The relationship between high sodium intake, blood pressure and CVD

Adequate intake (AI) of the essential nutrient sodium is crucial in sustaining health. Sodium is an electrolyte that is involved in vital physiological processes, including muscle and nerve function by controlling membrane potential of cells, active transport of molecules across cell membranes and controlling blood pressure through altering fluid and electrolyte balance in the body.4 Low sodium intake may affect insulin resistance, blood lipids, CVD risk and increase plasma renin activity, although more evidence is needed to substantiate these adverse events.4 Excessive intake of sodium is strongly associated with elevated blood pressure, which increases the risk for cardiovascular and renal diseases.4

Raised blood pressure and hypertension are major risk factors for CVD as they are underlying contributing factors in 62% of all stroke events and 49% of all coronary heart disease cases.5 At the global level, the prevalence of raised blood pressure affects 40% of adults aged 25 years and older and accounts for 12.8% of all deaths.6 In the USA, approximately one-third of the adult population suffers from hypertension with 76% taking medication to manage the disease.7 Hypertension is prevalent in 7.3% of adults aged 18 years and over, 32.4% of adults aged 40–59 years and 65% of adults aged 60 years and older.7 Proper blood pressure control is critical in avoiding cardiovascular-related mortality and remains an area of great public health concern. For the past 40 years, heart disease has remained the top leading cause of mortality in the USA (23.4% of all deaths).8 In 2015, stroke was ranked as the fifth cause of mortality in the USA (5.2% of all deaths).8 Maintaining an optimal level of sodium intake can help manage blood pressure and prevent cardiovascular-related mortality since studies have shown that reducing sodium consumption can reduce blood pressure.9 Given these data, it is imperative that healthcare professionals and public health efforts aim to ensure sodium intake among the population is within a healthy range.

Recommended daily intake of sodium for optimal physiological health

Table 1 10 summarises the dietary reference values, including the reference nutrient intake (RNI) and tolerable upper intake levels (ULs) set by the UK government through the Committee on Medical Aspects of Food and Nutrition Policy for the UK population. Table 2 4 summarises the dietary reference intake (DRI) levels, including the AI and tolerable ULs of sodium set by the Institute of Medicine for the US population, which are similar to the guidelines recommended for Canadians.11 12 In line with these DRI levels, the 2015–2020 Dietary Guidelines for Americans recommends that adults limiting sodium intake to less than 2.3 g per day as part of a healthy eating pattern.13 The WHO recommends a level of sodium intake less than 2 g per day for adults in order to reduce blood pressure, risk of CVD, stroke and coronary heart disease.14 15 There is insufficient high-quality data associating a low sodium diet (<2.3 g or <1.5 g per day) with an increased or reduced cardiovascular risk and mortality for the general population.16 17 Better quality randomised trials and cohort studies are needed in this area to better understand the effects of low sodium intake on cardiovascular outcomes.18

Sodium consumption levels

Current sodium consumption levels around the world exceed recommendations and are above levels that are considered physiologically optimal. Global mean intake of sodium in 2010 was estimated to be almost twice the level recommended by WHO at 3.95 g per day.19 Highest sodium intake levels were observed in central Asia (5.51 g per day) and lowest in east sub-Saharan Africa (2.18 g per day).19 A similar trend of excessive consumption of sodium is observed in the USA, with approximately 90% of the US population over the age of 2 years old consuming on average 3.4 mg of sodium per day.20 21 Main contributors of sodium in the diet for the US population comes from food bought from stores (~60.8%) and restaurants (~29.4%).20

Interventions to decrease dietary sodium intake

Excessive sodium consumption is recognised as a global issue. A global initiative backed by the United Nations and the WHO aims to reduce salt intake at the population level by 30% by 2025, and 75 countries have already adopted national sodium reduction programme to help meet this goal.22 Strategies to reduce sodium intake at the population level have taken different approaches, including working with industry to reformulate food products, establishing sodium content targets for foods, educating consumers, revising labelling schemes on food packages, taxing high-salt foods and developing interventions in public institutions.22

