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Sodium and potassium intake, blood pressure, and cardiovascular prevention 

Sodium and potassium intake, blood pressure, and cardiovascular prevention
Chapter:
Sodium and potassium intake, blood pressure, and cardiovascular prevention
Author(s):

Francesco P. Cappuccio

DOI:
10.1093/med/9780198784906.003.0568
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date: 06 December 2021

Summary

Salt consumption is now much greater than needed for survival. High salt intake increases blood pressure in both animals and humans. Conversely, a reduction in salt intake causes a dose-dependent reduction in blood pressure in men and women of all ages and ethnic groups, and in patients already on medication. The risk of strokes and heart attacks rises with increasing blood pressure, but can be decreased by anti-hypertensive drugs. However, most cardiovascular disease events occur in individuals with ‘normal’ blood pressure levels. Non-pharmacological prevention is therefore the only option to reduce such events in the population at large. Reduction in population salt intake reduces the number of vascular events. It is one of the most important public health measures to reduce the global cardiovascular burden. Salt reduction policies are powerful, rapid, equitable and cost saving. The World Health Organization recommends reducing salt consumption below 5 g per day aiming at a global 30% reduction by 2025.

A high potassium intake lowers blood pressure in people with and without hypertension. Its beneficial effects extend beyond blood pressure, and may include a reduction in the risk of stroke (independent of blood pressure changes). Potassium intake in the Western world is relatively low, and a lower potassium intake is associated with increased risks of cardiovascular disease, especially stroke. A moderate increase in potassium intake, either as a supplement or with diet, reduces blood pressure, and the World Health Organization has issued global recommendations for a target dietary potassium intake of at least 90 mmol/day (≥3510 mg/day) for adults. (In this chapter, salt (NaCl sodium chloride) and sodium are used to refer to sodium intake. Please note the following conversion: 2.5 g (2500 mg) of salt = 1.0 (1000 mg) of sodium.)

Salt intake in the development of human kind: evolutionary observations

The consumption of salt began to rise between 5000 and 10,000 years ago. The earliest use of salt is reported to have taken place on Lake Yuncheng in Northern China around 6000 bc.1 All known human societies, even the most primitive, consume per capita more salt than they physiologically require. Salt has been referred to as the ‘primordial addiction’. It is important to consider our intakes of salt in the light of our evolutionary history, as discordance between our modern-day diet and the traditional hunter-gatherer diet under which our genome was selected may provide insight into fundamental mechanisms of chronic disease pathogenesis.2,3 The Neolithic revolution, of approximately 10,000 years ago, saw a move away from traditional hunter-gatherer practices and the introduction of human settlement, agriculture, and animal husbandry. These practices mark the beginning of a period of profound change in the composition of the human diet and the availability of various foods, finally culminating in today’s modern diet. These changes have occurred over an evolutionarily minute timescale and are in conflict with our genetically determined biochemistry which has evolved over a protracted length of time.4 For reasons not fully understood, the initial rise in human salt consumption paralleled the advent of agriculture and the decline of meat consumption of hunter-gatherer societies. Salt became a necessity of life and the first international commodity of trade, giving it great symbolic importance and economic value, representing one of the earliest industries and the first state monopoly. Primitive methods of salt production were not simple; salt was a relative—but bulky—luxury, posing distribution challenges. Salt use became a way to affirm ‘social distance’ because of its unique properties of enhancing flavours and fulfilling hedonic rewards.5 This mechanism was later understood to be an acquired characteristic of salt taste buds regulation.6 Probably the most important factor leading to an increased human salt consumption was the discovery that putting meat and other foods into concentrated salt solution could preserve them. Until modern times, salt provided the principal way of preserving food and to protect against decay.1 With the advent of electricity and refrigeration, particularly in the developed world, the need for salt as a preservative has rapidly diminished. However, the human consumption of salt has not declined, and in some instances has seen an increase,7 with significant contribution to the development of chronic diseases.

Salt intake and blood pressure

The concept that high salt intake would be associated with high blood pressure was first attributed to The Yellow Emperor’s Classic of Internal Medicine (Huang Ti Nei Ching Su Wen, 2698–2598 bc). In the early twentieth century, Ambard and Beaujard described the clinical association between levels of salt intake and levels of blood pressure in humans, later clarified by Kempner in 1948 with the salt-free rice-diet experiments.

Animal experiments

Since Kempner’s work, the effects were studied in detail in numerous experimental rat models such as Dahl’s salt-sensitive rats, Aoki’s spontaneously hypertensive and stroke-prone hypertensive rats, and Bianchi’s Milan strain of rats. In all cases, a clear dose-dependent effect was described between the levels of salt intake and the levels of blood pressure and cardiovascular (CV) complications. Chimpanzees, the species phylogenetically closest to humans, were studied by Denton in two landmark experiments.8,9 In the first, a colony of 26 free-living chimpanzees in Gabon were studied on their low-salt, high-potassium diet and then fed a high-salt diet for 6 months. Their diet was then reversed to the usual diet. During these periods both blood pressure and urinary sodium and potassium were measured. The results showed unequivocally for the first time that increasing salt intake caused a large rise of blood pressure, which was reversed upon returning to a low-salt diet. The study was repeated in 110 chimpanzees housed in Bastrop, Texas, United States, who were randomized to either receiving a 250 mmol sodium diet (about 14.5 g of salt) per day or half of it (about 7.3 g of salt) for 2 years. At the end of the study the group eating the half-salt diet (a 7 g salt difference) had a 6/4 mmHg lower blood pressure compared to the other group. This study confirmed the significant effect of salt reduction within human dietary limits and the sustained effect over 2 years.

Salt and blood pressure in humans

Epidemiological and migration studies, natural experiments, population-based intervention studies, and randomized controlled clinical trials all provide evidence of a direct link between salt intake and blood pressure.10 The INTERnational Studies of SALT and Blood Pressure (INTERSALT) cooperative study well summarizes the results of an association between salt intake and blood pressure and of a steep relationship between salt intake and the rise in blood pressure observed with age.11 Numerous randomized clinical trials have been performed over the last 40 years. They have been repeatedly and systematically reviewed and meta-analysed since 1984.12,13 Figure 44.6.1 shows the collective estimates of all meta-analyses published to date on the effect of salt reduction on blood pressure in adults. The meta-analyses differ for the time of the analysis, hence the number of overall studies available, the inclusion criteria (short-term studies <4 weeks vs longer-term studies >4 weeks), the proportion of normotensive and hypertensive participants, the study designs (cross-over, parallel group, blinded and unblinded), the proportion of relevant subgroups (by sex, age, ethnic group). In light of these differences between studies, the range of pooled weighted estimates of effect ranged from −10.2 to −1.2 mmHg for systolic and −4.08 to −0.05 mmHg for diastolic blood pressure, respectively, in favour of salt reduction. More importantly, the 95% confidence intervals (CIs) of all the pooled estimates were compatible with each other indicating consistency with differences between them to be likely due to random variation. These analyses, despite different interpretations at the time of their publication, all agree on the following: (1) salt intake is one of the major determinants of blood pressure in populations and individuals; (2) a reduction in salt intake causes a dose-dependent reduction in blood pressure; and (3) the effect is seen in both sexes, all ages and ethnic groups, and with all starting blood pressures. Similar results are described in children.14, 15

Figure 44.6.1 Forest plot summarizing the results of published meta-analyses of randomized controlled trials of the effects of salt reduction on systolic blood pressure. Results report weighted mean effects and 95% confidence intervals (CI).

