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Moving the Needle on Hypertension

What Knowledge Is Needed?

Frame, Alissa A. BA; Farquhar, William B. PhD, FACSM; Latulippe, Marie E. MS, RD; McDonough, Alicia A. PhD, FAHA; Wainford, Richard D. PhD, FAHA; Wynne, Brandi M. PhD, FAHA

doi: 10.1097/NT.0000000000000375
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This review highlights the gaps in knowledge and methodological challenges discussed during the Experimental Biology 2019 expert panel session titled “Moving the Needle on Hypertension: What Knowledge Is Needed?” Hypertension is a critical public health burden. Despite a demonstrated benefit of blood pressure reduction on measures of hypertension-related morbidity and mortality, rates for successful blood pressure control remain low. Dietary sodium reduction has been shown to reduce both systolic blood pressure by approximately 3.2 mm Hg and diastolic blood pressure by 2.3 mm Hg, depending on baseline blood pressure and degree of sodium reduction. The updated Dietary Reference Intakes for adults released by the National Academies of Sciences, Engineering, and Medicine include a Chronic Disease Risk Reduction sodium intake level of 2300 mg/d, highlighting the importance of dietary sodium intake in reducing elevated blood pressure and indicating that reducing intakes to this level is expected to reduce blood pressure and risk of cardiovascular disease. The average US daily sodium intake of 3400 mg/d is well above the Chronic Disease Risk Reduction of 2300 mg/d, suggesting that dietary sodium reduction has the potential to significantly improve public health. Although the National Academies of Sciences, Engineering, and Medicine report presents intake recommendations based on a systematic, comprehensive, and thorough evaluation of the evidence, several challenges to moving the needle on hypertension remain. Success will require a more advanced understanding of sodium and potassium physiology, as well as development of the tools needed to effectively address existing research gaps and reduce barriers to sodium intake reduction.

Alissa A. Frame, BA, is an MD/PhD student at Boston University School of Medicine, Boston, Massachusetts.

William B. Farquhar, PhD, FACSM, is a professor of kinesiology and applied physiology in the College of Health Sciences at the University of Delaware, Newark, Delaware.

Marie E. Latulippe, MS, RD, is a senior program manager at ILSI North America, Washington, DC.

Alicia A. McDonough, PhD, FAHA, is a professor of physiology and neurosciences at the University of Southern California Keck School of Medicine, Los Angeles, California.

Richard D. Wainford, PhD, FAHA, is an associate professor of pharmacology and medicine at Boston University School of Medicine, Boston, Massachusetts.

Brandi M. Wynne, PhD, FAHA, is an assistant professor of medicine at Emory University School of Medicine, Atlanta, Georgia and University of Utah School of Medicine, Salt Lake City, Utah.

This article is based on the session “Moving the Needle on Hypertension: What Knowledge Is Needed?” held at the Experimental Biology 2019 Annual Meeting in Orlando, Florida. The symposium was hosted by the American Physiological Society and organized by the International Life Sciences Institute (ILSI) North America Sodium Committee. W.B.F., A.A.M., R.D.W., and B.M.W. received travel support to attend the meeting. A.A.F. received funding for writing of the summary. ILSI North America is a public, nonprofit science foundation that provides a forum to advance understanding of scientific issues related to the nutritional quality and safety of the food supply. ILSI North America receives support primarily from its industry membership. The opinions expressed herein do not necessarily represent the views of the funding organization.

B.M.W., PhD, assistant professor at University of Utah, acted as co-chair for the session. A.A.M., PhD, professor of physiology and neurosciences at the University of Southern California Keck School of Medicine, spoke at the session about gaps in knowledge about the role of sodium and potassium in hypertension regulation. W.B.F., PhD, professor of kinesiology and applied physiology in the College of Health Sciences at the University of Delaware, spoke at the session about the effects of dietary sodium on brain and blood vessel function. R.D.W., PhD, associate professor of pharmacology and medicine at the Boston University School of Medicine, spoke at the session about the approach to combating salt-sensitive hypertension. M.E.L., MS, RD, senior program manager, organized the session and assisted with article preparation. A.A.F., BA, MD/PhD candidate at Boston University School of Medicine, attended the session and received funding from ILSI North America to draft the article. All authors critically reviewed the article and approved the final version. All participants were involved in a panel discussion and debate and received travel funding from ILSI North America to participate in the session.