In the UK, the National Institute for Health and Clinical Excellence (NICE) has responded to this excessive sodium intake level with recommended policy goals. The UK has been aiming to reduce sodium intake among adults to 2.4 g per day by 2015 and down to 1.2 g per day by 2025.23 The UK reported a population level reduction of sodium intake by 14.7% (3.8 g to 3.24 g) during 2001–2011.22 This reduction in sodium intake is in part due to the UK Food Standards Agency’s salt reduction programme that were implemented 2003–2010. Sodium content in food items was reduced (some as high as 70%) and educational campaigns led to 43% of adults (vs 34% before the campaigns) making efforts to reduce sodium intake.24

In the US, the Food and Drug Administration (FDA) has responded to this excessive sodium consumption among the US population through a 2016 Draft Guidance for Industry that outlines short-term (2 years) and longer term (10 years) goals for sodium content reduction in commercially processed and packaged foods.25 This guidance document recognises the importance of a supportive food environment through engagement with industry to help the US population meet the sodium intake levels recommended in the 2015–2020 Dietary Guidelines for Americans. Although voluntary, it will be imperative for food companies to recognise the need to reduce sodium levels in their food products in ways that will not compromise the integrity of their products since sodium serves many functions beyond affecting taste, including texture, preservation and microbial safety.26

In addition to addressing this issue from the food environment perspective, individuals with high blood pressure can work one-on-one with their dietitians to lower their sodium intake. A commonly prescribed heart-healthy diet for individuals with elevated blood pressure is the Dietary Approaches to Stop Hypertension (DASH) diet.27 Broadly, the DASH diet emphasises the consumption of vegetables, fruits and whole grains while limiting foods high in saturated fat, sugar sweetened beverages and sweets. Low-fat and fat-free dairy products, fish, poultry, beans, nuts and vegetable oils are also emphasised.27 One of the core recommendations of this diet is to consume less than 2.3 g of sodium each day and further recommends an intake of 1.5 g of sodium each day for better blood pressure control.27 A major randomised controlled trial studying the effects of the DASH diet in comparison with a control diet high in sodium observed a 7.1 mm Hg drop in blood pressure for non-hypertensive subjects and a 11.5 mm Hg drop in blood pressure for subjects with hypertension.28 The results of a meta-analysis that included 17 randomised controlled trials indicated that adhering to the DASH diet is associated with reduced blood pressure (6.74 mm Hg drop in systolic blood pressure and 3.54 mm Hg drop in diastolic pressure).29 In addition to the DASH diet, sodium reduction, weight loss in overweight an obese individuals, potassium supplementation, limiting alcoholic drinks and increased physical activity are other non-pharmacological interventions that are recommended for US adults with elevated or blood pressure hypertension.2 NICE guidelines recommend limiting alcoholic consumption and excessive caffeine-rich products, reducing sodium intake, avoiding calcium magnesium or potassium supplementation, smoking cessation, social support organisations that promote healthy lifestyle change, increasing exercise and engaging in relaxation therapies as non-pharmacological approaches to reducing blood pressure.30

Salt sensitivity: an independent risk factor for mortality—not everyone responds to sodium with changes in blood pressure

While elevated blood pressure is an established surrogate marker for CVD and a risk factor meriting pharmacological and dietary interventions,2 3 31 what tends to be ignored in discussions on this topic is the concept of salt sensitivity and the difference in response individuals can have to sodium intake. Considering the salt sensitivity phenotype is important since many dietary interventions aim to decrease sodium intake to lower blood pressure, but this assumes individuals are all salt sensitive, which is not the case for many.

Salt sensitivity is defined by a change in blood pressure in response to a change in sodium chloride intake. Salt sensitivity is influenced by many factors, including genetics, age, gender, race/ethnicity, body mass index and diet.32 The exact numeric change in blood pressure to classify an individual as salt sensitive varies and is not consistently defined.33 A 5%–10% blood pressure change or a >4 mm Hg in mean blood pressure are two commonly used cut-offs in response to a change in sodium chloride intake.34 35 Salt sensitivity has also been defined by a >10 mm Hg increase in mean blood pressure by comparing blood pressure on a normal 2 L saline (0.9%) infusion over a 4-hour period to blood pressure on a combination of a low-sodium diet (10 mmol) and a loop diuretic.34 35 Despite the numerous ways salt sensitivity can be determined, the most robust method for assessing salt sensitivity is through dietary sodium intake using a crossover study design where a 5–7 day intervention period is given for a normal (~3.6 g), low (~1.2 g) and high (~7.9 g) dietary sodium intake level.34 35 When a change in blood pressure is not observed despite changes in sodium chloride intake, the individual is classified as salt resistant.