Figure 44.6.1 Forest plot summarizing the results of published meta-analyses of randomized controlled trials of the effects of salt reduction on systolic blood pressure. Results report weighted mean effects and 95% confidence intervals (CI).

Reproduced from Aburto N.J. et al. Effect of lower sodium intake on health: systematic review and meta-analyses. Br. Med. J. 346, f1326 (2013) with permission from BMJ.

The concept of ‘salt sensitivity’

A moderate reduction in salt intake reduces blood pressure in most individuals, but not all.16 The effect on blood pressure varies largely from person to person. Salt sensitivity has a variety of determinants, including race/ethnicity, age, body mass index, diet quality, as well as associated disease states (e.g. hypertension, diabetes, and renal dysfunction). It is partially under genetic control since these individuals, whether considered ‘normotensive’ or ‘hypertensive’, tend to frequently have a positive family history for hypertension. The blood pressure response to a moderate change in salt intake in normally distributed. Many experimental models have been used for the past 40 years to attempt an individual characterization of so-called salt sensitivity. These methods have included blood pressure response to (1) acute and large changes in salt intake, with or without diuretic-induced volume depletion; and (2) moderate changes in salt intake over days in normotensive volunteers,17 patients, or general population,18 response of the renin–angiotensin–aldosterone system,18,19 the clearance of endogenous lithium, a non-invasive method for assessing segmental renal tubular sodium handling,19 and considered a proxy for ‘salt-sensitivity’.20, 21

Measures of ‘salt sensitivity’ are associated with more severe CV risk factor profiles and they are negative prognostic indicators. Though less easy to detect, salt sensitivity is also present in normotensive people. In a small clinical study with a long-term follow-up, normotensive ‘salt-sensitive’ individuals had a cumulative mortality as high as that of hypertensive patients.22 Finally, proximal tubular sodium reabsorption in normotensive men is associated with an increased risk of developing hypertension in a prospective population study.23

Skin as a buffer?

Recent experimental studies in humans suggest that large amounts of sodium can accumulate without associated water retention,24 supporting the existence of non-osmotic sodium retention in a compartment other than the extracellular space. Animal studies indicate that the skin is capable of osmotically inactive sodium storage, resulting in a potentially important mechanism to buffer volume expansion and blood pressure increases with increases in salt intake.25 However, the relevance of these mechanisms in humans is still unclear. A short-term experiment in young, human, healthy volunteers using a double-blind randomized crossover design of salt loading versus placebo showed that skin sodium increases with dietary salt loading, essentially in men though.26 This skin sodium retention was associated with the blood pressure responses to salt loading, in that women who did not have much of an increase in skin sodium showed a rise in blood pressure with salt loading, whereas men, who showed the greatest skin sodium retention, did not. This study, in spite of the short-lived intervention and other limitations, suggests that skin sodium retention may be contributing to the blood pressure salt-sensitivity by buffering the haemodynamic effects of acute salt loading.

Interaction with drug-therapy

Hypertension control remains suboptimal in many countries, despite recent improvements. Most people require more than one drug to control their high blood pressure to target27 and resistant hypertension is now becoming a reason for concern.28 One of the main causes of resistant hypertension is a high salt intake and one of the therapeutic tools to potentiate a drug-induced fall in blood pressure is to accompany drug therapy with moderate salt reduction. In fact, a moderate reduction in salt intake is effective in lowering blood pressure on its own but is also additive to pharmacological therapy and can be as effective as a low-dose thiazide diuretic.29 The degree of renal protection seen with sodium reduction is not seen with the use of diuretics.30 A reduction in sodium intake reduces sodium delivery to the distal tubule by increasing proximal tubular sodium reabsorption, whereas diuretics will not. Increased sodium delivery to the distal tubule, especially in the outer medulla, is the site of the kidney most vulnerable to ischaemic injury. This mechanism would explain why high sodium intake is harmful to the kidney even when associated with the use of diuretics.30 Finally, the blood pressure-lowering effect of dietary salt reduction would be more pronounced when associated with drug classes that block the renin–angiotensin–aldosterone system (such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, renin inhibitors, anti-aldosterone compounds, and beta blockers) (Table 44.6.1; see also chapters 5.15.3).

Table 44.6.1 Effect of a moderate reduction in dietary salt in patients already on antihypertensive therapy

Drug class

Additive efficacy

Monotherapy

All diuretics [D]‌

No additive effect

Angiotensin-converting enzyme inhibitors [A]‌

Additive effect due to blockade of compensatory activation of renin–angiotensin–aldosterone system in response to salt reduction (reduced conversion of AI to AII with reduced compensatory vasoconstriction and fall in blood pressure)

Angiotensin receptor blockers [A]‌

Additive effect due to blockade of the AII response to salt reduction (competitive AII receptor blockade with reduced compensatory vasoconstriction and fall in blood pressure)

Renin inhibitors [A]‌

Additive effect due to reduced renin production and reduced substrate for compensatory response

Beta blockers [B]‌

Additive effect due to reduced renin production and reduced substrate for compensatory response

Dihydropyridine calcium-channel blockers [C]‌

Small additive effect—blunted by mild diuretic and natriuretic effect

Non-dihydropyridine calcium-channel blockers [C]‌

Mild additive effect—diuretic and natriuretic effect minimal with both diltiazem and verapamil

Alpha blockers

Small additive effect

Combination therapy

A+C

Additive effect—comparable to a diuretic

Multiple therapy with 3+ drugs

Additive effect

See reference29 for further details.

Blood pressure and cardiovascular disease

Blood pressure is responsible for approximately 50% of deaths from coronary heart disease (CHD) and over 60% of those from stroke, the two leading causes of preventable death, morbidity, and disability in the world.31 The risk of these cardiovascular diseases (CVDs) increases progressively with increasing blood pressure and there is a graded relationship between blood pressure and CVD, down to or even below 115/75 mmHg.32 When high blood pressure (i.e. 140/90 mmHg or higher) is lowered with drugs, there is a reduction in both CHD and stroke events of the magnitude consistent with observational studies.33 However, the majority of CVD events attributable to blood pressure occur at around 130/80 mmHg or less, because there are so many more individuals in the population with this ‘normal’ blood pressure.34 Since we would not treat with drugs the majority of individuals with a blood pressure of 130/80 mmHg,35 a population-based approach through non-pharmacological measures (diet and lifestyle) is the only feasible option. Achieving a small downward shift in the distribution of blood pressure in the whole population would achieve a surprisingly large CVD reduction (a 2.5% decrease in mortality rates for every 1 mmHg decrease in systolic blood pressure).

