
      For all analyses, P values are 2-tailed, with alpha <0.05. Statistical analyses were performed with STATA (Version 8; StataCorp LP, College Station, Tex) and SUDAAN (Version 9; Research Triangle Institute, Research Triangle Park, NC) software, accounting for the NHANES II complex sampling design.

      Results

      The 7154 individuals who met our preinclusion and exclusion criteria represented 78.9 million noninstitutionalized US adults aged 30-74 years at the time of study entry. During 13.7 years mean follow-up (range 0.5-16.8) there were 1343 deaths, of which 541 were for CVD, including 282 CHD and 79 cerebrovascular. Dietary sodium intake (mean = 2718 ± 23 mg) as a continuous variable was directly correlated with calories (r = 0.66, P <.001), weight (r = 0.15, P <.001), and physical activity (r = .07, P <.001) but had an inverse association with BMI (r = −0.03, P = .02).
      Table 1 shows the varied CVD risk profiles of the dichotomized sodium groups. Those with sodium <2300 (n = 3443) were more likely to be older, to have history of diabetes, less education, slightly higher cholesterol and BMI and were less likely to be physically active or drink alcohol. Conversely, those with sodium ≥2300 (n = 3711) were more likely to be male, white and smokers and had substantially higher calorie and potassium intake. There were no discernable blood pressure differences.
      Table 1Baseline Characteristics by Sodium Group
      Results for continuous variables are reported as mean values (with standard errors) with P values calculated by t test between the sodium categories. Categorical variables are reported as percentages with P values calculated by chi-square. Because of rounding, not all percentages total 100. All results take into account the complex sampling design of NHANES II.
      VariableSodium < 2300 n = 3443Sodium ≥ 2300 n = 3711Total n = 7154P
      Age (years)49 ± 0.3747 ± 0.2348 ± 0.26<.001
      Cholesterol (mg/dL)223 ± 1.4220 ± 1.3222 ± 1.1.09
      Dietary sodium intake (mg/day)
      To convert values to mmol divide by 23.
      1579 ± 9.83696 ± 202718 ± 23<.001
      Dietary calories (kcal)1411 ± 122248.27 ± 221861 ± 15<.001
      Dietary sodium/calories (mg/kcal)1.2 ± 0.011.8 ± 0.011.5 ± 0.01<.001
      Dietary potassium (mg/day)1942 ± 242814 ± 322411 ± 23<.001
      Body mass index (BMI kg/m2) (%)25.9 ± 0.1025.6 ± 0.0825.7 ± 0.07.02
      BMI (%).07
       <25 kg/m2495150
       25-29.9 kg/m2343535
       ≥30 kg/m2171416
      Weight (lb)156 ± 0.69164 ± 0.48160 ± 0.43<.001
      Race
       White (%)879088<.001
       Black (%)1179
       Other (%)232
      Education < high school (%)362932<.001
      Male (%)316047<.001
      Smoker (%)343836.01
      BP >140/90 mm Hg (%)313030.79
      Treatment for hypertension (%)4.13.73.9.44
      Systolic BP (mm Hg)127 ± 0.23127 ± 0.67127 ± 0.60.52
      Diastolic BP (mm Hg)81 ± 0.5582 ± 0.5581 ± 0.52.36
      History of diabetes (%)3.82.63.1.02
      Physically active (%)384542<.001
      Alcohol (%)404744<.001
      BMI = body mass index; lb = pounds; BP = blood pressure.
      low asterisk Results for continuous variables are reported as mean values (with standard errors) with P values calculated by t test between the sodium categories. Categorical variables are reported as percentages with P values calculated by chi-square. Because of rounding, not all percentages total 100. All results take into account the complex sampling design of NHANES II.
      To convert values to mmol divide by 23.
      When dietary sodium was expressed as a continuous variable (per 1000 mg), it had a statistically significant (P = .03) inverse association with CVD mortality after adjusting for calories and all above-mentioned covariables, meaning that lower sodium values were associated with greater CVD mortality (Table 2). Using the residuals-adjusted sodium as a continuous variable gave the exact same result. Sodium/calorie ratio also showed a statistically significant (P = .008) inverse association with CVD mortality. Inverse associations with all-cause mortality of continuous sodium and sodium/calorie ratio were consistent.
      Table 2Adjusted Mortality Hazard Ratios for Dietary Sodium Measures
      All models adjusted for age, sex, race, smoking, alcohol use, systolic blood pressure, anti-hypertensive treatment, body mass index, education <high school, physical activity, body mass index, dietary potassium, history of diabetes, serum cholesterol. Models for sodium (continuous) and sodium <2300 mg also adjusted for calories.
      Mortality OutcomeSodium MeasureHazard Ratio95 % Confidence IntervalP Value
      Cardiovascular diseaseSodium per 1000 mg
      To convert values to mmol divide by 23.
      Results for residuals adjusted sodium as a continuous variable were exactly the same as without that additional adjustment.
      0.890.80, 0.99.03
      Sodium mg per calorie0.800.68, 0.94.008
      Sodium <2300 mg1.371.03, 1.81.03
      Sodium <residuals adjusted median1.221.01, 1.49.04
