Editor's Note: Commentary based on Kalogeropoulos AP, Georgiopoulou VV, Murphy RA, et al. Dietary sodium content, mortality, and risk for cardiovascular events in older adults: the Health, Aging, and Body Composition (Health ABC) Study. JAMA Intern Med 2015;175:410-9.

Background

The link between dietary sodium intake and primary hypertension is well established.^1,2 It is also known that salt restriction results in significant reductions in both systolic and diastolic blood pressure (BP).³ It is unclear whether such dietary modifications have an impact on the incidence of cardiovascular events and mortality.^4,5 The Institute of Medicine recently convened a committee to review the effects of sodium intake on health outcomes, focusing on daily intake of 1.5 to 2.3 gjday and concluded that there were insufficient data to suggest that aggressive sodium restriction has an impact on the occurrence of cardiovascular disease (CVD), heart failure (HF), and associated mortality.⁶ The Health, Aging, and Body Composition (Health ABC) study represents one of few prospective cohort studies to evaluate this question.⁷

Methods

The Health ABC study examined sodium intake, (i.e., < 1,500 mg/d, 1,500-2,300 mg/d, and > 2,300 mg/d) in 2,642 older adults (age 70-79 years) with 10-year follow up data in a community-based, prospective cohort study that enrolled subjects between April 1, 1997 and July 31, 1998. The authors looked at adjudicated death, incident CVD, and incident HF. Sodium intake was assessed via a 108-item Food Frequency Questionnaire and surveillance was conducted by in-person examination, alternating with a telephone interview every 6 months. The study was powered to detect a 20% increase in mortality risk per 1 g of sodium intake.

Results

The overall 10-year mortality rate was 33.7%, the incidence of new CVD was 28.9%, and heart failure was 15.1%. For all three outcome events, the middle group (1,500-2,300 mg/d sodium intake) demonstrated the lowest rates of incident outcome events; however, the hazard ratios failed to attain statistical significance when the models were adjusted for confounding variables, most notably sex (Table 1).

Table 1: Association Between Baseline Dietary Sodium Intake and Outcome Events

Outcome Event	Dietary Sodium Intake
	< 1500 mg/d (n = 291)	1500-3200 mg/d (n = 779)	> 2300 mg/d (n = 1572)	Unadjusted HR (95% CI)	Adjusted HR (95% CI)
Mortality	97(33.8%)	236(30.7%)	548(35.2%)	1.09 [1.04-1.16)	1.03 [0.98-1.09]
Incident Cardiovascular Disease	63(21.6%)	161(20.7%)	348(22.1%)	1.15 [0.85-1.56]	1.03 [0.95-1.11]
Incident Heart Failure	45(15.5%)	111(14.2%)	242(15.4%)	1.03 [0.95-1.12]	1.00 [0.92-1.08]

Conclusion

The Health ABC study concluded that in older adults, sodium intake was not associated with mortality, CVD, or HF.

Commentary/Perspective

Given the potential benefits and relatively low associated risks, US and European guidelines recommend moderate dietary sodium restriction (i.e., < 2-2.3 g/d) for everyone and < 1.5 g for those with additional risk factors (i.e., hypertension, hyperlipidemia, diabetes mellitus, tobacco use, obesity, age, family history).^8,9 Yet, consistent with prior studies, the Health ABC study failed to demonstrate a significant relationship between dietary sodium intake and adverse events.⁴ First, the authors should be commended for the prospective nature of the study, as well as the large study population and long follow-up period; however, major limitations of the study should be noted. The study suffers from inherent selection and reporting biases, expected with a cohort study, as follows. Despite the reproducibility of Food Frequency Questionnaire results, it is difficult to imagine that having elderly patients self-report dietary sodium and portion size can adequately measure electrolyte intake. Cook et al. published post-trial surveillance results using 24-hour urinary sodium excretion among participants in the Trials of Hypertension Prevention (TOHP) and were able to demonstrate a significant risk increase per 1 g/day of sodium.¹⁰ Furthermore, by combining hypertensive and non­hypertensive patients, two heterogeneous groups with different baseline health risks, the results of the Health ABC study may be hard to interpret; across the sodium-level groups, there were major differences in the populations. By treating heart failure as a homogenous cardiovascular event, the study may have missed relationships that would have been evident if subgroups like diastolic dysfunction were treated as their own phenotypes. Lastly, the study design lacked a cross-over arm, so we cannot know the potential effects of changing the amount of salt intake once established. The subjects were followed for 10 years but the study only looked at the baseline measurement of salt intake, which for reasons including age, a new diagnosis of hypertension, or alterations in medications, is likely to change within the study follow-up period. There was also no mention of potassium intake, which has been associated with sodium sensitivity especially among African Americans.¹¹

Despite the clear relationship between sodium intake and BP and between hypertension and adverse health effects, the majority of research studies, including randomized controlled trials and meta-analyses, have similarly failed to support the guidelines; however, various prediction models have projected that as many as 1.65 million deaths per year are potentially related to sodium intake while simulation studies have associated reductions in salt intake with reductions in coronary artery disease and mortality.^12-14 Why are we not seeing such data translated into original research studies? The first problem is power. It has been argued that a randomized clinical trial adequately powered to detect the cardiovascular effects of sodium restriction would require > 20,000 patients followed for 5 years. It is not only an expensive task but also ethically questionable to randomize patients to a high salt diet for such an extensive period of time.⁵ Perhaps rather than focusing on individual risks, it is more sensible to consider the population at large. We also need to shift our focus to global intake rather than the US population alone, as studied in the Health ABC study, as 80% of the deaths in Bibbins-Domingo et al.'s 2010 CHD policy model computer simulation study, occurred in low- and middle-income countries.¹²

The results of the Systolic Blood Pressure Intervention Trial (SPRINT) trial, which demonstrated a remarkable 25% reduction in the occurrence of cardiovascular events with a lower BP goal (i.e., systolic < 120 mm Hg) resulting in early trial termination, further begs the need to clarify the link between sodium intake and health outcomes.¹⁵ Prospective studies using a reproducible, objective measure of sodium intake, such as urinary excretion, measured at regular intervals over an extended period of time, are desperately needed. Indeed, the increased sensitivity to anti-hypertensive therapy, especially to renin-angiotensin-aldosterone system blockers, in patients who are successfully able to limit their sodium intake suggests that salt restriction may be critical to the avoidance of polypharmaceutical drug regimens and the side effects likely to be engendered by multidrug therapy in an effort to successfully reach lower systolic BP targets.¹⁶

References

1. Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356:1966-78.
2. Engstrom A, Tobelmann RC, Albertson AM. Sodium intake trends and food choices. Am J Clin Nutr 1997;65:704S-7S.
3. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group. JAMA 1998;279:839-46.
4. Taylor RS, AShton KE, Moxham T, Hooper L, Ebrahim S. Reduced dietary salt for the prevention of cardiovascular disease: a meta-analysis ofrandomized controlled trials (Cochrane review). Am J Hypertens 2011;24:843-53.
5. He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk: meta ­analysis of outcome trials. Lancet 2011;378:380-2.
6. McGuire S. IOM (Institute of Medicine) and NRC (National Research Council). 2013. Supplemental Nutrition Assistance Program: Examining the Evidence to Define Benefit Adequacy. Washington, DC: The National Academies Press, 2013. Adv Nutr 2013;4:477-8.
7. Kalogeropoulos AP, Georgiopoulou VV, Murphy RA, et al. Dietary sodium content, mortality, and risk for cardiovascular events in older adults: the Health, Aging, and Body Composition (Health ABC) Study. JAMA Intern Med 2015;175:410-9.
8. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20.
9. U.S. Department of Agriculture, U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2010. 7th Edition, Washington, DC: U.S. Government Printing Office, December 2010.
10. Cook NR, Appel LJ, Whelton PK. Lower levels of sodium intake and reduced cardiovascular risk. Circulation 2014;129:981-9.
11. Huang CL, Kuo E. Mechanisms of disease: WNK-ing at the mechanism of salt-sensitive hypertension. Nat Clin Pract Nephrol 2007;3:623-30.
12. Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med 2010;362:590-9.
13. Mozaffarian D, Fahimi S, Singh GM, et al. Global sodium consumption and death from cardiovascular causes. N Engl J Med 2014;371:624-34.
14. Coxson PG, Cook NR, Joffres M, et al. Mortality benefits from US population-wide reduction in sodium consumption: projections from 3 modeling approaches. Hypertension 2013;61:564-70.
15. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015;373:2103-16.
16. Zuxman RM, Hui KY, Nussberger J, et al. R-PEP-27, a potent renin inhibitor, decreases plasma angiotensin II and blood pressure in normal volunteers. Am J Hypertens 1994;7:295-301.

Keywords: African Americans, Aged, Albumins, Antihypertensive Agents, Blood Pressure, Body Composition, Body Mass Index, Cholesterol, Cohort Studies, Computer Simulation, Confounding Factors, Epidemiologic, Coronary Artery Disease, Creatinine, Depression, Diabetes Mellitus, Electrocardiography, Electrolytes, Follow-Up Studies, Food Habits, Glucose, Heart Failure, Heart Rate, Hyperlipidemias, Hypertension, Lung Diseases, Motor Activity, Obesity, Phenotype, Potassium, Prospective Studies, Randomized Controlled Trials as Topic, Renin-Angiotensin System, Reproducibility of Results, Risk Factors, Smoking, Sodium, Sodium Chloride, Dietary, Sodium, Dietary, Systole, Secondary Prevention

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