The Effect of Electrolytes on Blood Pressure: A Brief Summary of Meta-Analyses

Nutrition is known to exert an undeniable impact on blood pressure with especially salt (sodium chloride), but also potassium, playing a prominent role. The aim of this review was to summarize meta-analyses studying the effect of different electrolytes on blood pressure or risk for hypertension, respectively. Overall, 32 meta-analyses evaluating the effect of sodium, potassium, calcium and magnesium on human blood pressure or hypertension risk were included after literature search. Most of the meta-analyses showed beneficial blood pressure lowering effects with the extent of systolic blood pressure reduction ranging between −0.7 (95% confidence interval: −2.6 to 1.2) to −8.9 (−14.1 to −3.7) mmHg for sodium/salt reduction, −3.5 (−5.2 to −1.8) to −9.5 (−10.8 to −8.1) mmHg for potassium, and −0.2 (−0.4 to −0.03) to −18.7 (−22.5 to −15.0) mmHg for magnesium. The range for diastolic blood pressure reduction was 0.03 (−0.4 to 0.4) to −5.9 (−9.7 to −2.1) mmHg for sodium/salt reduction, −2 (−3.1 to −0.9) to −6.4 (−7.3 to −5.6) mmHg for potassium, and −0.3 (−0.5 to −0.03) to −10.9 (−13.1 to −8.7) mmHg for magnesium. Moreover, sufficient calcium intake was found to reduce the risk of gestational hypertension.


Introduction
Hypertension is the major leading risk factor for atherosclerosis and several diseases, especially renal and cardiovascular disorders, including myocardial infarction, stroke, and heart failure [1]. Blood pressure is influenced by various genetic and lifestyle factors including nutrition [2]. In this regard, sodium is an important mineral which, besides its functions in fluid balance, action potential generation, digestive secretions and absorption of many nutrients, also plays an important role in blood pressure regulation with a reduced sodium intake being associated with a reduction in systolic and diastolic blood pressure [3]. Therefore, independent of body weight, sex and age, too much dietary salt (sodium chloride) is regarded as an established risk factor for hypertension [4]. Concomitant to sodium reduction, higher potassium intake or supplementation has also been repeatedly shown to reduce the blood pressure of especially hypertensive persons (reviewed in [5]). Therefore, the American Heart Association recently proposed a dietary potassium intake of 3500-5000 mg/day, in addition to the well-known advice to reduce the consumption of dietary sodium (<1500 mg/day or at least 1000 mg/day decrement) for adults with normal and elevated blood pressure [6]. In addition, the WHO recommends that sodium consumption should be less than 2000 mg (5 g of salt) and potassium intake at least 3510 mg for adults per day [7].
In addition to the blood pressure lowering effects of sodium reduction or higher potassium intake also in several studies and meta-analyses calcium supplementation has been shown to exert

Materials and Methods
This review summarizes meta-analyses of publications studying the effect or association between electrolytes and blood pressure. In this regard, we conducted a search in PubMed, Scopus, and Google scholar databases by entering the search terms "(hypertension or blood pressure) and (sodium or potassium or calcium or magnesium or chloride or sulphur or sulphate or phosphorus or phosphate or salt) and (meta-analysis or metaanalysis)". The literature search was conducted in June 2018 with a 10-year publication restriction in order to ensure more recent studies. Search results were limited to English language articles.

Eligibility Criteria
Meta-analyses of randomized controlled trials or observational studies were included in this review. The availability of (mean) blood pressure reductions and/or relative risk estimates e.g., risk ratios, odds ratios, weighted mean difference and confidence intervals were a prerequisite for the inclusion of the meta-analyses. Reviews and summaries of meta-analyses, meta-analysis not including the primary outcome, (e.g., blood pressure reduction or hypertension risk), or meta-analysis with combined effects of two minerals were excluded.
The initial search revealed a total of 2182 articles ( Figure 1). After screening irrelevant, duplicate and other studies not meeting the inclusion criteria 32 meta-analyses were included in this review [8,11,.

Data Extraction
Two reviewers (C.E and N.K) independently extracted the information from the papers. A third reviewer (S.I) rechecked the data and discrepancies were resolved through consensus. Study outcomes with defined number of trials/participants, study type/aims, patient characteristics, average study duration, minerals dosage (diet/supplements) and dietary modification were extracted from the selected meta-analyses. Also (mean) change in systolic and diastolic blood pressure (SBP and DBP), or relative risks (RR), odds ratios or effect sizes with 95% CI were extracted as main outcomes measures from the papers.