In a 27-year-long observational study, salt sensitivity was found to be an important risk factor for mortality independent of blood pressure level that mimics mortality risk observed in hypertensive and salt resistant individuals.36 The survival curve with the best survival over the 27-year period was observed in individuals who were normotensive and salt resistant, and individuals with the worst survival were those who were hypertensive and salt sensitive.36 Survival over this 27-year period was not significantly different between those who were normotensive plus salt sensitive and those who were hypertensive plus salt resistant.36 Individuals who were normotensive and salt resistant had significantly better survival than the other three subgroups investigated (normotensive and salt sensitive, hypertensive and salt resistant, and hypertensive and salt sensitive) (p<0.001).36 An OR of 1.73 (95% CI 1.02 to 2.94, p=0.042) for death was observed for individuals who were salt sensitive.36 One major limitation of this observational study is the lack of dietary information on individuals in this cohort to understand the relationship between sodium intake levels and mortality risk for salt sensitive and resistant individuals. It has been shown, however, that salt-sensitive individuals tend to have higher blood pressures over time when compared with salt-resistant individuals, suggesting that reduced sodium intake interventions may reduce the progression of hypertension overtime for salt sensitive individuals.37 In addition, numerous studies have also observed adverse effects of high sodium on organ damage independent of blood pressure.38–41

Given that sodium intake for most individuals is excessive, the majority of the population would benefit from an overall reduction in sodium intake towards UL levels. The salt sensitivity phenotype is an important factor to consider in determining optimal sodium intake levels instead of relying solely on blood pressure. In addition, focusing on aggressive salt intake reduction for salt resistant individuals may not be an effective dietary intervention strategy in managing blood pressure.

Prevalence and identification of individuals with the salt sensitivity phenotype

The salt sensitivity phenotype is more common in several subgroups, including individuals who are black, older adults and patients with hypertension.41 42 In the USA, approximately 26.4% is salt sensitive (58 million), 30.4% is hypertensive (66.9 million) and 11.8% is both hypertensive and salt sensitive (26 million).34

Currently, there are no practical methods to assess this phenotype in the clinical setting as it involves weeks of careful dietary monitoring using a crossover study design. The genetics that characterise this phenotype has been extensively studied in an attempt to use genetic screening tools to predict this phenotype for more precise dietary and pharmaceutical interventions. Numerous genes have been identified and associated with the salt sensitivity phenotype.34 35 43–48 Table 3 49–53 summarises the genetic variants with the strongest links to salt sensitivity.

Variants in the GRK4 and SLC4A5 genes have the strongest and most consistent genetic links to salt sensitivity.49 50 The GRK4 gene codes for a protein that is responsible for regulating the dopamine D₁ receptor, which is involved with regulating the renal tubule ion transport.51 The SLC4A5 gene codes for a protein that transports sodium and bicarbonate ions in renal tubule cells back into circulation.49

A randomised crossover study of blood pressure in response to a low (230 mg sodium/day) and high salt (6.9 g sodium/day) diet was conducted in 185 Caucasians (55 hypertensive; 130 normotensive).49 Salt sensitivity defined by mean arterial pressure increase of ≥7 mm Hg on high versus low salt diet. Out of all the polymorphisms that were studied in the 17 genes, two single nucleotide polymorphisms (SNPs) in SLC4A5, rs7571842 and rs10177833 were found to be associated with salt sensitivity (p value 1.0×10^–4 and 3.1×10^–4, respectively) in an unadjusted regression model.49 G allele carriers for rs7571842 and rs10177833 had a protective effect against salt sensitivity even after adjusting for body mass index and age (OR=0.210, p=8.9×10^-5 and 0.286, p=2.6×10^-4, respectively).49 These two SNPs were investigated for replication purposes in a second hypertensive cohort of 211 subjects (low sodium diet: 230 mg/day; high sodium diet: 4.6 g/day, salt sensitivity defined by mean arterial pressure increase of ≥7 mm Hg on high vs low salt diet).49 G allele carriers also had a protective effect against salt sensitivity for rs7571842 (OR=0.32, p=0.02) and rs10177833 (OR=0.36, p=0.06).49 Although these studies were well designed, one limitation to note with the SLC4A5 variants is the generalisability of this result since the two populations studied were Caucasian. Variants in the SLC4A5 gene have also been associated with hypertension.54–56