Salt intake and cardiovascular disease

Natural experiments of salt reduction programmes in Japan and Finland over the last 40 years have consistently suggested a substantial benefit of these policies in contributing to a reduction in population blood pressure and hence stroke and CHD incidence. There are almost no long-term randomized trials of salt reduction and CV outcomes. This is due to ethical considerations, methodological challenges regarding compliance over time, extended duration, large sample size, and difficulty in securing financial support.36 Observational prospective cohort studies with many years of follow-up and assessments of exposure (salt intake) and outcomes (heart attacks and strokes) therefore remain the next best option. A meta-analysis of these studies suggests that a 5 g higher salt intake is associated with a 17% greater risk of total CVD and, crucially a 23% greater risk of stroke.37 However, the nature of these studies does not let us establish causality. The risk of methodological problems in cohort studies that relate sodium intake to CVD outcomes is high: systematic as well as random errors in sodium assessment, potential for residual confounding, likelihood of reverse causality, and, crucially, the selection of high-risk and sick, older patients on multiple drug therapy can all lead to biased conclusions.38 These problems are seen in some cohort studies that suggest an increased CHD risk at lower levels of salt intake. How do we know then whether the higher salt intake is the ‘direct’ cause of the higher risk of stroke? Many years ago, Sir Austin Bradford Hill indicated a number of criteria an observational epidemiological study should fulfil in order to support the concept of causality.39 These criteria, for example, were used to suggest the causal link between cigarette smoking and lung cancer, for which there were no clinical trials available. Many of these criteria in support of causality apply to the association between salt intake and CVD. The association between higher salt intake and stroke is moderately strong, with pooled adjusted relative risks ranging between 1.10 and 1.30.13,37 There is a dose–response relationship between level of salt intake and risk of stroke.37 The association with outcomes is consistent across different countries. High salt intake precedes the development of outcomes in prospective studies. One study, the Trials of Hypertension Prevention (TOHP, phases I and II), provides to date the only evidence of a randomized trial of salt reduction on outcomes. Compared to a control group, a 25–30% reduction in salt consumption in the intervention group caused a fall in blood pressure at 18 and 36 months and a reduction in CV events.40 After 10–15 years, the blood pressure and the CV mortality were still lower in participants who had originally been randomized to the intervention group (TOHP I–II). Finally, a meta-analysis of randomized clinical trials of salt reduction where vital outcomes were also recorded during follow-up ranging from 7 months to 11.5 years indicates a statistically significant 20% reduction in total CV outcomes (relative risk 0.80; 95% CI 0.64–0.99)41 (Figure 44.6.2).

Figure 44.6.2 Forest plot of relative risk of cardiovascular disease (CVD) events in a meta-analysis of outcome trials of salt reduction at longest follow-up combining hypertensive and normotensive individuals. Duration of follow-up ranged from 7 months to 11.5 years. Fixed effect model with normotensives and hypertensives combined. Heterogeneity χ‎2 = 3.20, degrees of freedom = 3 (p = 0.36); I2 = 6%. Test for overall effect Z = 2.02 (p = 0.04).

Figure 44.6.2 Forest plot of relative risk of cardiovascular disease (CVD) events in a meta-analysis of outcome trials of salt reduction at longest follow-up combining hypertensive and normotensive individuals. Duration of follow-up ranged from 7 months to 11.5 years. Fixed effect model with normotensives and hypertensives combined. Heterogeneity χ‎2 = 3.20, degrees of freedom = 3 (p = 0.36); I2 = 6%. Test for overall effect Z = 2.02 (p = 0.04).

Reproduced from He F.J. & MacGregor G.A. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials. Lancet 378, 380–382 (2011) with permission from Elsevier.

Other effects of dietary salt reduction

High salt intake is an independent predictor of left ventricular mass and a reduction in salt intake causes a regression of left ventricular hypertrophy. It causes an increase in renal blood flow and glomerular filtration rate and a reduction in salt intake appears to normalize the hyperfiltration seen in normotensive individuals more sensitive to the effect of salt. A high salt intake increases urinary calcium losses. This in turn causes increased levels of parathyroid hormone, 1,25-dihydroxy-vitamin D, serum osteocalcin (a marker of bone formation), urinary cyclic AMP, and urinary hydroxyproline (a marker of bone resorption).42 If substantial calcium losses are sustained over many decades, increased excretion of calcium in the urine may result in an increased risk of urinary tract stones,42 and the increased movement of calcium from bone may result in higher rates of bone mineral loss, thereby increasing the risk of osteoporosis, particularly in menopausal women.43 A reduction in salt intake is therefore an effective strategy to reduce hypercalciuria in hypertensive patients as well as in kidney stone formers and a useful long-term preventive strategy to help reduce the risk of bone mineral density loss and osteoporosis in later life.42 In a recent meta-analysis of prospective studies, dietary salt intake was directly associated with the risk of gastric cancer, with progressively increasing risk across consumption levels.44 In the pooled analysis, ‘high’ and ‘moderately high’ versus ‘low’ salt intake were both associated with an increased risk of gastric cancer (relative risk 1.68; 95% CI 1.17–2.41, and RR 1.41; 95% CI 1.03–1.93, respectively). High salt intake induces thirst and increased fluid intake that is then retained in the intravascular compartment causing an increase in total blood volume. Both the heart and the kidney are the main organs to compensate for these changes through hormonal responses (renin–angiotensin–aldosterone axis and atrial natriuretic peptide), increased systolic ejection, increased blood flow, and renal clearances. Dysregulations of these systems may lead to fluid retention that can be aggravated by high salt intake and ameliorated or cured by a reduction in salt intake. Congestive heart failure may be triggered by high salt intake, ‘rebound’ sodium, and fluid retention following diuretic withdrawal can be minimized or avoided by low salt intake prior to withdrawal.45 Finally, there is evidence to suggest a direct effect of high salt intake, independent of its blood pressure effect, on endothelial cell signalling, oxidative stress, and the progression of kidney disease.

Population-wide salt reduction for the prevention of cardiovascular disease

Time-line of the development of public health and policy recommendations

The importance of a population reduction in salt intake for the prevention and control of high blood pressure and of CVD had been recognized since the 1970s with successful national and regional programmes in Japan and Finland. In 1985, the World Health Organization (WHO) issued recommendations to Member States for a reduction in salt intake down to an average of 5 g per day. However, no action plans were put in place. In the meantime, Finland implemented a national programme successfully pursued over more than 20 years. Salt intake fell from 13 g to 10 g per day in men and from 10.5 g to 7.6 g per day in women.46 At the same time, there was a 20% reduction in blood pressure,47 even though body mass index increased. These reductions were associated with a substantial decline in both CHD (55% in men and 68% in women)48 and stroke mortality (66% in men and 60% in women).46 These benefits were clear even after adjusting for the concomitant decreases in total and low-density lipoprotein cholesterol.46 Indeed, two-thirds of the falls in CVD mortality seen in all Western countries have been attributed to risk factor improvements (mainly falls in blood pressure reflecting dietary salt reduction, reduced smoking rates, and total cholesterol levels).47,48,49 Since the 1980s, both scientific evidence and public health initiatives reflecting decreased intake of salt have accumulated leading to renewed recommendations from the WHO in 200750 and 201251 not to exceed a population average salt intake of 5 g per day. These recommendations are now followed by numerous countries worldwide.52 The most recent significant steps towards global policy actions were the 2011 United Nations high-level meeting on non-communicable diseases, setting a population salt reduction of 25% as a priority to reduce premature mortality by 2025. The revised WHO guidelines now recommend a 30% reduction of salt intake by 2025 with a final maximum target of 5 g per day.51 The latter target was then adopted by the 66th World Health Assembly through its resolution in 2013. At present, salt intake exceeds the recommended level in almost all countries in the world with small differences by age and sex.52, 53

Three-pronged approach and policy options to reduce salt intake in entire populations

The issue is no longer ‘whether’ reducing salt intake is of public benefit, but rather ‘how’ best to achieve a steady, significant, and sustained reduction in salt consumption. What are the options available to governments, health organizations, individuals, and stakeholders? Which policies are best suited for the local needs? How effective are they? And how do we monitor success?