The authors have no conflicts of interest to disclose.

Correspondence: Marie E. Latulippe, MS, RD, ILSI North America, 740 15th St NW, Ste 600, Washington, DC 20005 (mlatulippe@ilsi.org).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Hypertension is the leading risk factor for stroke, myocardial infarction, and chronic kidney disease and has been estimated to contribute to more than 10% of deaths worldwide.1,2 It accounts for more cardiovascular disease (CVD)-related deaths than any other modifiable or lifestyle-related risk factor.3 Despite the critical public health burden posed by hypertension and global calls to action, hypertension-related mortality continues to rise4 and therapeutic blood pressure control remains challenging.5 There is some evidence that excessive dietary sodium intake plays a pathological role in hypertension6 and increased dietary potassium intake may be protective.7 Meta-analyses performed by the National Academies of Sciences, Engineering, and Medicine (NASEM) suggest that dietary sodium reduction lowers both systolic and diastolic blood pressure by approximately 3.2 and 2.3 mm Hg, respectively, depending on baseline blood pressure and degree of sodium reduction.8 Currently, the average daily sodium intake in the United States is nearly 3400 mg/d.9 This far exceeds the American Heart Association and World Health Organization recommendations, as well as the Tolerable Upper Intake Level (UL) for adults of 2300 mg/d as defined in the 2005 Dietary Reference Intakes (DRIs) and adopted by the 2015–2020 Dietary Guidelines for Americans.10–13 Importantly, the NASEM recently released an update to the 2005 DRIs that provides a new Chronic Disease Risk Reduction (CDRR) intake for adults of 2300 mg/d for sodium based on the relationship between dietary sodium intake and CVD, hypertension, systolic blood pressure, and diastolic blood pressure.8 This review summarizes the updated DRIs for sodium and potassium and highlights the remaining gaps in knowledge and methodological challenges brought to light during the Experimental Biology 2019 expert panel session titled “Moving the Needle on Hypertension: What Knowledge Is Needed?” organized by the North American Branch of the International Life Sciences Institute (ILSI North America).14

The 2019 Dietary Reference Intakes for sodium established a Chronic Disease Risk Reduction value for sodium of 2300 mg/d based on the relationship between dietary sodium intake and CVD, hypertension, systolic blood pressure, and diastolic blood pressure.

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2019 UPDATES TO THE DRIS FOR SODIUM AND POTASSIUM

An Agency for Healthcare Research and Quality systematic review was foundational to the development of the 2019 DRIs for sodium and potassium.15 Intake-response relationships, causality, and strength of the evidence presented in the Agency for Healthcare Research and Quality systematic review were assessed by an ad hoc NASEM committee and synthesized to establish DRIs for adequacy, toxicity, and chronic disease.8 Among apparently healthy adults, the Adequate Intake (AI) indicates the intake level estimated to be adequate, the UL indicates the intake level above which toxicological risk is expected, and the CDRR intake indicates the intake level above which reducing intake is expected to reduce the risk of chronic disease.8 As in 2005, there was insufficient evidence in 2019 to establish sodium or potassium DRIs for adequacy in the form of estimated average requirements or recommended dietary allowances, indicating that there is a lack of sufficient, consistent evidence and further high-quality studies are required to establish these values.8 The 2019 potassium AI, based on median intake reported in national surveys from the United States and Canada, was defined as 3400 mg/d for men and 2600 mg/d for women. These values for potassium are notably lower than the 2005 value of 4700 mg/d for all adults.16 The 2019 sodium AI, in contrast, was established at 1500 mg/d for both sexes using evidence from randomized controlled trials. This value did not change from that recommended in 2005 (Table).16