The GRK4 variants rs296036, rs1024323 and rs1801058 have been studied in three major ethnic groups (ie, Japanese, Italian and European American) and have been most consistently associated with salt sensitivity.49 50 57 In the crossover study investigating these GRK4 SNPs in the Japanese cohort, 184 subjects followed a normal (3.6 g/day), low (1.2 g/day), and high (7.9 g/day) sodium diet to assess salt sensitivity.50 Salt sensitivity was defined by a ≥10% change in mean arterial pressure going from a low to high sodium diet. It was found that Japanese subjects carrying three or more variants at any of the three sites were more likely to be salt sensitive than salt resistant. Using this criterion, 94% of the cohort was correctly classified by their response to sodium.50 The GRK4 rs1024323 variant was the most accurate predictor of salt sensitivity, with a 78.4% accuracy rate among hypertensive Japanese.50 Although the study was well conducted, replication of these findings in additional populations is needed to understand the extent to which these conclusions can be further generalised. Several studies have also found GRK4 variants to be associated with hypertension.35

Current practice in managing sodium intake in hypertension and changes to current practice with the identification of the salt sensitivity phenotype

Current standard of practice in the nutrition field intervenes on an individual’s sodium intake when blood pressure is elevated. This standard of practice misses an opportunity to intervene and reduce sodium intake for approximately 14% of the population who are salt sensitive but normotensive.34 In addition, this standard of practice is also ineffective for 16% of individuals who are hypertensive and salt resistant.34 Current intervening strategies for elevated blood pressure is appropriate for 11.8% of adults who are both hypertensive and salt sensitive.34 Excessive sodium intake can cause hypertension, but this threshold for what is considered excessive differs depending on how the body is able to handle sodium homeostasis. In addition, elevated blood pressure has traditionally been the marker for reduced sodium intake but perhaps the salt sensitivity phenotype should also be considered. This varied response to sodium intake highlights the need to move away from the current ‘one-size-fits-all’ approach in sodium recommendations to a paradigm that is more precise in characterising sodium response.

Current practice related to reducing sodium intake is appropriate for the subset of the population who are hypertensive and salt sensitive, but how would dietary recommendations change if we knew how individuals responded to salt? Knowing that salt sensitivity is an independent risk for mortality, it may be beneficial for salt sensitive individuals to follow a diet lower in salt regardless of blood pressure. There are no formal guidelines on the amount of dietary sodium intake that is appropriate for salt sensitive individuals, but keeping intake close to the AI/RNI and at the very least below the UL might be beneficial. For those who are hypertensive, it would be important to know whether blood pressure will be affected by sodium intake. For those who are salt resistant and hypertensive, focusing on dietary interventions beyond sodium intake may result in better control over blood pressure. Following a diet lower in sodium can be burdensome, so identifying those who would most benefit from such drastic dietary restrictions can focus healthcare resources to ensure this subpopulation is identified and managed appropriately. Being able to tease out someone’s response to sodium can potentially better individualise dietary recommendations for optimal health outcomes. With current sodium intake well above the recommended amount, it would be imperative for salt-sensitive individuals to especially pay particular attention to this recommendation given their increased chances of mortality. Further research investigating the optimal level of sodium intake for salt sensitive individuals is needed.