Results
We identified meta-analyses for sodium, potassium, calcium and magnesium. No meta-analyses were found for the electrolytes chloride, sulphur and phosphorus.
Moreover, two meta-analyses included observational studies, including 10-18 trials with 8093-134,916 participants. The observational study of Talukder et al. [36] observed a mean difference in blood pressure of 0.1 (−0.2 to 0.3) mmHg for SBP and 0.2 (0.1 to 0.4) mmHg for DBP with exposure of 4-405 mg/L water sodium levels. Subasinghe et al. [37] showed effect sizes of 1.36 (1.24 to 1.48) and 1.28 (1.13 to 1.45) for high salt exposure (6.9 to 42.3 g/day) on hypertension risk in rural and urban populations of low-and-middle income countries, respectively.

Calcium Intake in Form of Supplements or Diets and Risk for Gestational Hypertension or Blood Pressure Lowering
We identified six meta-analyses which evaluated the association of dietary calcium intake on the risk for gestational hypertension [8,[43][44][45] or the effect on blood pressure [46,47]. Five meta-analyses of randomized controlled trials with a range of 4-16 trials and 2947-36,806 participants were included. The follow up intervention period was between 8 weeks to 7 years and the calcium intake was found to be between 0.5 g/day to 2 g/day. The results showed RR ranging from 0.55 to 0.91 for gestational hypertension while, the meta-analysis of Cormick et al., [47] found a mean difference of −1.4 (95% confidence interval: −2.2 to −0.7) mmHg for SBP and −1 (−1.5 to −0.5) mmHg for DBP reduction in normotensive people.
Furthermore, we found one meta-analysis including 16 observational trials of 757-41,214 pregnant women showing a lower OR for gestational hypertension [OR: 0.63 (95% CI = 0.41-0.97)] for highest versus lowest category of calcium intake [45].
Most of the meta-analyses showed that calcium supplements were associated with a reduced risk of gestational hypertension (Table 3). Besides, based on the results from the meta-analysis of Wu and Sun [46] calcium plus vitamin D supplementation non-significantly slightly increased SBP with no effects on DBP.

Effect of Magnesium on Blood Pressure or Hypertension Risk
Eight meta-analyses of randomized control trials (n = 5) and observational studies (n = 3) were included to summarize the effects of magnesium on blood pressure or association with hypertension risk, respectively [11,45,[48][49][50][51][52][53] The randomized control trials included 7-28 number trials with 135-1694 of participants with the trial durations varying between 3-24 weeks. Magnesium intake ranged between 120-1006 mg/day. The summary showed SBP reductions in the range of −0.2 (95% confidence interval:  (Table 4). However, the meta-analysis of Rosanoff and Plesset (2013) [51], which showed the largest effects, only included a small sample of treated hypertensive patients, which probably responded highly to magnesium. When omitting this meta-analysis, the blood pressure lowering effects of magnesium would switch to a rather low to moderate level.
Moreover, observational studies showed a lower risk for hypertension with increasing magnesium intake [52] or higher circulating magnesium levels [53], respectively.  Overall pooled net effect of diets: This meta-analysis shows that dietary interventions (including low sodium diets) provide clinically significant net blood pressure reductions, and that some dietary patterns may be more effective than others.    Reduction in SBP was significant in both black and white people and in women and men. Significant effects on blood pressure were seen in hypertensives and normotensives. Dose-response relation: the greater the reduction in salt intake, the greater the fall in blood pressure.   Effect seen in people with hypertension but not in those without hypertension. Intake above 120 mmol/day did not seem to have any additional benefit. Potassium may be more effective in reducing blood pressure at higher levels of sodium consumption. Potassium supplementation is associated with reduction of blood pressure in patients who are not on antihypertensive medication, and the effect is significant in hypertensive patients.    Assessing the effect of magnesium supplementation on blood pressure. Adults from 12 different countries were included. and DBP of 2-3 mmHg. Magnesium supplementation appears to achieve a small but clinically significant reduction in blood pressure. A significant inverse linear association was observed between circulating magnesium levels and incidence of hypertension. SBP = Systolic blood pressure; DBP = Diastolic blood pressure; NA = not applicable.

Discussion
The major findings of this review were especially that sodium (salt) reduction and a higher intake of potassium have convincing blood pressure lowering effects. In addition, higher magnesium intake is suggested to possibly reduce blood pressure, especially in patients with hypertension. Moreover, sufficient calcium intake confers a protective effect regarding the risk for gestational hypertension.
There are several mechanistical explanations for the association between high sodium intake and blood pressure like enhanced reabsorption and retention of filtered sodium through the renal tubules [54], or activation of the brain renin-angiotensin-aldosterone system (RAAS), which is suggested to increase blood pressure through angiotensin II and aldosterone promoting locally oxidative stress and activating the sympathetic nervous system [55]. Furthermore, based on the "vasodysfunction theory" of salt induced hypertension, salt loading results in subnormal decreases in systemic vascular resistance leading to an increase in blood pressure [56]. In this regard salt sensitivity, which varies among individuals, is suggested to play an important role [3,55].
In addition to blood pressure, in a recent systematic review and meta-analysis of randomized controlled trials it was analyzed that restriction of dietary sodium intake can reduce arterial stiffness, as expressed by carotid-femoral pulse wave velocity [57].
In addition to sodium modification, several studies and meta-analysis showed that potassium supplements reduce blood pressure and also the risk of hypertension [58]. Suggested mechanisms of the blood pressure lowering effects of potassium are (reviewed in [5]): improvement of endothelial function and NO release, vasodilatation by lowering cytosolic smooth muscle cell calcium, increasing natriuresis, and lowering the activity of the sympathetic nervous system. Furthermore the supportive blood pressure reducing effects of sodium modification in combination with potassium is well-documented [59].
Besides the interdependent effect of sodium and potassium, calcium and magnesium have also been implicated in the regulation of blood pressure [60]. Based on our results, magnesium showed a moderate blood pressure reducing effect in general, while the effects of calcium were primarily restricted to the prevention of gestational hypertension. The potential antihypertensive effects of magnesium are for example suggested to be related to calcium channel blockage, increases in nitric oxide, and better endothelial function [10]. In vascular smooth muscle cells, magnesium antagonizes Ca 2+ by inhibiting transmembrane calcium transport and calcium entry with low magnesium levels causing an increase in intracellular free Ca 2+ concentration and subsequently vascular contraction [61].
On the other hand, low dietary calcium intake is shown to be a risk factor for the development of hypertension especially for women with a history of gestational hypertension [62]. In this regard the World Health Organization recommends daily calcium supplementation of 1.5-2.0 g oral elemental calcium for pregnant women in populations with low dietary calcium intake to reduce the risk of pre-eclampsia and related complications [63].
Lifestyle modifications including weight loss, exercise, and healthy diets are proved to be important predictors to lower blood pressure or the risk for hypertension, respectively. For example, the Canadian hypertension education program guidelines (2016) proposed health behavior management for the prevention of hypertension such as physical exercise, weight management, limited alcohol consumption, stress management, reduce sodium intake and recommended dietary modification as the preferred method of increasing potassium intake (in patients who are not at risk of hyperkalemia) to get additional nutritional benefits of whole foods over prescribed supplements [64]. Similarly, the study findings of a systematic review and meta-analysis of randomized control trials showed that healthy dietary patterns including the dietary approaches to stop hypertension (DASH) diet, Nordic diet, and Mediterranean diet significantly lowered systolic and diastolic blood pressure [65].

Conclusions and Future Perspectives
Our brief exploration of meta-analyses showed that lowering sodium and increasing potassium intake would exert convincing blood pressure lowering effects, especially in hypertensive patients. The maximum extent of systolic blood pressure lowering was approximately in the order of 8 to 9 mmHg, which roughly equals a monotherapy with an antihypertensive drug [66]. This reflects the significant importance of healthy nutrition, in this case salt reduction and increase of dietary potassium intake, on blood pressure. Our summary of meta-analytic reviews also suggests that higher magnesium intake may exert beneficial effects on blood pressure, although the results were rather moderate. However, in some (treated) hypertensive patients ("high-responders") higher magnesium intake might result in larger effects. So, increasing/optimizing dietary magnesium intake could also be a helpful recommendation in patients with hypertension. Furthermore, there is convincing evidence that increasing/optimizing calcium intake can lower the risk for gestational hypertension, especially in women with initial low calcium intake.
We did not find any meta-analyses summarizing the effects of chloride, phosphorus and sulphur on blood pressure or hypertension risk. In general, few studies are available, which assessed the effect of these electrolytes on blood pressure. There are indications from observational studies that there might be some effects, however robust evidence is missing. For example, a very recent systematic review from McClure et al. (2019) did not detected a consistent association between total dietary phosphorus intake and blood pressure [67].
Relating to earlier studies replacing the chloride component of salt with other anions like bicarbonate or citrate might be a certain strategy, which could not only beneficially affect blood pressure but could show co-benefits regarding a (western) diet induced metabolic acid load [68]. Obviously, randomized (controlled) trials are necessary to study this assumption. Also, future clinical trials could determine the effect of different electrolytes on blood pressure by patients' self-assessment of blood pressure with new validated mHealth devices, like a previous study in obese individuals has shown [69].