TABLE

TABLE

The updated DRIs for risk of toxicity and chronic disease reflect a refinement of the original concept of toxicity. These changes are in alignment with recommendations outlined in the 2017 NASEM report titled, “Guiding Principles for Developing Dietary Reference Intakes Based on Chronic Disease.”17 In 2005, the UL for sodium was 2300 mg/d based on the relationship between sodium and blood pressure; no UL was established for potassium because of insufficient evidence. In 2019, the UL for sodium was redefined to selectively reflect toxicological risk only (separate from chronic disease risk, which is reflected in the CDRR), and the evidence supporting the 2005 UL was reassessed and incorporated into the newly introduced CDRR. It should be noted that there was insufficient evidence to establish ULs for both sodium and potassium or a CDRR for potassium. However, evidence indicating that a reduction in dietary sodium intake reduces risk of CVD and hypertension and lowers systolic and diastolic blood pressure supported a sodium CDRR of 2300 mg/d, reflecting the intake level above which intake reduction is expected to reduce chronic disease risk within an apparently healthy population. In summary, the recommended limit and basis are similar across the 2005 and 2019 evaluations for sodium, but designation as a CDRR rather than a UL clarifies that the 2019 basis is specifically evidence regarding chronic disease risk.

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ARE SODIUM AND POTASSIUM INEXTRICABLY LINKED TO HEALTH OUTCOMES?

Sodium and potassium are essential nutrients that have critical and interdependent physiological roles. In all human cells, sodium and potassium are exchanged by the membrane-bound sodium-potassium adenosine triphosphatase in a process that maintains extracellular fluid volume, regulates cell volume, generates the resting membrane potential that governs the activity of excitable cells, and creates an electrochemical gradient that facilitates the transport of other nutrients and wastes across cellular membranes. Plasma sodium and potassium levels are tightly regulated in healthy individuals, and the importance of potassium to cardiovascular health is highlighted by fatal cardiac arrhythmias that can arise secondary to both hyperkalemia and hypokalemia.18 Although there was insufficient evidence to establish a CDRR for potassium, the NASEM committee noted that there was moderate strength of evidence suggesting that potassium supplementation may reduce systolic and diastolic blood pressure, highlighting the need for randomized controlled trials investigating the relationship between dietary potassium intake and hypertension along with other chronic disease end points.8

Recent animal studies demonstrated that dietary potassium intake influences renal sodium handling in both the proximal and distal tubules such that increased potassium levels stimulate sodium excretion and low-potassium diets promote sodium retention.19–23 Noting that evidence from animal studies is only supportive in a DRI evaluation, these observations nonetheless raise the possibility that the relationship between sodium intake and hypertension can be modulated in part by potassium: the beneficial impact of lowering dietary sodium is amplified by raising dietary potassium and blunted by lowering dietary potassium. These data support observational human studies indicating that a higher intake ratio of potassium to sodium may be beneficial to cardiovascular health.24–26Figure 1 presents a hypothesized relationship between potassium, sodium, and blood pressure in humans, considering these data. Of note, the newly mandated inclusion of potassium on nutrition labels reflects the designation of dietary potassium as a “nutrient of concern” in the 2015 Dietary Guidelines for Americans and will aid consumers in the evaluation of daily sodium and potassium intake and their ratio. The intrinsic link between sodium and potassium suggests that the independent DRIs for sodium and potassium may be insufficient and that reference intakes for a sodium-to-potassium ratio that considers the new CDRR for sodium may be warranted. Notably, the NASEM DRI panel concluded that the evidence for an effect of potassium/sodium in the diet was insufficient for recommendation development at the time of review.8

FIGURE 1

FIGURE 1

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IS SODIUM-EVOKED END-ORGAN DAMAGE BLOOD PRESSURE INDEPENDENT?