An effective programme to reduce population salt intake is based on three fundamental pillars: communication, reformulation, and monitoring52 (Figure 44.6.3). These three pillars will cover a variety of complementary and mutually reinforcing approaches, including health promotion and awareness campaigns, collaboration with industry to progress voluntary or regulatory reformulation programmes, the use of salt substitutes in households and in food manufacturing, and, crucially, monitoring of salt content in food and population salt consumption. A successful example is the salt reduction campaign in the United Kingdom achieving a 15% (1.4 g per day) reduction in salt intake over 7 years.54 Here the Food Standard Agency pursued a sustained programme to facilitate progressive reformulation by industry. Though officially ‘voluntary’, successive health ministers had clearly signalled their readiness to legislate if necessary.

Figure 44.6.3 Three-pronged strategy for successful population dietary salt reduction policies with continuous research support.

Figure 44.6.3 Three-pronged strategy for successful population dietary salt reduction policies with continuous research support.

In cases where the majority of the population salt intake comes from processed food and the catering sector, voluntary collaboration with the industry reinforced by a regulatory framework is advocated.55 A good self-regulatory voluntary system has benefits in that it saves government resources, is less confrontational, more flexible, and speedier than government regulation.56 Self-regulation tends to be less effective than legislation,56 hence often less cost-effective. Indeed, there is consistent evidence that the addition of a regulatory framework is more effective and cost-effective than the voluntary approach alone.57,58 Successful examples of these approaches can be seen in Finland and, more recently, in the New York City initiative. Where salt is mainly added to food at household levels, as in some cases of rural Africa,59 health promotion and education may still be an option. Finally, salt-substitution policies are being tested in China, where it might provide an alternative for that country60 as the majority of salt intake, unlike in most Westernized countries, derives from salt added to food through salted condiments and during food preparation at home.

Evaluation and quantitative comparison of contrasting policy approaches through modelling

Taking the Argentinian example, policies adopted in that country may reduce salt intake by about 0.8 g per day.61 According to the CHD Policy Model, this should translate into a systolic blood pressure reduction of between 0.9 and 1.8 mmHg. This could in turn avert approximately 20,000 deaths, 13,000 myocardial infarcts, and 10,000 strokes over the next decade. Similar results come from a variety of different modelling methodologies applied to diverse populations. Many are based on the effect sizes from a previous meta-analysis.37 In the United Kingdom population, a 3 g per day reduction in salt intake could result in approximately 6600 fewer CVD deaths per year62 or, according to a more conservative approach,63 some 4450 fewer CV deaths and 30,000 fewer CV events per annum, along with total 95,000 life years gained, 130,000 quality-adjusted life years, and overall financial savings of approximately £35 million per decade. Further supportive evidence comes from empirical data. These consistently demonstrate that with diet-based, population-wide risk factor reductions, substantial declines in event rates can happen very rapidly, in years rather than decades. When comparing different policy approaches, an effectiveness hierarchy becomes apparent (Sodium and potassium intake, blood pressure, and cardiovascular prevention Figure 44.6.4(online)). Thus, individually based approaches such as advice or social marketing are relatively weak, whereas more ‘upstream’ population-wide policy approaches generally achieve much larger reductions in salt intake.64

Figure 44.6.4(online) Comparison of different policy approaches to salt reduction: the effectiveness hierarchy.

Figure 44.6.4(online) Comparison of different policy approaches to salt reduction: the effectiveness hierarchy.

Reproduced from Cappuccio F.P., et al. Policy options to reduce population salt intake. Br. Med. J. 343, 402–405 (2011) with permission from BMJ.

Cost-effectiveness

The application of policies to reduce salt intake across the entire population is an effective and cost-saving public health measure. Several studies have assessed the health effects and the healthcare-related costs of reducing population salt intake. Albeit applying different methods and models of assessment in different healthcare systems and under different assumptions, their results have invariably demonstrated that a reduction in salt intake is cost saving for the healthcare system.57,58,63 For example, in the United States, a salt reduction of 3 g per day would result in an estimated annual gain of 194,000–392,000 quality-adjusted life years and estimated savings of $10–$24 billion in healthcare costs. That represents a $6–$12 return on investment for each dollar spent on the regulatory programme.57 Even a modest 1 g per day reduction achieved gradually over 10 years would be more cost-effective than using medications to lower blood pressure in all patients with hypertension.65 These economic savings would be achieved with either voluntary or mandatory reductions in the salt content of processed foods. However, health benefits would be up to 20 times greater with government legislation on salt limits in processed foods. Cost savings are also estimated for a reduction in salt intake of 15% in low- and middle-income countries (LMICs) with 13.8 million deaths averted over 10 years at an initial cost of less than $0.40 per person per year.58 These models do not include, however, costs to industry when reformulating food as well as non-healthcare related savings and social benefits that arise from reduction of morbidity, disability, and death.

Inequalities

The Marmot Review66 reviewed the evidence that social inequalities are important determinants of ill health in the British population, highlighting the social gradient in health inequalities, whereby people of poorer background not only die sooner but spend more of their lives with disabilities. Health inequalities arise from a complex interaction of many factors, all affected by one’s economic and social status. One of these factors is bad diet and nutrition.

CVD and hypertension are both more prevalent in socioeconomically deprived sections of the population. These groups are more likely to depend on cheaper, unhealthy, processed food diets, high in salt. Furthermore, in the United Kingdom, knowledge of government guidance was lower and voluntary table salt use and total salt intake was higher among disadvantaged occupational and ethnic groups. Salt intake can thus be 5–10% higher in socioeconomically deprived groups.67 In England and Wales, despite a national reduction of salt intake of approximately 1.4 g per day, the socioeconomic difference has remained.68

Marmot’s report, Fair Society, Healthy Lives,66 subsequently emphasized that health inequalities are preventable through policies aiming at reducing health inequalities, because they are usually ‘structural’.69 Indeed, the more ‘upstream’ policies are, the greater the potential to reduce health inequalities in CV benefit64 (Figure 44.6.5). The mandatory reformulation of processed foods to reduce salt content has the potential to be both effective and inequality reducing. Further voluntary reformulation, being optional on the part of industry, would still represent a substantial benefit but it might only modestly narrow inequality in mortality. The agentic options, further social marketing, and nutrition labelling, would bring substantially less benefit, and with highly uncertain effects on inequality in mortality.69 Finally, there is evidence that the risk of chronic disease, such as hypertension, associated with low parental social status can be decreased by subsequent improvement in social status.70

Figure 44.6.5 Policy effectiveness and inequality of effect. The cumulative changes to the total number of coronary heart disease (CHD) deaths from 2015 up to 2025 (x-axis) plotted against the socioeconomic differentials in change (y-axis). Negative values for total change indicate fewer deaths. Negative values for the socioeconomic differential indicate more deaths prevented or postponed in the most deprived (i.e. a reduction of inequality). Crosses indicate the 95% prediction intervals; where each set of vertical–horizontal lines cross, these are the mean predictions of effect.