Pharmacological interventions to control blood pressure

A common approach to controlling blood pressure is through pharmacological agents, as 76% of hypertensive individuals are taking medication to manage the disease.7 Most drugs achieve 10–15 mm Hg reduction in systolic blood pressure and 8–10 mm Hg reduction in diastolic blood pressure when used as monotherapy, although combination therapy has been found to be more effective in achieving target blood pressure control.58 59 For first-line antihypertensive agents in the UK, NICE recommends an ACE inhibitor or ARB (angiotensin-receptor blockers) for individuals less than 55 years old and a CCB for blacks or for those 55 years old or older.30 In the USA, a thiazide-type diuretic, ACE inhibitor, ARB or CCB are first-line antihypertensive agents for non-blacks; and a thiazide-type diuretic or CCB for blacks is recommended.3

Despite many pharmacological agents available to help control blood pressure, 60% of hypertensive individuals treated with pharmacological agents do not have their blood pressure controlled adequately.60 Many factors can lead to this suboptimal control of blood pressure, including the lack of efficacy of antihypertensive agents in 40%–60% of patients.61 62 The practice of pharmacogenetics, which attempts to tailor drug therapies based on genetic information, is one way for predicting efficacy and/or prevent adverse outcomes when selecting antihypertensive medications. Currently, there are no validated pharmacogenetic guidelines endorsed by the FDA or the international Clinical Pharmacogenetics Implementation Consortium (CPIC), but there are promising genetic markers associated with specific antihypertensive drug classes and blood pressure response and/or cardiovascular outcomes (online supplementary table 1 51 53 63–70).63 Replication is currently needed for these genetic markers to investigate the robustness of the ability for these genetic makers to predict blood pressure response and/or cardiovascular outcomes in the presence of antihypertensive agents before clinical validation is achieved. It has been hypothesised that the model that will guide antihypertensive a gene selection will likely use a combination of genetic variants, with each variant exerting a modest effect size on relevant outcomes, instead of using the traditional model that associates a single genetic marker to an outcome in the presence of a prescribed drug.63 Therefore, drug prescribing of these agents will depend on the genetic make-up of the patient. The resulting guideline, like other CPIC guidelines, will translate pertinent genetic research into clear directions regarding which agents and doses are recommended based on genetic markers so that clinicians can implement the information directly into the drug prescribing process for their patients.

Treatment of individuals with resistant hypertension

Finding effective antihypertensive agents is especially important for individuals with resistant hypertension (uncontrolled hypertension despite use of three or more different classes of antihypertensive agents, including a diuretic) and refractory hypertension (uncontrolled hypertension despite use of five or more different classes of antihypertensive agents, including a diuretic).71 The prevalence of resistant hypertension is estimated to affect 10%–15% of hypertensive patients treated with antihypertensive agents and approximately 3.6%–10% of these patients have refractory hypertension.71

Using pharmacogenetic information to guide selection of antihypertensive agents may be a way to help optimise blood pressure control and could potentially reduce the overall number of agents prescribed. Online supplementary table 1 51 53 63–70 lists a few genetic markers that are associated with response to antihypertensive agents and cardiovascular outcomes. This genetic testing would be beneficial for this population to receive to reduce the likelihood of being prescribed an ineffective antihypertensive agent. In addition, several genetic markers in candidate genes associated with resistant hypertension have been identified, although not ready for clinical implementation since these associations have not been replication and many of these studies lack adequate sample sizes.72 Online supplementary table 2 53 67 72–80 summarises the genetic markers that have been associated with resistant hypertension.

According to the DASH diet on dietary sodium intake, consuming less than 2.3 g of sodium each day and further recommends an intake of 1.5 g of sodium each day for better blood pressure control is suggested for hypertensive individuals.27 Sodium restriction in individuals with resistant hypertension has been shown to be an effective strategy to help decrease blood pressure.81 82 In a crossover randomised controlled trial of 12 patients with resistant hypertension in the USA, blood pressure was monitored, while a low (1.15 g/day) and high (5.75 g/day) sodium diet were provided to subjects while maintaining their prescribed antihypertensive medication regimens.82 Average blood pressure on entering the study was 145.8±10.8/83.9±11.2 mm Hg, which was being controlled with 3.4±0.5 antihypertensive agents.82 Average blood pressure (mm Hg) on the high sodium diet was 145.6±15.1/84.0±12.1, and 122.8±14.0/74.9±12.5 on the low sodium diet.82 Systolic (−22.7 mm Hg, (−33.5 to −11.8), p=0.0008) and diastolic (−9.1 mm Hg, (−15.1 to −3.1),74 p=0.0065) blood pressure decreased significantly when subjects were on the low sodium diet in comparison with the high sodium diet.82 Further research is needed to evaluate whether reducing sodium intake among this population is effective based on the salt sensitivity phenotype or if salt-sensitive individuals are more likely to have resistant hypertension.