The recently developed CDRR for sodium was established based on studies of the relationship between sodium intake and CVD, hypertension, and systolic and diastolic blood pressure.8 Evidence concerning other end points, including chronic kidney disease and specific subtypes of CVD such as myocardial infarction and stroke, was considered insufficient. Further research on these outcomes is needed, as is research to understand the mechanism of action. Decades of preclinical and clinical evidence indicate that high dietary sodium intake impairs endothelial and microvascular function,29,30 increases central blood pressure31 and left ventricular hypertrophy,32 and reduces glomerular filtration rate.33 High dietary sodium intake may also increase arterial stiffness.34 Many of these adverse effects have been observed in normotensive adults.35 These blood pressure–independent pathological changes may reflect primary dietary sodium-evoked target organ damage that can subsequently drive hypertension, creating a feedforward cycle that promotes further end-organ damage (Figure 2). Although the underlying mechanisms are not fully understood, sodium-induced increases in oxidative stress and reduced nitric oxide bioavailability likely play a role.36 Studies characterizing the blood pressure–independent effects of excessive dietary sodium in normotensive individuals are particularly informative, because these effects may be detected before an elevation in blood pressure.

FIGURE 2

FIGURE 2

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ASSESSMENT OF SODIUM AND POTASSIUM INTAKE

The accuracy of sodium and potassium intake estimates can influence the strength and magnitude of intake-response relationships; as such, the assessment of dietary nutrient intake is an important methodological challenge. Measurement of sodium and potassium intake using a 24-hour urine collection is currently considered the most robust method, although a recent study demonstrating a circaseptan (7-day) renal sodium excretion pattern37 suggests that 7 consecutive 24-hour urine collections would be required to accurately determine sodium intake. Although the NASEM committee considered studies using a 24-hour collection to have a low risk of bias,8 the use of 24-hour collections also poses severe logistical challenges, may bias the study population toward individuals able to perform the collection, and is often complicated by incomplete collections.38

Other studies use spot urine collection and various equations to extrapolate sodium intake. Although spot urine collection is technically simple, this method tends to overestimate sodium excretion during low sodium intake and underestimate sodium excretion during high sodium intake.39 Furthermore, spot urine sodium varies throughout the day depending on fluid and dietary intake, among other factors. Sodium intake extrapolated from a single morning fasting urine collection demonstrates similar associations with chronic disease end points when compared with those determined using a 24-hour urine collection and yet presents a much smaller logistical burden for researchers and study participants.38 However, the equations used to estimated usual dietary intake from a collection of morning fasting urine may not be generalizable to all populations, including aging individuals.40

More research is needed on whether high sodium intake may promote blood pressure–independent organ damage, which could drive the development of hypertension.

Self-report dietary intake assessments, including food frequency questionnaires, food records, and 24-hour dietary recall, present a number of limitations in estimating dietary sodium intake. These studies rely on general estimates of sodium content in homemade, restaurant-prepared foods and prepackaged foods, although the actual sodium content of these foods varies widely. Because of the self-reported nature of these methods and reliance on participants' memory, inaccurate reporting (most commonly underreporting) is a particular challenge. The NASEM committee considered studies using self-reported dietary intake as having a high risk of bias unless a food record was used as supporting evidence for urine collections.8 Therefore, advances in methodology to assess dietary sodium and potassium intake are needed to reduce participant and researcher burden (from that currently required by a 24-hour urine collection) and increase the accuracy of sodium and potassium intake (from that of spot urine or self-reported dietary intake assessments).

Dietary sodium and potassium intakes are difficult to assess accurately.