Figure 44.6.5 Policy effectiveness and inequality of effect. The cumulative changes to the total number of coronary heart disease (CHD) deaths from 2015 up to 2025 (x-axis) plotted against the socioeconomic differentials in change (y-axis). Negative values for total change indicate fewer deaths. Negative values for the socioeconomic differential indicate more deaths prevented or postponed in the most deprived (i.e. a reduction of inequality). Crosses indicate the 95% prediction intervals; where each set of vertical–horizontal lines cross, these are the mean predictions of effect.

Reproduced from Gillespie DOS et al. The Health Equity and Effectiveness of Policy Options to Reduce Dietary Salt Intake in England: Policy Forecast. PLOS ONE 10(7), e0134064 (2015).

Salt intake in low- and middle-income countries

A reduction in dietary salt intake is also feasible in LMICs since it is possible to decrease salt content in low-cost foods, while maintaining some level of familiar meals.71 Thus, modest reductions in salt intake could substantially reduce CVD throughout India without affecting the current effectiveness of local iodization programmes, due to low intake of iodized salt.72

Value and feasibility of population-wide salt reduction in LMICs

Three policy approaches in diverse Middle Eastern countries were recently compared: a health promotion campaign, labelling of food packaging, and mandatory reformulation of salt content in processed food. In all four countries most policies were cost saving compared with the baseline. The combination of all three policies (reducing salt consumption by about 30%) could achieve cost savings of approximately $6 million in Palestine, $39 million in Syria, $235 million in Tunisia, and $1300 million in Turkey per decade, plus gaining approximately 2700, 6450, 31,000 and 380,000 life years, respectively.73 However, in spite of the United Nations World Health Assembly Declaration, there is still disconnection between the burden of non-communicable diseases and national policy responses, particularly in LMICs. Furthermore, a gradient across measures of inequalities is present for the degree of implementation of current salt reduction policies in Western countries.74

Role of the food and beverage industry

The important shift in the public health debate from ‘whether’ salt reduces the risk to ‘how’ to best lower salt intake to reduce CVD has not occurred without obstinate opposition from organizations concerned primarily with the profits deriving from population high-salt intake and less with public health benefits. Among them, the food and beverage industry has been particularly obstructive either directly or through their public relation organizations to delay public health actions. Their strategies have included mass media campaigns, biasing research findings, co-opting policymakers and health professionals, lobbying politicians and public officials, and encouraging voters to oppose public health regulation,75,76 similar to the tactics used in the past by the tobacco industry, and applied by the food industry to any campaign asking for reductions of salt, saturated and trans fats, refined sugar, calorie-dense foods, and regulation of food reformulation to prevent current epidemics of chronic diseases.56,77 Key components of this denial strategy are misinformation with ‘pseudo’ controversies, and the peddling of numerous rather tired myths.78 Generally, poor science has been used to create uncertainty and to support inaction. A clear example in the last few years is the growing debate generated by publications suggesting that a population-wide moderate reduction in salt consumption would cause harm by increasing total and cause-specific mortality in those with lower than average salt intake. These studies have been recently reviewed in great detail in the latest European Heart Network report.79 These studies have invariably used flawed methodologies38,80 (Table 44.6.2). In particular, claims that a lower salt intake is dangerous in people with heart failure81,82 were robustly rebutted,41 and subsequently retracted as based on dubious and not identifiable data sources.83 Sadly this ‘false’ evidence is still used to date to support the controversy. In particular, the claim that a low salt intake may ‘cause’ CHD84,85,86 has been—again—robustly rebutted by the scientific community,87,88,89,90,91,92,93 and proven to be not true, by American, Dutch, and global studies using valid and appropriate methods.94,95,96 Finally, reiterated myths have been disseminated to consumers and lay audience to create doubts.78 A comprehensive table of the ‘salt myths’ used by the food and beverages industry and their public relations companies to undermine science and resist regulation and the answers to them is extensively published elsewhere.78

Table 44.6.2 Methodological issues in the assessment of prospective observational studies of salt consumption and cardiovascular outcomes

Domain 1: errors with the greatest potential to alter the direction of association

Systematic error in sodium assessment

  • Lower risk: 24 h urine collections not part of routine clinical practice, no quality assurance, not excluding incomplete collections

  • Higher risk: other 24 h urine collections, all dietary assessments, spot and overnight urine collections

Reverse causality

  • Lower risk: participants recruited from general population and pre-existing CVD excluded

  • Intermediate risk: sick populations not excluded or included despite stated otherwise; presence of CVD risk factors; specific sick populations

  • Higher risk: specific sick populations (e.g. heart failure, kidney disease, diabetes); removal of sick participants from analysis changes direction of association

Domain 2: errors with some potential to alter the direction of association

Potential for residual confounding

  • Incomplete adjustment: not including two or more of age, sex, race, socioeconomic status, cholesterol, BMI or weight, smoking, diabetes; if diet-based, total calories; if urine-based, weight, BMI or creatinine excretion

  • Imbalance across sodium intake levels: age difference across sodium groups >5 years; sex or race distribution across sodium groups >20%

  • Inadequate follow-up: low level of follow-up (<80%) or of uncertain quality for outcome assessment

Domain 3: errors with the potential to lead to a false null result

Random error in sodium assessment

  • Lower risk: more than four 24 h urine assessments on average; Food frequency questionnaires

  • Intermediate risk: between two and four 24 h urine collections, or corrections for regression dilution bias; dietary reports

  • Higher risk: urine collection <24 h or single 24 h urine collection; single dietary recall or 1-day food record

Insufficient power

  • <80% power to detect a 10% reduction in relative risk for every standard deviation in sodium intake

Studies using same data with divergent results

  • NHANES I studies: same age group, same follow-up—inverse versus positive association

  • NHANES III studies: different age groups, different follow-up—inverse versus positive association

BMI, body mass index; CVD, cardiovascular disease; NHANES, National Health and Nutrition Examination Survey.

Source data from Cobb LK et al. Methodological issues in cohort studies that relate sodium intake to cardiovascular disease outcomes: a science advisory from the American Heart Association. Circulation 2014;129:1173–86.