      All-causeSodium per 1000 mg0.930.87, 1.00.06
      Sodium mg per calorie0.890.79, 1.00.05
      Sodium <2300 mg1.281.10, 1.50.003
      Sodium <residuals adjusted median1.120.97, 1.30.13
      Coronary heart diseaseSodium per 1000 mg0.910.79, 1.05.21
      Sodium mg per calorie0.790.63, 0.99.04
      Sodium <2300 mg1.210.87, 1.68.25
      Sodium <residuals adjusted median1.190.93, 1.52.16
      Cerebrovascular diseaseSodium per 1000 mg0.950.75, 1.21.68
      Sodium mg per calorie0.910.60, 1.37.63
      Sodium <2300 mg1.780.89, 3.55.10
      Sodium <residuals adjusted median1.050.58, 1.88.87
      low asterisk All models adjusted for age, sex, race, smoking, alcohol use, systolic blood pressure, anti-hypertensive treatment, body mass index, education <high school, physical activity, body mass index, dietary potassium, history of diabetes, serum cholesterol. Models for sodium (continuous) and sodium <2300 mg also adjusted for calories.
      To convert values to mmol divide by 23.
      Results for residuals adjusted sodium as a continuous variable were exactly the same as without that additional adjustment.
      Those with dietary sodium <2300 mg had significantly higher age-sex adjusted mortality rates for CVD and all causes compared with ≥2300 mg (Figure 1). CHD mortality rates per 1000 person years for <2300 and ≥2300 mg were 3.14 and 2.74, respectively (P = .26). Cerebrovascular mortality rates were 0.99 and 0.66, respectively (P = .07). Using the residuals method calorie-adjusted median sodium, instead of 2300 mg, showed age-sex adjusted rates for CVD mortality as 6.06 and 4.97 for lower and higher sodium, respectively (P = .03). For all-cause, CHD, and stroke mortality, using the residuals calorie-adjusted median attenuated the differences that were not statistically significant.
      Figure thumbnail gr1
      Figure 1Age-sex adjusted rates of CVD and all-cause mortality events per 1000 persons by sodium category, without weighting. Numbers of events are in parentheses. †To convert values to mmol per day divide by 23.
      Adjusting for calories and all previously mentioned CVD risk factors, sodium intake <2300 mg was associated with 37% greater risk of CVD mortality (P = .03) and 28% increased risk of all-cause mortality (P = .003) (Table 2). Residuals method, calorie-adjusted median sodium was similarly associated with CVD mortality (P = .04), but the association with all-cause mortality was not statistically significant (P = .13). For quartiles of sodium, using the highest quartile as reference, CVD mortality hazard ratios (HRs) were 1.31 (95% confidence interval [CI]: 0.90-1.89, P = .14), 1.39 (95% CI: 0.91-2.11, P = .11), 0.89 (95% CI: 0.64-1.25, P = .49) for quartiles 1, 2, and 3, respectively. All-cause, CHD, and stroke mortality followed a similar pattern.
      There were no statistically significant interactions of sodium with any covariable. Subgroup analyses by each of the covariables separately showed consistency for the majority of subgroups in these fully adjusted models (Figure 2). However, association of sodium with CVD was not apparent among those <55 years old and was substantially attenuated for those with less than median weight and those with median or higher cholesterol.
      Figure thumbnail gr2
      Figure 2Hazard ratios of CVD mortality for sodium intake <2300 mg in selected subgroups estimated by Cox models adjusting for age, sex, race, smoking, alcohol use, systolic blood pressure, anti-hypertensive treatment, body mass index, education < high school, physical activity, calories, dietary potassium, history of diabetes, serum cholesterol except for the factor defining the subgroup. low asterisk Denotes median values.
      Non-whites and the obese (BMI ≥30) were the only 2 of 26 subgroups examined whose HR for lower sodium was <1, and neither was statistically significant (P = .70 and 0.83, respectively).
      Stratification by median calories showed a statistically significant association of lower sodium with CVD mortality in the lower calorie half (HR: 1.56; 95% CI: 1.08-2.27, P = .02) and a consistent, albeit attenuated and not statistically significant association in the upper calorie half (HR: 1.22; 95% CI: 0.77-1.94, P = .39).
      Sensitivity analyses for the sample without excluding any sodium or calorie values, for a subset excluding individuals with the highest or lowest 2.5% of sodium or calories, when deleting 18 cases with imputed BP, and when using a continuous rather than dichotomized alcohol measure, all gave results similar to the primary analyses. For the whole sample, alternate thresholds ranging from 1900 to 2700 mg in 100-mg increments, as well as the median 2368 mg, all showed consistent statistically significant associations of CVD risk with lower sodium and an HR range from 1.35 (P = .03) for 1900 mg to 1.42 (P = .04) for 2700 mg. Only 20% of the study sample had daily sodium intake ≤1500 mg. In a subgroup comprised of black, hypertensive or middle-aged individuals, for whom the recommended sodium threshold is 1500 mg,