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MANIPULATING NUTRIENT INTAKE IN THE EXPERIMENTAL SETTING

The 2300-mg/d CDRR for sodium was established based on randomized parallel and crossover trials (the strongest types of scientific data) that demonstrated benefits for blood pressure as well as CVD and hypertension risk, with sodium intake reduction down through 1500 mg/d.8 Observational studies, which do not allow for causal inference, provided evidence that there is an increased risk of CVD and mortality with sodium intakes less than 3000 mg/d.41 Although these observational findings suggesting a J- or U-shaped response between dietary sodium and CVD outcomes have been challenged because of the use of spot urine collection (a single sample collected at any time of day), potential confounding effects of chronic kidney disease and diabetes, and relatively small numbers of participants on a low-sodium diet,42 the controversy highlights a strong need for large randomized controlled trials in which dietary sodium intake is carefully manipulated and participants are followed for a sufficiently long time to directly measure CVD incidence and mortality. In 2017, a joint working group of the World Heart Federation, European Society of Hypertension, and European Public Health Association called for a trial to compare sodium intake less than 3000 mg/d with sodium intake between 3000 and 5000 mg/d to clarify the controversy.43 This echoed a 2013 statement from the Institute of Medicine (now the NASEM Health and Medicine Division) describing the need for a large randomized controlled trial in a controlled environment that would allow for strict compliance to dietary sodium manipulation over a time range up to several years.44 Such studies require considerable time and expense and are limited by both challenges in funding and availability of tightly controlled environments in which diet can be manipulated and monitored. An expert panel recently convened to discuss the feasibility of such a trial and several potential existing study populations, including military personnel, nursing homes, and the prison system. Despite the inherent ethical concerns surrounding prison research, the panel identified the federal prison system as the best option for a rigorous, randomized controlled trial of dietary sodium intake.45 Although the panel's recommendation is controversial, it highlights the severity of the challenges facing the study of dietary sodium intake.

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ASSESSING SALT SENSITIVITY OF BLOOD PRESSURE

Salt sensitivity of blood pressure is defined broadly as an exaggerated pressor response to increased dietary sodium intake. It was not considered in the DRI evaluation because of extensive challenges with characterizing whether an individual is salt sensitive or not.8 Oh et al46 highlighted salt sensitivity as a priority research topic in the “National Heart, Lung, and Blood Institute Working Group Report on Salt in Human Health and Sickness” in 2016. Studies performed in the 1980s suggest that salt sensitivity may be present in approximately 50% of hypertensive patients and 25% of normotensive patients. Other studies from 1997 and 2001 indicate that salt sensitivity is an independent predictor of cardiovascular risk.47,48 Further studies of salt sensitivity have been largely hindered by the absence of a standardized and accessible method for the assessment of salt sensitivity. Current methods range from a month-long (29-day) protocol that includes a 2-week run-in period of normal salt intake followed by 3 consecutive 5-day periods in which sodium intake varies, to an abbreviated 5-day protocol that includes a 4-hour saline infusion followed by a 1-day period of sodium depletion using low sodium intake combined with a loop diuretic.49 Further complicating the spectrum of techniques, the amount of sodium included in low-, normal-, and high-sodium diets is variable across studies.

Uniform diagnostic criteria for salt sensitivity of blood pressure would support cardiovascular risk stratification in the clinical setting and improve targeted recommendations for preventive and therapeutic interventions involving dietary sodium intake.

In each protocol, blood pressure is measured during sodium-replete and sodium-depleted states and the calculated difference is used to determine salt sensitivity versus salt resistance. Most studies use a blood pressure difference threshold of 5% to 10% between the sodium-depleted and sodium-replete state to define salt-sensitive individuals, although this cutoff varies and is arbitrarily defined. It is important to note that defining individuals as salt sensitive or salt resistant based on an arbitrary cutoff may obscure or create significant associations. Studies examining the relationship between salt sensitivity of blood pressure as a continuous phenotype, rather than a bimodal trait, and associated cardiovascular outcomes and other chronic disease end points would provide the critical evidence needed to select a clinically relevant threshold for the diagnosis of salt sensitivity. Given the link between the effects on blood pressure of dietary sodium and dietary potassium, studies of salt sensitivity in which dietary potassium intake is controlled would also be informative.

The variability in methodology highlights the pressing need for a standardized protocol to assess salt sensitivity of blood pressure. The cumbersome nature of current protocols also creates a barrier to effective research due to financial burden, time constraints, and compliance issues during long-term dietary interventions. The identification of a rapid and reliable biomarker of salt sensitivity would overcome these challenges, and recent studies have focused on urinary exosomes, microRNA profiles, and genetic markers as potential diagnostic tools.49 Although a genetic biomarker of salt sensitivity was recently identified in the Genetic Epidemiology Network of Salt Sensitivity cohort,50 these findings must now be validated in larger and more diverse populations. Such studies are limited by the absence of large study populations in which the salt sensitivity of blood pressure has been assessed. A standardized diagnostic threshold would facilitate the search for clinically relevant biomarkers. In addition, research-based standardization would promote mechanistic and physiological studies, as well as aid in the assessment of antihypertensive drug efficacy in defined salt-sensitive versus salt-resistant patients. Furthermore, a uniform definition of salt sensitivity determined using a standardized protocol and/or biomarker would aid in cardiovascular risk stratification and allow for better targeted recommendations for preventive and therapeutic interventions, including reducing dietary sodium intake, in the clinical setting.

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IMPLEMENTING DIETARY RECOMMENDATIONS

Sodium reduction efforts have been underway in the United States since the late 1960s51 because of mounting evidence showing that excessive sodium intake is linked to increased blood pressure. However, in opposition to these efforts, dietary sodium intake has either increased or remained steadily above recommended limits for the past several decades.52,53 This trend highlights the complexity of making progress on population-wide sodium reduction: a strong scientific rationale is rarely sufficient to induce individual behavior change, particularly when consumers view that taste may be compromised.54,55 The World Health Organization recently reviewed successful sodium reduction policies and synthesized the SHAKE package, a framework for a population-wide intervention that includes the following: (1) surveillance (S) efforts geared toward monitoring sodium intake, the sodium content of food, and the efficacy of population-level sodium intake reduction efforts; (2) harnessing (H) the industry to define voluntary sodium content targets and implement mandatory targets if necessary; (3) adopting (A) standards for labeling and marketing that are accessible and easy to understand; (4) improving the knowledge (K) base of the general public regarding, in particular, sources of dietary sodium and the deleterious effects of sodium on human health; and (5) supporting environments (E) that promote healthy eating in schools and workplaces.56

Each of these elements raises its own set of challenges, many of which have been described in this brief review. Surveillance efforts are hindered by the accuracy of the methods used to assess sodium intake. The definition of sodium content targets, and dietary intake recommendations, requires further studies to clarify the controversy surrounding the benefits versus risks of sodium reduction lower than 3000 mg/d. Education efforts may prove particularly challenging. For patients with hypertension, there are significant barriers to medication adherence, including cultural and behavioral issues, inconvenience of treatments, and a poor understanding of disease risks and treatment benefits.57 These issues are amplified when the disease is asymptomatic and the benefit of treatment is not readily discernible to the patient. Population-wide sodium reduction efforts are challenged by the same barriers, as nutritional interventions often conflict with various cultural and lifestyle habits. The prepackaged foods designed to give greater convenience and optimal taste are often high in sodium and low in potassium. Furthermore, there is also a strong rationale for sodium reduction efforts targeting both hypertensive and normotensive populations. Particularly among normotensive individuals, risk perception will likely underestimate the associations that exist between high sodium intake and hypertension and other cardiovascular outcomes, as well as blood pressure–independent target organ damage.

Moving the needle on hypertension will require the development of standardized methodology to accurately assess dietary sodium and potassium intake, a uniform protocol and diagnostic threshold or biomarker for salt-sensitive blood pressure, randomized controlled trials clarifying the benefits and risks of sodium reduction in normotensive and hypertensive individuals, and careful implementation of sodium reduction efforts at the population level.

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Acknowledgments

Barbara O. Schneeman, PhD, emeritus professor at the University of California, Davis, acted as chair for this EB 2019 session and provided an overview of the 2019 DRI updates. Dr Schneeman approved the final version of the article with respect to representation of her contributions to the session.

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