Why is the food and beverage industry so opposed to a global reduction in salt intake of approximately one-third? Salt is a cheap commodity in the modern world, even in LMICs. In 2009, more than 27 million tons of salt were sold in the United States with a revenue of $2 billion. Of those, only 1.5 million tons were food grade salt sales fetching more than $320 million (Source: Salt Institute). Notwithstanding these figures, the use of salt in food manufacturing generates substantial profits for the food and beverage industry. The world’s ten largest food and non-alcoholic beverage companies—feeding daily an estimated global population of several hundred million in more than 200 countries—generated, in 2012, combined annual revenue of more than $422 billion (Source: International Food & Beverage Alliance). How does a high salt intake in populations contribute to this profit? Figure 44.6.6 gives a schematic indication of the ‘cycle of profit’ associated with a high salt intake. A high salt intake will generate demand for salty foods through a slow process of desensitization of the taste buds. A high-salt diet downregulates taste buds allowing habituation, a requirement for higher salt concentrations to provide the ‘saltiness’ reward, a condition of ‘salt addiction’. Sodium salts are often hygroscopic, absorbing and binding water. Industrialized meat production has for years used the practice of injecting meat products with sodium salt bound to stabilizers with the consequence of increasing the weight of meat products before packaging. The proportion of water trapped into the meat is then sold at the price of meat. Salt has the property of making cheap, unpalatable food edible at no extra cost. Finally, a high salt intake causes thirst and an increase in the use of mineral waters, soft drinks, and, often, alcoholic beverages. The use of sugar-containing drinks would contribute to the epidemic of obesity, particularly in children,97 and it might encourage an increase in alcohol intake. It is, therefore, no surprise to see that a large proportion of the snack industry is indeed owned, or associated with, the large beverage corporations. Studies of salt reduction have clearly shown that a reduction in salt intake as recommended by the WHO would result in an average reduction in fluid consumption of approximately 350 mL per day per person.98 In children, this reduction would also lead to a reduction of at least 2.3 sugar-sweetened soft drinks per week per child.99 While this would result in large beneficial effects to the health of the population97 with financial gains for governments, it would represent a multibillion dollar loss to the industry from the reduction in the sales of bottled water and soft drinks.

Figure 44.6.6 The ‘cycle of profit’: how adding salt is lucrative to food and beverage industries but harmful to health.

Figure 44.6.6 The ‘cycle of profit’: how adding salt is lucrative to food and beverage industries but harmful to health.

Salt: conclusion

Human salt consumption has increased to levels that are at least ten times greater than needed, contributing to the secular epidemic in CVD through its effect on blood pressure. The higher the salt intake, the higher the blood pressure. A reduction in salt consumption reduces blood pressure effectively in everyone, young and old of all ages and ethnic background, and with all levels of initial blood pressure. A high salt intake is also associated with a greater risk of developing CVD, stroke in particular. The WHO, the World Health Assembly, and many countries around the world have all independently appraised the scientific evidence of the health benefits and the cost savings associated with the implementation of a population-wide moderate reduction in sodium intake (30% by 2025) and agreed upon global targets. Reducing dietary sodium will save tens of thousands of lives every year. Future governments and civil society will be increasingly unwilling to accept the burden of eminently avoidable disease. A gradual decrease in the sodium concealed in food products offers perhaps the easiest change for the general population with the greatest potential for success. The responsibility of food manufacturers in contributing to the epidemic of CVD must be acknowledged. The industry can therefore now voluntarily contribute to disease prevention through effective food reformulation, or risk being subjected to state-led market interventions and mandatory actions.

Potassium: introduction

In recognition of a growing body of evidence in support of the benefits of increasing potassium intake, the WHO has, for the first time, issued recommendations for a target daily dietary intake for potassium of at least 90 mmol for adults100 (conversion for potassium (K+) 1 mmol = 39 mg). In doing so, WHO states that ‘the successful implementation of these recommendations would have an important public health impact through reductions in morbidity and mortality, improvement in the quality of life for millions of people, and substantial reductions in health-care costs’. The following sections review the evidence underpinning this recent guidance with specific emphasis placed on reduction of stroke risk. The methods by which this target may be achieved in those at high risk of stroke are also briefly explored.

Stroke and blood pressure lowering

Stroke is the third most common cause of death in developed countries and annually, accounts for 10% of all deaths worldwide (see also section 29).101 Of the 15 million strokes suffered each year, 5 million are fatal and a further 5 million result in permanent disability.101 Stroke is the principal cause of acquired disability, the second cause of dementia, and the fourth cause of disease burden.102 The economic burden of stroke is very high and, due to ageing populations and increasing prevalence of stroke risk factors, is almost certain to increase.102 Stroke prevention is key to reducing both the personal and economic burden of stroke and could dramatically ameliorate the rate of death and disablement if effectively implemented.

Long-term blood pressure lowering following stroke or transient ischaemic attack confers substantial benefit to both hypertensive and normotensive patients by reducing the risk of recurrent stroke and other vascular events.103,104 Presently, for secondary prevention of stroke, achieving a target blood pressure of 130/80 mmHg with a combination of any available antihypertensive drugs is recommended.104,105,106,107,108 Despite this, there is consistent evidence to suggest that blood pressure is poorly controlled in a proportion of this high-risk group as much as 5 years post stroke.106,107,108 The NEMESIS trial reported that 37% of hypertensive 5-year stroke survivors had above-target blood pressure readings and 18% were not taking any antihypertensive medications.108 Although the reasons for poor blood pressure control in this population are likely to be complex, emergent populations of both difficult-to-treat and resistant hypertensives are likely to contribute to this effect28 as is the side effect profile associated with commonly prescribed antihypertensives.109 Therefore, novel approaches of blood pressure lowering within this population may be particularly useful, especially if they possess a unique mechanism of action or exhibit an improved side effect profile.

Prevention by nutrition

The effect of excess salt (sodium) intake on blood pressure, CVD, and stroke is well established and salt reduction programmes comprise a central tenet of public health initiatives internationally (see earlier in this chapter).

It has been known since the 1950s that the sodium:potassium ratio may be a more important predictor of blood pressure and hence CV and stroke risk than sodium intake per se.110 That is, that a low sodium:potassium ratio, achieved through proportionately low sodium and high potassium intakes, may predict lower blood pressure, CV, and stroke risk. Despite this, public health initiatives to date have focused exclusively on salt (sodium) reduction policies and yet there is growing evidence to suggest that increasing potassium intake could be equally beneficial.111

What do we learn from human evolution?