      U.S. Department of Health and Human Services, U.S. Department of Agriculture. Dietary guidelines for Americans. Available at: http://www health gov/dietaryguidelines/dga2005/document/pdf/DGA2005 pdf 2005. Accessed March 10, 2005.

      the increased CVD mortality risk associated with that threshold (with ≥2300 mg as reference) was not statistically significant (HR: 1.16; 95% CI: 0.87-1.55, P = .30). This association was borderline significant, however, among the whole sample with sodium <1500 mg (HR: 1.32; 95% CI: 0.99-1.74, P = .05).

      Discussion

      The principal finding in this representative sample of US adults is that sodium intake, measured as a continuous variable and adjusted for calories by each of three distinct methods, had a statistically significant and inverse association with CVD mortality, independent of known cardiovascular risk factors. Results were consistent for all-cause, CHD, and cerebrovascular-specific mortality, although these latter associations were not statistically significant. In addition, individuals reporting consumption of sodium consistent with the most recent US dietary guidelines of <2300 mg had 37% higher CVD mortality and 28% higher mortality from all causes, compared with those whose reported sodium intake exceeded 2300 mg.
      Although an inverse association was not apparent in those <55 years old, the obese, or among non-whites, and was much attenuated in those with less than median weight and those with greater than median serum cholesterol, it was consistent in 22 of the 27 subgroups examined along with the group as a whole. Most importantly, sodium <2300 mg was not significantly associated with better CVD mortality outcome in any subgroup.
      Eight previous observational studies examined clinical outcomes associated with sodium levels.
      • Kagen A.
      • Popper J.S.
      • Rhoads G.G.
      • Yano K.
      Dietary and other risk factors for stroke in Hawaiian Japanese men.
      • Alderman M.H.
      • Madhavan S.
      • Cohen H.
      • Sealey J.E.
      • Laragh J.H.
      Low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men.
      • Tunstall-Pedoe H.
      • Woodward M.
      • Tavendale R.
      • A’Brook R.
      • McCluskey M.K.
      Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish heart health study cohort study.
      • Alderman M.H.
      • Cohen H.
      • Madhavan S.
      Dietary sodium intake and mortality the National Health and Nutrition Survey (NHANES I).
      • He J.
      • Ogden L.G.
      • Vupputuri S.
      • Bassano L.A.
      • Loria C.
      • Whelton P.K.
      Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults.
      • Cohen J.D.
      • Grandis G.
      • Cutler J.A.
      • Neaton J.D.
      • Kuller L.H.
      • Stamler J.
      Dietary sodium intake and mortality MRFIT Follow-up Study Results (abstract).
      • Tuomilehto J.
      • Jousilahti P.
      • Rastenyte D.
      • et al.
      Urinary sodium excretion and cardiovascular mortality in Finland a prospective study.
      • Nagata C.
      • Takatsuka N.
      • Shimizu N.
      • Shimizu H.
      Sodium intake and risk of death from stroke in Japanese men and women.
      Sodium intake was inversely and significantly associated with higher CVD mortality for the entire sample of NHANES I,
      • Alderman M.H.
      • Cohen H.
      • Madhavan S.
      Dietary sodium intake and mortality the National Health and Nutrition Survey (NHANES I).
      with myocardial infarction among male participants in a prospective cohort study of treated hypertensives
      • Alderman M.H.
      • Madhavan S.
      • Cohen H.
      • Sealey J.E.
      • Laragh J.H.
      Low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men.
      and with all-cause mortality in men in the Scottish Heart Study.
      • Tunstall-Pedoe H.
      • Woodward M.
      • Tavendale R.
      • A’Brook R.
      • McCluskey M.K.
      Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish heart health study cohort study.
      By contrast, a statistically significant direct association of sodium with CVD and all-cause mortality was observed in a Finnish community sample,
      • Tuomilehto J.
      • Jousilahti P.
      • Rastenyte D.
      • et al.
      Urinary sodium excretion and cardiovascular mortality in Finland a prospective study.
      among the overweight subset of NHANES I,
      • He J.
      • Ogden L.G.
      • Vupputuri S.
      • Bassano L.A.
      • Loria C.
      • Whelton P.K.
      Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults.
      with CHD incidence among women in the Scottish study,
      • Tunstall-Pedoe H.
      • Woodward M.
      • Tavendale R.
      • A’Brook R.
      • McCluskey M.K.
      Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish heart health study cohort study.
      and with stroke in a community sample in Japan.
      • Nagata C.
      • Takatsuka N.
      • Shimizu N.
      • Shimizu H.
      Sodium intake and risk of death from stroke in Japanese men and women.
      No statistically significant associations were reported either among Japanese-American men of the Honolulu Heart Study
      • Kagen A.
      • Popper J.S.
      • Rhoads G.G.
      • Yano K.
      Dietary and other risk factors for stroke in Hawaiian Japanese men.
      or in the MRFIT cohort.
      • Cohen J.D.
      • Grandis G.
      • Cutler J.A.
      • Neaton J.D.
      • Kuller L.H.
      • Stamler J.
      Dietary sodium intake and mortality MRFIT Follow-up Study Results (abstract).
      Although the available data can best be described as inconsistent and inconclusive, some of the variability in the results may be related to differences in characteristics of the studied populations. For example, while a significant association was observed in the Finnish sample as a whole, when examined by sex the elevated hazard ratios were statistically significant for males but not females. For the Finnish males
      • Tuomilehto J.
      • Jousilahti P.
      • Rastenyte D.
      • et al.
      Urinary sodium excretion and cardiovascular mortality in Finland a prospective study.
      and the Japanese sample as a whole,
      • Nagata C.
      • Takatsuka N.
      • Shimizu N.
      • Shimizu H.
      Sodium intake and risk of death from stroke in Japanese men and women.
      mean daily sodium intake was about 5000 mg. This is considerably higher than observed for US adults in NHANES I (2022 mg),
      • Alderman M.H.
      • Cohen H.
      • Madhavan S.
      Dietary sodium intake and mortality the National Health and Nutrition Survey (NHANES I).
      this study (2642 mg), or among Chicago adults in the Intersalt study (3222 mg), the latter determined by 24-hour urinary excretion.
      Intersalt
      An international study of electrolyte excretion and blood pressure: results for 24-h urinary sodium and potasium excretion: Intersalt Cooperative Research Group.
      Perhaps the association of sodium with CVD differs at markedly different levels of sodium intake.
      The overweight subgroup of NHANES I
      • He J.
      • Ogden L.G.
      • Vupputuri S.
      • Bassano L.A.
      • Loria C.
      • Whelton P.K.
      Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults.
      stands out as an inconsistent finding in studies carried out in moderate sodium intake settings. In the present study, overweight and normal weight subgroups had findings similar to the group as a whole, and obese individuals showed no association. Authors of the earlier study did not find any direct association of sodium with CVD or mortality outcomes in the 72% of their sample who were not overweight, nor in any other subgroup that could have been defined by a dozen other covariables. Perhaps subgroup multiplicity might have played a role.
      • Schulz K.F.
      • Grimes D.A.
      Multiplicity in randomised trials II subgroup and interim analyses.
      To date, there have been no clinical trials with sufficient data to lend support one way or the other regarding the effect of sodium restriction on CVD morbidity or mortality.
      • Hooper L.
      • Bartlett C.
      • Davey S.G.
      • Ebrahim S.
      Advice to reduce salt for prevention of cardiovascular disease.

       Study Limitations

      Our study has several limitations. There was only a single sodium measure at baseline—a limitation shared by all the longitudinal studies. Also, there was no quantitative measure of table or cooking salt that might have been added. Assessments of usual dietary intake and particularly of sodium are difficult, and the 24-hour dietary recall may be an imprecise estimation of actual consumption.
      • Willett W.
      Mean sodium intake in this study was only 18% lower than that observed among Chicago residents by the Intersalt study, which measured sodium by 24-hour urinary excretion.
      Intersalt
      An international study of electrolyte excretion and blood pressure: results for 24-h urinary sodium and potasium excretion: Intersalt Cooperative Research Group.
      If one assumes that table and cooking salt can add as much as 11%,
      • Mattes R.D.
      The taste for salt in humans.
      this difference from the Intersalt value might actually fall to about 9%.
      A uniform underestimation of actual dietary intake by the 24-hour recall would not differentially bias the results. The possibility that there was a differential bias in reporting food intake according to BMI or other CVD risk factors is mitigated by sub-group analysis by BMI, statistical adjustment for the measured CVD risk factors, and by the use of four distinct methods of adjusting for calories. Adjusting for calories as a covariable, or with the density method, the residuals method, or by stratification all gave consistent results.
      The P values for analyses using CHD and cerebrovascular disease outcomes were, for the most part, not statistically significant. However, with smaller numbers of events in these specific classifications, statistical power was substantially lower. For death certificate data, the more specific the outcome, the greater the chance of measurement error. Nonetheless, the direction and magnitude of the point estimates were consistent with CVD and all-cause outcomes. This also applied to the quartile analysis.
      It is possible that those defined as consuming <2300 mg had actually consumed more or less. However, it is important to note that individuals from the general public trying to conform to sodium guidelines will not assess their sodium intake by 24-hour urinary excretion. It is much more likely they will try to apply food label values to a recall of their food intake—a method that resembles the 24-hour dietary recall of NHANES. Thus, the 2300-mg classification used in our study might be a reasonable approximation of the target that individuals would aim for when assessing their dietary intake under real life circumstances. As is usually the case in observational studies, the two main comparison groups were not balanced in baseline characteristics, including sex, potassium, and alcohol, among others. We attempted to account for the imbalance both by multivariable adjustment and by subgroup analyses, which gave consistent results for the majority of subgroups. However, we recognize that the potential problem of confounding, including from unmeasured variables, cannot be fully overcome in an observational study. Finally, we were unable to assess the impact of any genetic variability that is likely to introduce heterogeneity with regard to the impact of sodium on health outcomes.
      • Kuznetsova T.
      • Staessen J.A.
      • Stolarz K.
      • et al.
      European Project on Genes in Hypertension (EPOGH) Investigators. Relationship between left ventricular mass and the ACE D/I polymorphism varies according to sodium intake.

       Study Strengths

      This study has several important strengths. The sample is large and was constructed to represent the US civilian, noninstitutionalized population. Long follow-up resulted in a large number of endpoints. The adjusted hazard ratios of CVD and all-cause mortality per 1000 mg of sodium (0.9) was approximately the same as those observed in NHANES I.
      • Alderman M.H.
      • Cohen H.
      • Madhavan S.
      Dietary sodium intake and mortality the National Health and Nutrition Survey (NHANES I).
      The internal validity of the sodium measure is reflected in the anticipated correlation with calories, weight and physical activity.
      These findings were consistent, whether sodium was assessed as a continuous or dichotomous variable and in multiple subgroups. Although we have fixed special attention on the 2300-mg threshold for comparison to recent guidelines, this happened to be very close to the median value of this sample (2360 mg) and median-based analyses yielded indistinguishable results. Further, the use of alternate thresholds ranging from 1900 to 2700 mg in 100-mg increments in sensitivity analyses all gave consistent results.
      The recently revised recommendation in the US government Dietary Guidelines for Americans, 2005, is that all adults should reduce sodium intake to below 2300 mg/day.

      U.S. Department of Health and Human Services, U.S. Department of Agriculture. Dietary guidelines for Americans. Available at: http://www health gov/dietaryguidelines/dga2005/document/pdf/DGA2005 pdf 2005. Accessed March 10, 2005.

      It is justified primarily on the basis of well-documented effects on blood pressure
      • Sacks F.M.
      • Svetkey L.P.
      • Vollmer W.M.
      • et al.
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      • Graudal N.A.
      • Galloe A.M.
      • Garred P.
      Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride a meta-analysis.
      and the belief that the adverse consequences of sodium restriction pose no important safety concern.

      United States Department of Agriculture. Nutrition and your health: dietary guidelines for Americans; Part D: Science base; Section 7: Fluid and electrolytes. Available at: http://www health gov/dietaryguidelines/dga2005/report/HTML/D7_Fluid htm. Accessed March 10, 2005.

      There are, nevertheless, several plausible reasons to question the validity of the assumption of safety. Reduced-sodium diet stimulates the renin angiotensin system, and elevated plasma renin activity has been associated with increased risk of myocardial infarction.
      • Alderman M.H.
      • Madhavan S.
      • Ooi W.L.
      • Cohen H.
      • Sealey J.E.
      • Laragh J.H.
      Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension.
      Lower sodium has been associated with stimulation of the sympathetic nervous system
      • Grassi G.
      • Dell’Oro R.
      • Seravalle G.
      • Foglia G.
      • Trevano F.Q.
      • Mancia G.
      Short- and long-term neuroadrenergic effects of moderate dietary sodium restriction in essential hypertension.
      • Darbar D.
      • Fromm M.F.
      • Dellorto S.
      • Roden D.M.
      Sympathetic activation enhances QT prolongation by quinidine.
      that, in turn, has been associated with adverse CVD and mortality outcomes.
      • Hozawa A.
      • Ohkubo T.
      • Kikuya M.
      • et al.
      Prognostic value of home heart rate for cardiovascular mortality in the general population the Ohasama study.
      Sodium restriction may also influence insulin resistance either directly
      • Petrie J.R.
      • Morris A.D.
      • Minamisawa K.
      • et al.
      Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus.
      • Feldman R.D.
      • Schmidt N.D.
      Moderate dietary salt restriction increases vascular and systemic insulin resistance.
      or indirectly through sympathetic nervous system elevation.
      • Bjorntorp P.
      • Holm G.
      • Rosmond R.
      Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus.
      • McCarty M.F.
      Elevated sympathetic activity may promote insulin resistance syndrome by activating alpha-1 adrenergic receptors on adipocytes.
      To what extent, if any, these potential mechanisms may mediate sodium intake and CVD outcomes is unknown and is subject to debate based on a paucity of data. Nonetheless, the possibility of such adverse effects cannot be dismissed a priori.
      The close correlation between sodium intake and total energy intake suggests that sodium may also be associated with essential nutrients that were not measured. Lower sodium may be a marker for a less than optimal overall diet.

       Implications

      Observational studies have inherent limitations and no single observational study can confirm a causal inference. Nor is it possible to infer from these data what might have occurred if there had been an intervention to alter sodium intake. On the other hand, basing a lower sodium recommendation primarily on intermediate effects such as blood pressure reduction is also unsatisfactory. Unintended health consequences can result from seemingly reasonable expectations. For example, earlier recommendations to restrict weight gain in pregnancy were later found to increase infant mortality.
      • Simpson J.W.
      • Lawless R.W.
      • Mitchell A.C.
      Responsibility of the obstetrician to the fetus. II. Influence of prepregnancy weight and pregnancy weight gain on birthweight.
      In the case of sodium, extrapolations from positive effects on blood pressure may be offset by extrapolations from potentially adverse effects on the sympathetic nervous system, the renin-angiotensin system, insulin resistance, and the potential that other important nutrients might be decreased when free-living individuals alter diets to decrease sodium. In the absence of a definitive clinical trial, additional well-designed observational studies that examine clinical outcomes merit consideration.
      The data here cannot sustain a conclusion that lower sodium is harmful. However, these findings, along with the inconsistent results of other epidemiologic studies, and the propensity for substantial variability among individuals, do not lend support to any universal prescription for salt intake. More likely, optimal sodium intake will vary based upon genetic, behavioral, and environmental circumstances.
      In sum, the inverse associations of sodium to CVD mortality observed in this large, nationally representative sample, raise questions regarding the likelihood that a survival advantage will necessarily result from a universal recommendation for a lower dietary sodium intake. These findings highlight the need for further studies that go beyond intermediate outcomes like blood pressure, to convincingly establish the relation of dietary sodium to mortality.

      Acknowledgment

      The authors wish to acknowledge the NHANES II investigators for making the public use data available. However, the authors take full and sole responsibility for the integrity and accuracy of the data analyses and the contents of this article.

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