Patients with resistant hypertension should work with registered dietitians to keep their sodium intake in line with the recommendations outlined in the DASH diet, especially if individuals are salt sensitive. As a result, assessing for salt sensitivity in this population would be beneficial in the management of blood pressure. In cases where sodium intake is within recommended levels, it would also be important for registered dietitians to educate these individuals on the importance of maintaining their sodium intake at these levels.

Strategies to manage sodium intake and blood pressure, including the potential for pharmaconutrigenetics to be an effective approach

One of the top priorities at the moment for better cardiovascular health at the global level is reducing sodium intake since daily consumption far exceeds recommended levels. Public health interventions to help reduce sodium intake at the population level have been developed and implemented in many countries, and continued progress is needed.

Next, accounting for salt sensitivity in assessing cardiovascular health will be an important factor to consider. Salt sensitivity is an independent risk factor for mortality and provides information on how the individual will respond to restricting sodium intake and whether restricting sodium intake closer to the AI/RNI is warranted to control blood pressure. Currently, there is no practical method for assessing salt sensitivity, although genetic markers to predict this phenotype have shown a lot of promise for individualising sodium recommendations.

Lastly, as many patients engage in pharmacological and dietary interventions to manage their blood pressure, using genetic information to help optimise efforts in these two fields could potentially lead to better blood pressure control and cardiovascular outcomes. Pharmacogenetic information can help guide antihypertensive medication selection to optimise drug efficacy and minimise adverse outcomes. Nutrigenetic information can help identify individuals who are salt sensitive among those who are normotensive and hypertensive, and dietitians can work with these patients to ensure reduced sodium intake is being followed. Taken together, the synergy of using pharmaconutrigenetics and nutrigenetics to manage blood pressure may be an effective approach since an optimal approach is selected in both fields based on genetics to maximise the response achieved in managing blood pressure. At the patient level, the synergy between these two fields working together to manage blood pressure more efficiently may result in scenarios such as patients requiring fewer pharmacological agents, or relying solely on sodium reduction given the presence of the salt sensitivity phenotype, among other possible outcomes. To this end, a better alignment of medication and nutrition decisions has the potential to help patients manage their blood pressure and sodium intake more optimally and ensure their cardiovascular risk is minimised.

Table 4 4 10 13 14 34 63 72 summarises what practice patterns could look like if precision medicine in this area became validated as currently known. Most notably, sodium target levels will not differ much from the established AI, RNI and UL levels, but having salt-sensitive individuals aim for sodium intake closer to the AI/RNI levels might be beneficial, while a focus on interventions beyond sodium intake level may be needed for salt-resistant individuals. The other major paradigm shift in this area is not relying on blood pressure to dictate sodium intervention, but instead using the salt sensitivity phenotype to guide the priority placed on sodium intake levels.

Summary

CVD is a huge public health concern that affects a large proportion of the population in many countries, including the UK and the USA. Management of blood pressure through nutrition and pharmacological interventions has traditionally been the approach in reducing CVD. Although not yet commonly done, considering the salt sensitivity phenotype can point to individuals at highest risk for adverse health outcomes with high sodium intake and most likely to benefit from lower sodium intake targets. Several predictive genetic markers for probabilistic identification of the salt sensitivity phenotype have already been replicated and would become even more credible with further clinical validation. In addition, for those receiving antihypertensive agents, drug selection guided by such genetic markers promises better efficacy, lower risk of adverse events and more efficient use of limited healthcare resources. Precision medicine, in particular combining pharmacological and nutritional genetic information to guide individualised medication and nutritional decisions (pharmaconutrigenetics), can help improve blood pressure management.