It is important to consider our intakes of sodium and potassium in the light of our evolutionary history, as discordance between our modern-day diet and the diet under which our genome was selected may provide insight into fundamental mechanisms of chronic disease pathogenesis.2,3 The Neolithic revolution, of approximately 10,000 years ago, saw a move away from traditional hunter-gatherer practices and the introduction of human settlement, agriculture, and animal husbandry. These practices mark the beginning of a period of profound change to the composition of the human diet and the availability of various foods, culminating in today’s modern diet.2 These changes have occurred over an evolutionarily minute timescale and are in conflict with our genetically determined biochemistry which has evolved over a protracted length of time.3 With specific reference to sodium and potassium intakes, prehistoric sodium consumption may have been as low as just 10 mmol per day and potassium consumption is believed to have been as high as 200–300 mmol per day.3 As a consequence, the human genome has been selected, within this environment, to provide an appetite for sodium consumption along with its retention. However, due to the abundance of potassium in the prehistoric diet, no such mechanisms have evolved in its case.2,3,112

Today, sodium and potassium intakes vary considerably between both individuals and populations. The ‘gold standard’ method for evaluating sodium and potassium intake is via 24 h urinary collection as the mass of these electrolytes ingested through the diet is largely excreted in the urine over the following 24 h period. A large international cross-sectional study conducted in the 1980s demonstrated daily sodium excretion was as high as 242.1 mmol and daily potassium excretion as low as 23.4 mmol in some populations.11 Weighted means of all participating centres yielded average daily excretion for sodium and potassium of 156.0 mmol and 55.2 mmol, respectively.11 These values give a sodium:potassium ratio of 2.8 compared to an estimated value of approximately 0.05 for the prehistoric diet.3 Although rare in the modern world, there are small populations of traditional hunter-gather societies subsisting on diets of traditional unrefined foods and which yield sodium:potassium ratios comparable to those of the prehistoric diet. Within such societies, individuals do not exhibit a rise in blood pressure with age and the incidence of hypertension overall is less than 1%; stroke is similarly rare.112

There is strong evidence to suggest that increasing dietary potassium intake reduces blood pressure and stroke risk and this is, in part, the justification for the current guideline for daily potassium intake issued by the WHO.100 Although the best understood mechanism of action is blood pressure lowering through reduction of the sodium:potassium ratio, there is good evidence to suggest that potassium may be protective of stroke via other processes.

Potassium, blood pressure reduction, and cardiovascular disease

Observational evidence in humans

The INTERSALT study collected international cross-sectional data including blood pressure as well as 24 h urinary potassium and sodium excretion from over 10,000 participants in 52 centres. These results showed a negative association between potassium excretion (proxy for its intake) with blood pressure.11 Moreover, the rate at which blood pressure increases with age is negatively associated with potassium intake and positively so with the sodium:potassium ratio, thus suggesting delayed progression of age-dependent hypertension in populations with high potassium diets.

Recent meta-analyses of prospective studies, all including a measurement of potassium intake and outcomes of stroke and CVD, demonstrate a 24% lower relative risk for stroke with an average higher potassium intake of 42.1 mmol per day 111,113,114 (Figure 44.6.7). A separate meta-analysis evaluated fruit and vegetable intake, which is positively correlated with potassium intake. This analysis demonstrated lower relative risk for stroke of 11% and 26% for those consuming three to five and more than five portions of fruit and vegetables per day, respectively, when compared to those consuming less than three portions per day.115 Although increasing the portions of fruit and vegetables consumed will confer a number of changes to the composition of the diet, this meta-analysis adds weight to the argument for the protective effects of potassium against stroke.

Figure 44.6.7 Risk of incident stroke associated with higher potassium intake in prospective population studies.

Figure 44.6.7 Risk of incident stroke associated with higher potassium intake in prospective population studies.

Randomized clinical trials in humans

A recent meta-analysis included randomized controlled trials comprised of at least two groups of participants where the intervention group had a higher potassium intake than the control group and where this was achieved either by supplementation or dietary modification.111 This analysis demonstrated that an increase in potassium intake significantly decreases blood pressure by 3.49 mmHg and 1.96 mmHg for systolic and diastolic blood pressure, respectively (Figure 44.6.8). When the achieved potassium intake was 90–120 mmol per day, the blood pressure reductions were 7.16 and 4.01 mmHg for systolic and diastolic blood pressure, respectively. The blood pressure reductions were shown to be independent of the baseline potassium intake and the largest decrease in blood pressure was observed in those consuming the largest quantity of sodium, perhaps due to modification of the sodium:potassium ratio.

Figure 44.6.8 Forest plot of the effect of increased potassium intake on resting systolic blood pressure in adults.

Figure 44.6.8 Forest plot of the effect of increased potassium intake on resting systolic blood pressure in adults.

Siani and colleagues successfully increased the potassium intake of a group of well-controlled hypertensives through providing dietary advice.116 Antihypertensive medication was reduced in a stepwise manner over a 1-year period providing that blood pressure targets were maintained. At 12-month follow-up, blood pressure was controlled with less than 50% of initial antihypertensive therapy in 80% of the subjects in the intervention group, compared with just 29% of the subjects in the control arm. These data demonstrate the feasibility of blood pressure-lowering through increasing potassium intake.

Additional animal experiments

The blood pressure-lowering effect of increased potassium consumption can be demonstrated convincingly in animal models. Experiments in animal models also support the existence of additional mechanisms of action for stroke prevention. Tobian and colleagues investigated the effects of increased potassium consumption in spontaneously hypertensive stroke prone rats. In this model, when fed a high sodium diet, the mortality rate was very high and death principally occurred as a result of stroke (thromboembolic and haemorrhagic). By supplementing the same diet with potassium, either with the chloride or citrate salt, mortality was reduced by 98% from 83% to 2% at 16 weeks of feeding for the control and supplementation groups respectively117 (Sodium and potassium intake, blood pressure, and cardiovascular prevention Figure 44.6.9a(online)). Potassium supplementation significantly reduced blood pressure in this model, however the reduction in mortality was still observed between blood pressure-matched pairs, suggesting the mechanism of action to be multifactorial118 (Sodium and potassium intake, blood pressure, and cardiovascular prevention Figure 44.6.9b(online)).

Figure 44.6.9(online) The effects of potassium (K) supplementation in stroke-prone spontaneously hypertensive rats (SP-SHR) and Dahl salt-sensitive (SS) rats. (a) High potassium diets reduce stroke mortality in both SP-SHRs and Dahl SS rats. (b) High potassium diets reduce stroke and death rate in hypertensive rats, even when blood pressure is matched.

Figure 44.6.9(online) The effects of potassium (K) supplementation in stroke-prone spontaneously hypertensive rats (SP-SHR) and Dahl salt-sensitive (SS) rats. (a) High potassium diets reduce stroke mortality in both SP-SHRs and Dahl SS rats. (b) High potassium diets reduce stroke and death rate in hypertensive rats, even when blood pressure is matched.

From references [117, 118].

In order to identify possible blood pressure-independent mechanisms, Rigsby and colleagues fed low- and high-potassium diets to normotensive Wistar Kyoto rats.119 This study demonstrated improved cerebrovascular structure in the high potassium group, specifically increased luminal and outer diameters of the middle cerebral artery. This study also evaluated the effect of potassium supplementation on experimentally produced cerebral ischaemia and demonstrated significant reductions in the physical size of the resulting cerebral infarct in the high potassium group.

The extensive work conducted by Young and colleagues is based on a premise that diets high in potassium result in an increased extracellular potassium concentration, which is nonetheless within the physiological range, and that low-potassium diets result in a relative and asymptomatic potassium depletion.120,121 This concept is supported by the observation that total body potassium and extracellular potassium concentration are positively associated. The detailed work of this group has aimed to assess how increased extracellular potassium concentration, achieved through increased intake, may be protective of stroke through inhibition of vascular atherosclerotic lesion formation and progression. In this series of in vitro and in vivo studies, compelling evidence has been accumulated, demonstrating the following effects of increased extracellular potassium concentration: decreased vascular smooth muscle cell proliferation, decreased vascular smooth muscle cell migration, decreased free radical formation, reduced low-density lipoprotein cholesterol oxidation, and decreased platelet aggregation. These findings support a role of increased potassium intake in prevention of thrombus formation, a major cause of ischaemic stroke.120

Achieving a minimum intake target for potassium

A number of approaches may be adopted in order to achieve a minimum daily intake target for potassium; these are considered as follows.

Dietary modification

Dietary modification is likely to represent an effective method to increase potassium intake in both a primary and secondary prevention setting. Appropriate dietary modification would involve substituting potassium-low foods for fruits, vegetables, beans, and nuts, as seen in the DASH diet.122,123 Much of this advice already forms the basis of public health programmes promoting healthy eating. Despite this, adapting existing campaigns to include information specific to high-potassium diets is likely to further bolster support and the inclusion of potassium contents on food labelling would be a practical measure enabling individuals to make healthier food choices. The generally high cost of achieving a minimum daily intake of potassium through dietary change may be an important obstacle for the socially deprived and as such may widen health inequalities. Therefore, dietary advice should be carefully tailored to local populations and individuals for primary and secondary prevention respectively.

Use of salt substitutes

Salt substitutes are commercially available salt mixtures in which a proportion of the sodium chloride is substituted for potassium and magnesium salts. Subsequently, the use of these products in place of salt can effectively reduce sodium consumption while concurrently increasing potassium intake. A meta-analysis of small randomized clinical trials showed that salt substitution reduces blood pressure effectively and suggests that such strategies are effective at lowering SBP and DBP, which supports a nutritional approach to preventing hypertension124 (Sodium and potassium intake, blood pressure, and cardiovascular prevention Figure 44.6.10(online)). The use of such substitutes in place of salt has been shown to effectively lower blood pressure in subjects in rural China.125 Moreover, although some difference in flavour is detectable, salt substitutes have been shown to be acceptable to such a population.126 The blood pressure reduction achieved through the use of salt substitutes in rural China can be attributed to the fact that a large proportion of dietary salt is added to food in the home. However, this is not true of much of the economically developed world where the majority of dietary salt is contained within processed foods, added at the point of manufacture.127

Figure 44.6.10(online) Forest plot of the effects of salt substitutes on blood pressure.

Figure 44.6.10(online) Forest plot of the effects of salt substitutes on blood pressure.

Reproduced from Hu J, et al. Effects of salt substitute on pulse wave analysis among individuals at high cardiovascular risk in rural china: A randomized controlled trial. Hypertension Res 32, 282–288 (2009) with permission from Springer Nature.

The use of salt substitutes as a method to increase potassium intake may therefore have varying impacts according to geographical region. In the developing world, salt substitution could represent an important public health intervention in both a primary and secondary prevention setting. In economically developed countries, salt substitution in the home may be more appropriate as a supplementary measure, targeting secondary prevention or those of high CV risk. As a public health intervention, the use of salt substitutes by the food industry should be considered, for example in bread production, where salt use is particularly high.127 A lowering of the dietary sodium:potassium ratio, however achieved, has a significant effect on blood pressure in randomized controlled trials.128 Therefore, fortification of appropriate foods with potassium is a similar method which could have an important public health impact. Recently, the Committee on Toxicity of the Scientific Advisory Committee on Nutrition in the United Kingdom, after careful assessment of the evidence, has concluded that at a population level the potential benefits of using potassium-based sodium replacers to help reduce sodium in foods outweigh the potential risks. The beneficial effects at an individual level are likely to be small in size but will impact a large proportion of the population.129

Potassium supplementation for prevention

Secondary prevention targets those with the highest risk of stroke and with proportionately worse outcomes. Therefore a strategy of targeted oral potassium supplementation may be justified in this setting. Supplementation with a potassium salt, such as potassium chloride, represents a cheap intervention to easily achieve a minimum daily target and is likely to be acceptable to patients in the setting of secondary prevention. Potassium supplementation trials to date have demonstrated no adverse effects with daily prescriptions of between 25 and 104 mmol.130,131 Moreover, potassium supplementation, particularly through the use of slow-release formulations, is generally considered safe.132 Hyperkalaemia is most likely to occur due to renal insufficiency rather than excessive intake and as such, monitoring of renal function should be conducted during supplementation.

Potassium supplementation for secondary stroke prevention represents a clear research opportunity. However, to date no randomized controlled trial has aimed to demonstrate feasibility, safety, or blood pressure lowering in a cohort of stroke patients. The evaluation of these outcomes is clearly a prerequisite to a study of definitive endpoints (stroke recurrence). Further research in this area should aim to evaluate the potential benefit of different daily doses of potassium on the above-mentioned outcomes and the evaluation of the use of different potassium salts (i.e. citrate, bicarbonate, and chloride) is also warranted.

Potassium: conclusion

Animal, epidemiological, and clinical evidence points to an important role that potassium intake may play both in contributing to the pathophysiology of stroke (low intake) and as an effective intervention tool (higher intake) for both primary (dietary increase) and secondary (supplementation) prevention of stroke and its complications. Randomized clinical trials are needed to support the potential, highly cost-effective, clinical guidelines for the prevention of stroke recurrence.

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Further reading

Aburto NJ, Hanson S, Gutierrez H, Hooper L, Elliott P, Cappuccio FP. Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses. BMJ 2013;346:f1378.Find this resource:

Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP, Meerpohl JJ. Effect of lower sodium intake on health: systematic review and meta-analyses. BMJ 2013;346:f1326.Find this resource:

Cappuccio FP, Capewell S, Lincoln P, McPherson K. Policy options to reduce population salt intake. BMJ 2011;343:402–5.Find this resource:

Cobb LK, Anderson CA, Elliott P, Hu FB, Liu K, Neaton JD, Whelton PK, Woodward M, Appel LJ, American Heart Association Council on Lifestyle and Metabolic Health. Methodological issues in cohort studies that relate sodium intake to cardiovascular disease outcomes: a science advisory from the American Heart Association. Circulation 2014;129:1173–86.Find this resource:

Cook NR, Cutler JA, Obarzanek E, Buring JE, Rexrode KM, Kumanyika SK, Appel LJ, Whelton PK. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP). BMJ 2007;334:885–8.Find this resource:

D’Elia L, Barba G, Cappuccio FP, Strazzullo P. Potassium intake, stroke, and cardiovascular disease a meta- analysis of prospective studies. J Am Coll Cardiol 2011;57:1210–9.Find this resource:

He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials. Lancet 2011;378:380–2.Find this resource:

Mozaffarian D, Fahimi S, Singh GM, Micha R, Khatibzadeh S, Engell RE, Lim S, Danaei G, Ezzati M, Powles J, Global Burden of Diseases Nutrition and Chronic Diseases Expert Group. Global sodium consumption and death from cardiovascular causes. N Engl J Med 2014;371:624–34.Find this resource:

Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER, Simons-Morton DG, Karanja N, Lin PH, DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (dash) diet. Dash-sodium collaborative research group. N Engl J Med 2001;344:3–10.Find this resource:

Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 2009;339:b4567.Find this resource: