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Published in final edited form as: Auton Neurosci. 2022 Jan 20;238:102947. doi: 10.1016/j.autneu.2022.102947

Dietary sodium and health: how much is too much for those with orthostatic disorders?

Joseph M Stock 1, Gisela Chelimsky 2, David G Edwards 1, William B Farquhar 1
PMCID: PMC9296699  NIHMSID: NIHMS1777878  PMID: 35131651

Abstract

High dietary salt (NaCl) increases blood pressure (BP) and can adversely impact multiple target organs including the vasculature, heart, kidneys, brain, autonomic nervous system, skin, eyes, and bone. However, patients with orthostatic disorders are told to increase their NaCl intake to help alleviate symptoms. While there is evidence to support the short-term benefits of increasing NaCl intake in these patients, there are few studies assessing the benefits and side effects of long-term high dietary NaCl. The evidence reviewed suggests that high NaCl can adversely impact multiple target organs, often independent of BP. However, few of these studies have been performed in patients with orthostatic disorders. We conclude that the recommendation to increase dietary NaCl in patients with orthostatic disorders should be done with care, keeping in mind the adverse impact on dietary NaCl in people without orthostatic disorders. Modest, rather than robust, increases in NaCl intake may be sufficient to alleviate symptoms but also minimize any long-term negative effects.

Keywords: Dietary salt, sodium recommendations, blood pressure variability, target organ damage, orthostatic disorders

1. INTRODUCTION

Historically, high dietary salt (NaCl) has been shown to increase blood pressure (BP) in those who are salt-sensitive (Grillo et al., 2019). Moreover, high dietary salt can modestly increase plasma osmolality and serum sodium. For example, an increase of sodium from a low sodium diet of 460 mg of sodium per day to a high sodium diet of 6,900 mg of sodium per day increased serum sodium from 138.6 to 140.2 mOsm/kg H2O and increased plasma osmolality from 286.4 to 288.5 mmol/L in healthy adults, respectively (Ramick et al., 2019). High dietary salt can adversely impact multiple target organs, sometimes independent of changes in BP (Farquhar et al., 2015; Robinson et al., 2019). Decreasing habitual dietary salt is a common dietary recommendation for the general population and is endorsed by the American Heart Association (AHA) (Lloyd-Jones et al., 2010) and the most recent U.S. Dietary Guidelines for Americans (U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020–2025. 9th Edition., 2020). Salt reduction decreases BP and may prevent the development of hypertension (Grillo et al., 2019; He et al., 2013). Nonetheless, average intake of salt among the U.S. population is estimated to be ~8,700 mg of salt per day (~3,400 mg of sodium) (Fig 1) (Quader et al., 2017). In spite of some controversial findings associating a low sodium diet with increased morbidity and mortality (García-Ortiz et al., 2012; O’Donnell et al., 2011), there is a broad consensus that 8,700 mg of salt per day (3,400 mg of sodium) is too high, and public health would be improved and healthcare costs reduced if this value were decreased (Benjamin et al., 2019; Bibbins-Domingo et al., 2010; Cappuccio et al., 2011; Webb et al., 2017).

Figure 1.

Figure 1.

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Dietary sodium recommendations and possible target organ damage. AHA’s recommended daily sodium limit for the general population is less than 2,300 mg of sodium per day (i.e., less than 6,000 mg of salt per day), whereas clinicians often recommend those with orthostatic disorders to consume greater than 2,300 mg of sodium per day. Possible target organ damage of consuming a diet high in sodium is thought to occur through BP independent mechanisms. Created with BioRender.com

AHA proposed an attainable goal to decrease sodium intake to less than ~6,000 mg of salt per day (2,300 mg of sodium). However, more than 6,000 mg of salt per day (2,300 mg of sodium) is routinely prescribed for patients with orthostatic disorders like orthostatic hypotension (OH), postural tachycardia syndrome (POTS), idiopathic orthostatic tachycardia, and syncope (Fig 1). They are told to increase their salt intake, to help combat their symptoms. The American Society of Hypertension recommendations vary from 6,000 – 10,000 mg of salt per day (2,400 – 4,000 mg of sodium) (Loughlin et al., 2020; Shibao et al., 2013) and others have suggested 10,000 – 20,000 mg of salt per day (4,000 – 8,000 mg of sodium) (Figueroa et al., 2010) for patients with OH. Salt recommendations from the Canadian Cardiovascular Society are 10,000 mg of salt per day (4,000 mg of sodium) (Raj et al., 2020) and a Heart Rhythm Society Expert Consensus Statement recommended 10,000 – 12,000 mg of salt per day (4,000 – 4,800 mg of sodium) (Sheldon et al., 2015) for patients with POTS. Based upon the broad range of recommendations, sodium recommendations appear to not be different between POTS and OH. It appears that increasing dietary salt in patients with orthostatic disorders may similarly increase plasma sodium compared to healthy controls (Garland et al., 2021), however, randomized studies assessing the efficacy and long-term side effects of these recommendations are lacking (Loughlin et al., 2020). Some recommend increasing dietary salt if urinary sodium excretion is less than 170 mmol/24 hours (~3,900 mg of sodium/24 hours) and this is typically done by adding 1,000 – 2,000 mg of sodium to the diet three times per day (El-Sayed and Hainsworth, 1996; Lanier et al., 2011; Loughlin et al., 2020; Low and Singer, 2008). One study showed that in patients with posturally related syncope who excreted less than ~3,900 mg of sodium per day, two months of ~2,400 mg of sodium supplementation per day improved orthostatic intolerance, peripheral vascular control, and cerebral autoregulation (Claydon and Hainsworth, 2004).

A recent systematic review and meta-analysis by Loughlin et al. (2020) showed that, in patients with orthostatic intolerance syndromes, increased salt in the diet improved orthostatic symptoms (mean follow-up of 44 days), decreased orthostatic tachycardia (−4 bpm), increased time to pre-syncope (+1.57min), and increased head up tilt or standing systolic BP (12 mmHg), but only resulted in a small increase in seated or supine systolic BP (1 mmHg) compared to controls. Therefore, in this patient group, a high salt diet seems to affect mainly the orthostatic BP. The only short term side effects reported included nausea and intolerance to salt with little effect on supine BP (Loughlin et al., 2020).

While there is evidence to support the short-term benefits of increasing daily salt intake in patients suffering from orthostatic disorders to alleviate symptoms (Loughlin et al., 2020), there is a paucity of research on the long-term effects of this practice. In this article we will review the evidence demonstrating that high dietary salt can adversely impact multiple target organs, independent of BP (Fig 1). For consistency and clarity, we will refer to sodium in mg (1mmol/L of sodium = 23mg of sodium). This review, and the literature as a whole, does not generally include those with orthostatic disorders. However, the findings from this review may inform recommendations in these patients and advocate future research on the long-term effect of high dietary salt in those with orthostatic disorders.

2. DIETARY SALT AND BLOOD PRESSURE VARIABILITY

Very short-term (beat-to-beat) and short-term (over 24hr period) spontaneous fluctuations in BP is termed BP variability (BPV) (Parati et al., 2013). Augmented BPV is associated with elevated left ventricular (LV) mass index (Sega et al., 2002), cardiac and cerebrovascular events (Verdecchia et al., 2007), the severity and rate of progression of end-organ damage (Mancia and Parati, 2003; Parati et al., 1987; Sarafidis et al., 2018), and cardiovascular (CV) events and mortality (Stevens et al., 2016). Mechanisms contributing to BPV include modulation of central and reflex autonomic function, emotional and behavior fluctuations, and changes in humoral systems (Parati et al., 2013). Since dietary salt has been shown to exaggerate sympathetic activity responses (Simmonds et al., 2014), it is possible that the high salt-induced sympathetic activity may act on BPV in this pathway.

Data from salt-resistant, normotensive rodents suggest that excess dietary salt intake increases BPV (Simmonds et al., 2014). However, data in humans are conflicting. One study found that high habitual dietary salt intake positively correlated with 24hr BPV and independently predicted 24hr BPV in hypertensives across the lifespan, independent of resting BP (Ozkayar et al., 2016). Conversely, our lab recently demonstrated that 10 days of a high dietary sodium intake (~7,000 mg/day) did not increase beat-to-beat BPV or 24hr BPV compared with medium (~2,300 mg/day) or low (~1,000 mg/day) dietary sodium intake in young salt-resistant normotensives (Migdal et al., 2020a). The differences in these studies may reside in the study population (older hypertensives vs. younger normotensives, respectively). As such, it is important to consider study population and length of dietary intervention (habitual vs. controlled feeding) when interpreting results. More studies are needed to test the reproducibility of these prior findings and to evaluate if these results stand true in other diverse populations such as patients with orthostatic disorders.

To that effect, orthostatic hypotension is associated with increased day-to-day BPV in an elderly population-based sample (Cremer et al., 2020). Also, increasing severity of orthostatic intolerance symptoms in patients with orthostatic intolerance is associated with greater BPV (Sunwoo et al., 2017). To the best of our knowledge, to date there have not been any published studies that have investigated the effect of sodium supplementation on BPV in patients with orthostatic disorders. Dietary sodium or urinary excretion of sodium were not reported in the two aforementioned studies in patients with orthostatic hypotension (Cremer et al., 2020) and intolerance (Sunwoo et al., 2017). It is possible that sodium supplementation could augment BPV in patients with orthostatic disorders, although this has not been tested.

3. DIETARY SALT AND TARGET ORGAN EFFECTS

3.1. Vasculature

3.1.1. Arterial Stiffness

Carotid-femoral pulse wave velocity (PWV) is the gold-standard measure of central arterial stiffness (Laurent et al., 2006) and is a strong predictor of CV events and mortality (Vlachopoulos et al., 2010). Arterial stiffness (PWV) is increased in patients with OH (Cremer et al., 2020; Sung et al., 2014). To the best of our knowledge there have not been any studies that investigated the effect of sodium supplementation on arterial stiffness in patients with orthostatic disorders. Nonetheless, our lab demonstrated that 7 days of high dietary sodium (6,900 mg/day) increased PWV in young and middle-aged normotensive adults when compared to a low sodium diet (460 mg/day), however, there was no effect when covaried for mean arterial pressure (Muth et al., 2017). This suggests that the increase in PWV was dependent on blood pressure. Interestingly, another set of studies provided key evidence that high dietary salt is associated with higher PWV, independent of BP (Avolio et al., 1986, 1985). Lastly, a systematic review of clinical trials demonstrated that average reduction in sodium intake of ~2,000 mg/day was associated with a 2.84% reduction in PWV and may be, at least in part, independent of changes in BP (D’Elia et al., 2018).

3.1.2. Endothelial Function

Endothelial dysfunction is widely accepted as an antecedent of CV disease (CVD) (Anderson et al., 2011; Gokce et al., 2002; Perticone et al., 2001), therefore assessments of endothelial function can be used as an important early detection tool of vascular dysfunction. Flow-mediated dilation (FMD) and cutaneous vascular conductance are two primary macro and microvascular, respectively, non-invasive measurements of endothelial function in humans (Brunt and Minson, 2011; Holowatz et al., 2008; Thijssen et al., 2019). Assessments of macro- and microvascular function have been shown to be largely mediated by nitric oxide (NO) (Green et al., 2014; Patik et al., 2021). Growing evidence suggests that high salt decreases NO bioavailability by increasing reactive oxygen species (ROS) (Greaney et al., 2012; Ramick et al., 2019), largely superoxide (O2−), and by decreasing endogenous antioxidant activity (Guers et al., 2019). Specifically, high salt increases O2− by increasing NADPH oxidase and scavenging NO to form peroxynitrate, which oxidizes the eNOS cofactor tetrahydrobiopterin, resulting in less NO production and more O2− production (Patik et al., 2021). Indeed, local infusion of ascorbic acid (non-specific ROS scavenger), Tempol (O2− scavenger), or apocynin (NADPH oxidase inhibitor) restored microvascular function in response to local heating in subjects consuming a 7-day high sodium (6,900 mg/day) diet (Ramick et al., 2019). High salt has also been shown to decrease endogenous antioxidant activity by decreasing superoxide dismutase. For example, superoxide dismutase expression decreased in rats fed a high salt diet when compared to a normal salt diet (Guers et al., 2019). Collectively, the increased ROS production and decreased antioxidant activity promotes a pro-oxidative stress environment.

Cell culture studies have shown that hypernatremia causes stiffening, shortening, and degradation of the endothelial glycocalyx (Martin et al., 2018; Oberleithner et al., 2011; Schierke et al., 2017). Damage to the glycocalyx, a protective barrier between the lumen and endothelial cells (Möckl, 2020), could facilitate sodium entry into the endothelial cells, thereby contributing to salt-induced endothelial dysfunction. Also, high sodium conditions may increase inflammation and immune cell response (Hucke et al., 2016; Kleinewietfeld et al., 2013; Wenzel et al., 2019; Zhang et al., 2015), which have been associated with decreased endothelial function (Bhagat and Vallance, 1997; Kovacs et al., 2006; Zhang, 2008). Other potent vasoconstrictors may play a role in endothelial function with high salt. Indeed, a reduction in endothelin-1 with sodium restriction has been suggested to mediate improvements in endothelial and vascular smooth muscle function (Dickinson et al., 2014). Lastly, high salt intake has been shown to increase copeptin, which suggests arginine vasopressin may be increased during sodium loading (Tasevska et al., 2014). Together, these endogenous pro-constrictor agents that are increased during a high salt diet could potentially increase vascular tone and stiffness and decrease endothelial function. For a more thorough evaluation of the mechanisms by which dietary salt contributes to endothelial dysfunction, we direct the reader to a recently published review by our lab group (Patik et al., 2021).

Numerous studies have demonstrated that high dietary salt decreases FMD when compared to a lower salt diet in healthy adults (Cavka et al., 2016; DuPont et al., 2013; Lennon-Edwards et al., 2014; Matthews et al., 2015). Importantly, some of these studies determined that this effect occurred in salt-resistant adults, suggesting the effect of high dietary salt on endothelial function is independent of BP (DuPont et al., 2013; Matthews et al., 2015). Specifically, a 7-day high sodium (6,900 mg/day) diet reduced brachial artery FMD, compared to a low sodium diet (460 mg/day), with no difference in the reduction of FMD between salt-sensitive and salt-resistant adults (Matthews et al., 2015). In a sub-set of subjects, we demonstrated salt-resistant adults on the high sodium diet, had augmented vascular tone and attenuated low-flow mediated constriction (Shenouda et al., 2020), an emerging complimentary measure of FMD used to assess endothelial function (Gori et al., 2016, 2008). High dietary salt has also been shown to decrease measures of microvascular function when compared to a lower salt diet (Eisenach et al., 2012; Tzemos et al., 2008) and in some cases this effect appears to be independent of BP (Barić et al., 2019; Greaney et al., 2012; Ramick et al., 2019). For example, our lab demonstrated that cutaneous vascular conductance was decreased during local heating when subjects were on a 7-day high sodium (~8,000 mg/day) diet compared to a low sodium (460 mg/day) diet and that this was independent of BP (Greaney et al., 2012). Similarly, some have shown that lowering salt intake improved endothelial function independent of changes in BP (Dickinson et al., 2014; Jablonski et al., 2013), while the evidence of the effect of salt intake on endothelium independent vasodilation is conflicting (Dickinson et al., 2014; DuPont et al., 2013).

Patients with POTS demonstrate impaired endothelial function as shown by decreased FMD when compared to healthy controls in some (Chopoorian et al., 2021), but not others (Liao et al., 2010; Smith et al., 2021). Recently, Smith et al. (2021) examined the effect of a high sodium diet on cardiovascular health. Interestingly, they showed that a 6-day high sodium (6,900 mg/day) diet in female patients with POTS did not worsen endothelial function when compared to a low sodium (230 mg/day) diet (Smith et al., 2021). They suggest this finding may be because high dietary sodium has been shown to have a greater effect on FMD in men compared to women (Lennon-Edwards et al., 2014) but this has not been demonstrated in other studies. It is also possible no change in FMD may be a floor effect of the influence of high sodium on endothelial function in patients with orthostatic disorders, as one study showed patients with POTS have impaired FMD compared to healthy controls (Chopoorian et al., 2021). However, Smith et al. (2021) did not show differences in FMD between patients with POTS and healthy controls. As evident of the paucity of research, more investigations need to occur to 1) definitively determine endothelial function in patients with orthostatic disorders compared to healthy controls; and 2) investigate by what mechanisms endothelial function may be impacted by sodium supplementation in patients with orthostatic disorders.

3.2. Renal

The renin angiotensin aldosterone system (RAAS) is critical in the chronic maintenance of BP through neurohumoral alterations which affect vascular tone as well as sodium and water retention. Briefly, the macula densa cells are activated in response to a decreased sodium load in the distal convoluted tubule. The juxtaglomerular cells secrete prorenin and then activate renin. Renin then cleaves angiotensinogen, produced by the liver, into angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin converting enzyme. Angiotensin II binds to angiotensin II type 1 and/or type 2 receptors which can be found in the kidneys, adrenal cortex and medulla, systemic vasculature, cardiac cells, and brain. In short, when acting through angiotensin type I receptors, Ang II increases renal absorption of sodium in the proximal tubules, stimulates the release of aldosterone from the adrenal cortex which increases sodium reabsorption in the distal tubule and collecting duct, vasoconstricts systemic arterioles, stimulates thirst and water intake via the hypothalamus, and stimulates the release of vasopressin from the posterior pituitary which increase water reabsorption in the kidney by inserting aquaporin channels at the collecting duct. As a result of these actions, vascular tone, sodium and water retention are increased. Together these actions maintain blood volume and BP. Conversely, when sodium intake is high the RAAS is suppressed to prevent sodium retention, volume expansion, and an increase in blood pressure. However, when the RAAS is not suppressed in the presence of a high sodium diet, BP can increase in those who are “salt-sensitive” via vasoconstriction as well as sodium and fluid retention, causing an expansion of extracellular fluid volume. High dietary salt can also have deleterious effects on the kidneys through mechanisms independent of BP. Some rodent studies suggest that the intra-renal renin angiotensin aldosterone system is involved in the adverse effects of dietary salt on the kidney, independent of BP (Susic et al., 2011; Thomson et al., 2006; Varagic et al., 2008). For example, angiotensin II type 1 receptor blockade in hypertensive rats on a high salt diet ameliorated sodium-induced renal damage, kidney mass index, and proteinuria, despite no change in BP (Varagic et al., 2008). Another study showed increased NADPH activity and pro-oxidative stress mRNA expression in rats fed high salt (Kitiyakara et al., 2003). Lastly, others found that a high salt diet induced renal hypertrophy and collagen deposition in normotensive and hypertensive rats, possibly via TGF-B1 dependent pathways, suggesting the effect of high salt on renal structural changes is independent of BP (Yu et al., 1998).

Overtime, high dietary sodium may be associated with development of chronic kidney disease (CKD). Indeed, high salt intake is associated with biomarkers of early-stage renal damage, namely urinary vanin-1, neutrophil gelatinase-associated lipocalin, kidney injury molecule (Hosohata, 2017; Hosohata et al., 2016). If a high salt diet persists, this can lead to impairments in renal function and may ultimately progress to CKD. A systematic review found that a high sodium diet (>4,600 mg/day) is associated with adverse renal outcomes like proteinuria and declines in estimated glomerular filtration rate (eGFR) (Smyth et al., 2014). Specifically, high sodium intake was associated with declining eGFR in people without CKD (Lin et al., 2010) and increased risk of end stage renal disease in patients with CKD (Vegter et al., 2012). Indeed, Smyth et al. (2014) found that hypertensives consuming a higher salt diet over 10-years had a more rapid decline in eGFR compared to those consuming a lower salt diet (Ohta et al., 2013). A separate review found that when the average dietary sodium excretion was reduced from ~4,100 mg/day to ~2,400 mg/day, proteinuria and albuminuria decreased in people with CKD (Garofalo et al., 2018). This also held true in those without CKD when dietary sodium excretion was lower (~2,000 vs. ~3,900 mg/day) (P. A. Swift et al., 2005).

As expected, patients with POTS on a fixed dietary sodium intake (~3,400 mg/day) for 3 days had a lower plasma volume compared to healthy controls (Raj et al., 2005). However, the patients with POTS lacked a higher plasma renin activity and had a paradoxical lower concentration of aldosterone compared to healthy controls (Raj et al., 2005). This anomaly of the RAAS in patients with POTS may be contributing toward low water retention resulting in low blood volume and displaying of orthostatic intolerance symptoms. Another study showed that plasma volume was increased when patients with POTS consumed high dietary sodium (6,900 mg/day) for 6 days compared to a sodium consumption recommended by AHA for healthy adults (2,300 mg/day) (Garland et al., 2021). Furthermore, there was a compensatory reduction in plasma renin activity and aldosterone during the high compared to lower sodium condition (Garland et al., 2021). Lastly, more information is needed on the effects of a high sodium condition on renal function in patients with orthostatic disorders.

3.3. Cardiac

Rodent studies document an adverse effect of high sodium on pathological LV remodeling that can lead to varying degrees and types of LV dysfunction (Doi et al., 2000; Inoko et al., 1994; Klotz et al., 2006; Varagic et al., 2008; Yu et al., 1998). Rodent and cell studies suggest that sodium-induced LV hypertrophy and stiffening may be due to cellular hypertrophy in the vascular smooth muscle cells and myocardial cells, increased fibrosis, collagen expression, and TGF-B1 (Gu et al., 1998; Yu et al., 1998). In humans, high salt has been shown to be associated with increased congestive heart failure (He et al., 2002), coronary events and cardiovascular mortality independent of BP (Tuomilehto et al., 2001). Additionally, high sodium is associated with LV mass and thickness (Du Cailar et al., 2010; Haring et al., 2015; van der Westhuizen et al., 2019), in some cases even when controlled for BP (Jin et al., 2009; Rodriguez et al., 2011). Interestingly, one of these studies (Du Cailar et al., 2010) found that after a 3 year follow up period, LV mass continued to increase in hypertensive adults, regardless of sodium excretion, in those who had high plasma aldosterone concentrations. As such, it has been postulated that a high sodium intake may be a crucial contributing factor toward the development of LV hypertrophy in states of elevated mineralocorticoids and RAAS activity (Burnier et al., 2007). Consistent with this conclusion, both severe 12-week and moderate 12-month dietary salt restriction reduced LV mass, however, there was minimal improvement in LV function (Ferrara et al., 1984; Jula and Karanko, 1994). The mechanisms at play here are unclear but may include a reduction in preload and afterload. Regarding cardiac function, 14 days (Musiari et al., 1999) and as short as 5 days (Tzemos et al., 2008) of high dietary salt supplementation impaired LV diastolic function and this may be independent of LV mass (Langenfeld et al., 1998). However, these findings do not appear to be independent of high salt-induced BP in both normotensives (Tzemos et al., 2008) and hypertensives (Langenfeld et al., 1998), and may be due to increased LV stiffness, which can precede changes in LV function.

Another possible explanation of compromised LV structure and function induced by high salt may be due to augmented pressure wave reflection which can increase pulsatile load on the left ventricle (Chirinos and Segers, 2010a, 2010b). A 7-day high sodium (6,900 mg/day) diet has been shown to increase arterial pressure wave reflection compared to low sodium (460 mg/day) (Muth et al., 2017) and in another study this was independent of brachial BP (Starmans-Kool et al., 2011). When wave reflections return to the heart earlier and in greater magnitude, mid-to-late systolic afterload is increased. Over the course of years, central hemodynamic profiles like this can have deleterious effects on left ventricular structure and function, leading to increased LV mass or heart failure (Chirinos et al., 2012; Hashimoto et al., 2008; Zamani et al., 2015). Future studies need to determine whether reducing wave reflections via a low salt diet leads to improvements in LV structure or function.

Pressure wave reflections are increased in patients with OH (Sung et al., 2014). Additionally, OH is independently associated with higher risk of CVD outcomes in patients with CKD (Rouabhi et al., 2021). Separately, OH also predicts adverse cardiac changes such as LV hypertrophy (Magnusson et al., 2016) and is associated with incident heart failure with the exclusion of other co-morbidities (Jones et al., 2012). Yet, the acute or chronic effect of sodium supplementation on cardiac health in patients with orthostatic disorders is not known. Therefore, researchers should focus future investigations on the effect of sodium supplementation on cardiac structure and function as well as pressure wave reflections in patients with orthostatic disorders.

3.4. Cerebrovascular

High dietary salt also has deleterious effects on the cerebrovasculature. High dietary salt is associated with increased risk of stroke independent of BP (Perry and Beevers, 1992), and increase stroke related deaths (Li et al., 2012). Multiple rodent studies have demonstrated that cerebral autoregulation and reactivity are impaired with a high salt intake (Allen et al., 2019; Durand and Lombard, 2013; Lombard et al., 2003), some independent of BP (Cosic et al., 2016; Matic et al., 2018). The suggested mechanisms of impaired cerebrovascular function in rodent studies during a high salt diet revolve around reduced cerebral NO bioavailability from increased oxidative stress, specifically superoxide, and high salt-induced angiotensin II suppression which may decrease superoxide dismutase in the cerebral arteries (Allen et al., 2019; Durand and Lombard, 2013; Matic et al., 2018), with potentially a minor role of increased inflammation (Cosic et al., 2016). Longitudinal data indicates that impaired cerebrovascular reactivity to hypercapnia is a predictor of stroke in humans (Markus and Cullinane, 2001; Silvestrini et al., 2000). Unfortunately, to the best of our knowledge there have not been any chronic or habitual studies that assessed cerebral autoregulation or reactivity in humans on a high dietary salt diet. Yet, our lab recently demonstrated that an acute high sodium meal (1,495 mg) did not impair cerebrovascular reactivity during a hyper and hypocapnia perturbation in healthy young adults compared to an acute low sodium meal (138mg) (Migdal et al., 2020b).

OH is predictive of ischemic stroke (Eigenbrodt et al., 2000), and OH is present in ~¼ of patients with a stroke (Phipps et al., 2012). In response to a normocapnic head up tilt test, cerebral autoregulation is impaired in patients with POTS as demonstrated by decreased cerebral blood flow with greater variability compared to healthy controls (Ocon et al., 2009). Indeed two months of ~2,400 mg of sodium supplementation per day improved cerebral autoregulation among orthostatic intolerance and other symptoms (Claydon and Hainsworth, 2004) in patients with posturally related syncope who excreted less than ~3,900 mg of sodium per day. This study shows the benefit of a two-month sodium supplementation, however, the effect of longer term (years) sodium interventions in patients with POTS and OH are unknown.

3.5. Autonomic Function

Increased sympathetic outflow is related to poor CV, renal, and metabolic outcomes (Charkoudian and Wallin, 2014; Fisher et al., 2009). Acute intracerebroventricular and intravenous infusions of sodium increase sympathetic outflow in rodents (Kinsman et al., 2017; Stocker et al., 2015) and humans (Farquhar et al., 2006). Studies in hypertensives showed that extremely low dietary sodium intake (≤500mg/day) increased sympathetic outflow (Abrahão et al., 2002; Anderson et al., 1989; Grassi et al., 1997). However, consuming an extremely low sodium diet (≤500mg/day) is not representative of the population at large and is far below AHA’s ideal sodium intake of 1,500mg/day. Considering this, our lab showed that a more realistic 10-day reduction in sodium of 2,300mg/day to 1,000mg/day did not affect basal sympathetic outflow (Babcock et al., 2019). Interestingly, we reported that neurovascular transduction, which is the change in beat-by-beat blood flow and BP in response from muscle sympathetic nerve activity bursts, decreased on the low salt diet (Babcock et al., 2019). More studies are needed to investigate if a high salt diet that is representative of the population’s daily sodium intake (~3,400mg/day) alters sympathetic outflow when compared to a recommended salt diet (AHA’s recommended sodium limit of 2,300mg/day). Rodent and cell studies have identified specialized sodium chloride sensing neurons in the circumventricular organs (which lack a complete blood brain barrier), such as the organum vasculosum laminae terminalis and subfornical organ (Kinsman et al., 2017; Shi et al., 2007; Stocker et al., 2013). These neurons can sense increased serum and cerebrospinal fluid sodium but what is less clear is which sodium-sensing channel initiates these responses. Sodium-sensing channels that receive the most attention include furosemide-sensitive channels such as NKCC2 (Konopacka et al., 2015), benzamil-sensitive channels such as ENaC (Abrams and Osborn, 2008; Nishimura et al., 1998), and Nax-positive glial cells (Noda and Hiyama, 2015; Nomura et al., 2019). Nonetheless, when these sodium sensitive neurons are stimulated, they send a signal to the hypothalamic paraventricular nucleus onto the rostral ventrolateral medulla which ultimately controls sympathetic outflow to target organs that act on BP regulation (Stocker et al., 2013). Furthermore, these sodium sensing areas of the brain are responsible for initiating the release of arginine vasopressin, which acts a systemic vasoconstrictor (Henderson and Byron, 2007), in the presence of hypernatremia (Tasevska et al., 2014), which may be potentially through NKCC2 mechanisms (Konopacka et al., 2015). The effect of high dietary salt on sympathetic outflow may in part depend on central sodium sensing. Though central sodium sensing has been investigated in rodents (Kinsman et al., 2017; Shi et al., 2007; Stocker et al., 2013), human studies are lacking. Future studies should further investigate central sodium sensing in humans to determine the link between high salt and sympathetic activity in humans.

Although resting supine MSNA does not appear to be different between patients with POTS and healthy controls, patients with POTS demonstrated an exaggerated sympathetic outflow responses with orthostasis and baroreflex challenges (Bonyhay and Freeman, 2004; N. M. Swift et al., 2005). In contrast, hypotensive episodes are suggested to be closely related to a lack of sympathetic outflow (Mano and Iwase, 2003). For example, there is diminished sympathetic outflow during a head-up tilt test in healthy adults after 14-day head-down bed rest induced OH (Kamiya et al., 2003). However, studies of sympathetic outflow at rest and orthostasis are lacking in patients with chronic OH. Nonetheless, it appears as if the etiology of orthostatic disorder (POTS vs. OH) may determine the sympathetic outflow response. Norepinephrine, a catecholamine marker of sympathetic activity, is elevated in patients with POTS and a 6-day high sodium (6,900 mg/day) diet appears to reduce norepinephrine (Garland et al., 2021). Yet it is unknown what the effect sodium supplementation has directly on sympathetic outflow. Future investigations should determine 1) if sodium supplementation alters resting sympathetic outflow in patients with POTS and OH like seen in healthy adults; and 2) if improvements in heart rate and blood pressure to orthostatic stresses from sodium supplementation are influenced by changes in sympathetic outflow in POTS and OH.

3.6. Skin, Eyes, and Bone

3.6.1. Skin

Sodium loading has been shown to increase non-osmotic storage of sodium without commensurate water retention. As explained in reviews (Selvarajah et al., 2018; Wiig et al., 2018), sodium ‘leakage’ into the skin has been suggested to be primarily caused by paracellular diffusion and vascular damage of the glycocalyx and endothelium. Then sodium, and not water, binds to glycosaminoglycans, but when the sodium binding capacity of glycosaminoglycans is exceeded, interstitial hypertonicity develops (Titze et al., 2004, 2003). Macrophages are then signaled and lead to a cascade of events that secretes vascular endothelial growth factor (VEGF)-C to cause lymphangiogenesis (MacHnik et al., 2010, 2009). The enhanced lymphatic system allows for sodium to return back into the blood to be excreted through the kidneys. These mechanisms allow the skin to serve as a primary storage compartment of excess sodium and may play a key function in acute buffering volume and BP changes with high salt intake (Selvarajah et al., 2018; Wiig et al., 2018). Interestingly, one study showed that skin sodium to potassium ratio increased with 7 days of dietary sodium loading (4,600 mg/day pill supplement) in healthy humans and this may be influenced by sex (Selvarajah et al., 2017). Specifically, men experienced a significant increase in skin Na:K and no change in BP and weight. Conversely women did not have an increase in skin Na:K but did have an increase in BP and weight. Though why these sex differences exist is speculative, this along with animal studies (Titze et al., 2003) suggests the skin may play a key role in retaining sodium in effort to buffer blood volume and pressure with high salt intake. Sodium deposition in the skin appears to be more prevalent in populations that have salt-sensitive BP and is associated with hypertension and age (Kopp et al., 2013), hyperlipidemia (Crescenzi et al., 2018), diabetics on hemodialysis (Kopp et al., 2018), and LV hypertrophy in those with CKD unaffected by BP (Schneider et al., 2017). It has been suggested that chronic high skin sodium may impair VEGF-C induced lymphangiogenesis and this may reduce efflux of sodium from the skin to the systemic circulation and attenuate the vasodilatory response to salt loading (Selvarajah et al., 2018). Additional studies are needed to determine if the mechanisms of short-term accumulation of skin sodium differs from long term accumulation and whether decreasing skin sodium accumulation is effective in those with co-morbidities.

3.6.2. Bone

Several cross-sectional studies showed that elevated sodium excretion was associated with lower bone mineral density (BMD) in Asian women, but not men (Cao et al., 2017; Kim et al., 2015; Park et al., 2016). Additionally, a meta-analysis found that high dietary sodium, but not sodium excretion, increased the risk of osteoporosis, but not decreased BMD, in a more heterogenous sample of studies (Fatahi et al., 2018). Conversely, a prospective observational study of women in the United States demonstrated that sodium intake was not associated with BMD at common sites of bone degradation nor was associated with incident fractures (Carbone et al., 2016). These conflicting results may be dependent on the method of sodium assessment (intake vs. excretion), subject population, ethnicity, skin pigmentation, sex, and age (pre- vs. post-menopausal) (Fatahi et al., 2018). The mechanisms by which sodium may influence bone are unclear. One suggested mechanism is that excessive sodium intake may increase bone resorption biomarkers and decrease parathyroid hormone secretion (Cappuccio, 2013; Fatahi et al., 2018; Goulding, 1981; Goulding and Gold, 1986; Lin et al., 2003). Together these alterations may play a key role in decreasing calcium reabsorption, osteoblast differentiation and proper bone formation (Cappuccio, 2013; Fatahi et al., 2018; Parfitt, 1976; Sellmeyer et al., 2008). Future mechanistic studies are needed to further elucidate the effect of dietary salt on bone health.

3.6.3. Eyes

Observational studies in humans suggest that high salt is related to cataracts (Bae et al., 2015; Cumming et al., 2000; Tavani et al., 1996) and sodium restriction in rats decreases cataracts (Rodriguez-Sargent et al., 1989). The mechanisms of cataractogenesis due to high sodium intake is unclear but may be due to a rise in the aqueous humor and lenticular sodium concentrations causing an expansion of extracellular fluid volume and development of lens opacities (Bae et al., 2015; Mirsamadi et al., 2012). Salt loading has also been shown to damage the eyes by causing neuronal retinal edema (Qin et al., 2009), increased retinal venular but decreased retinal arteriole tortuosity (Wenstedt et al., 2021), and can aggravate neuronal retinal degeneration induced by ischemia-reperfusion injury (Li et al., 2019). These results are suggested to be through increased VEGF, inflammatory cytokines, and reduced bioavailability of NO (Li et al., 2019; Wenstedt et al., 2021). Interestingly, compared to a normal salt diet, a low salt diet in Sprague Dawley rats reduced oxygen-induced retinopathy in part by reducing neovascularization, VEGF, inflammatory cytokines, and mRNA of mineralocorticoid and angiotensin type 1 receptors (Deliyanti et al., 2014).

4. PERSPECTIVES

Increasing salt and fluid intake is one of the first non-pharmacologic changes introduced when managing orthostatic disorders (Arnold and Raj, 2017; Palma and Kaufmann, 2020; Stewart et al., 2018). The potential adverse effects of a high salt diet underscore the need to use salt judiciously in patients with orthostatic disorders. Caution should be exercised when interpreting the limited research as many unknowns remain regarding long-term effects of a high salt diet on other measures of cardiovascular health and target organ damage in patients with orthostatic disorders. Furthermore, questions persist concerning when to intervene and appropriate treatment. Systematic reviews and health organizations (Lanier et al., 2011; Loughlin et al., 2020; Low and Singer, 2008) suggest that patients with sodium excretions of <170 mmol/24 hours (~3,900 mg of sodium/24 hours) should supplement with 1,000 – 2,000 mg of sodium 3 times/day. This frequently echoed recommendation comes from a seminal paper that had a limited sample size (El-Sayed and Hainsworth, 1996), showing that 15 of 21 subjects given an additional 120 mmol/day (~2,800 mg/day) of sodium for 8 months improved orthostatic tolerance and expanded plasma volume. Further, these patients that responded to dietary sodium supplementation had an initial daily sodium excretion of <170mmol/day (~3,900 mg/day). Similarly, in pediatric and adolescent patients with POTS, sodium excretion of <124 mmol/24 hours seemed to be an indicator of the effectiveness of sodium supplementation (40–60 mg/kg per day for 1 month) (Zhang et al., 2012). As such, clinicians should consider utilizing 24-hour urinary sodium analyses for patients to better gauge which patients are viable candidates for the recommended sodium supplementation. Further, clinicians should weigh the potential risks and benefits of prescribing sodium to patients whose sodium excretion exceeds 170 mmol/24 hours (for adults) or perhaps 124 mmol/24 hours (for children) and consider alternative modes of treatment. The role of patient demographics (i.e., age, sex, pregnancy, ethnicity, and body mass) and method of salt supplementation should also be considered when prescribing dietary salt. For instance, prescribing patients to consume a diet higher in salt may promote an increased intake of salty processed foods that are calorie-dense and nutrient-deficient, which may lead to other comorbidities. On the other hand, pill capsules may cause GI distress and plasma volume loss via vomiting and dehydration (Fu and Levine, 2018). One solution to this may be the use of enteric coated capsules that do not release the sodium until it leaves the stomach and enters the small intestine. There is a clear need for future research to compare the effectiveness, dietary tolerance, and cardiovascular outcomes of different methods of salt supplementation.

5. CONCLUSION

The literature suggests high dietary sodium has deleterious effects on blood pressure and major organ systems. This is concerning given the high habitual dietary sodium intake in the U.S. The effect of high dietary sodium in patients with orthostatic disorders is less studied although high dietary sodium is routinely prescribed to these patients. As such, more research is needed to investigate these areas. We suggest that the recommendation to increase dietary salt in patients with orthostatic disorders should be done with care. Modest, rather than robust, increases in salt intake may be sufficient to alleviate symptoms but also minimize any long-term negative effects.

ACKNOWLEDGEMENTS

We would like to thank Darshil Patel, Ronald McMillan, and Nathan Romberger for their assistance in gathering references and proofreading this review article.

FUNDING

Some of the authors have been supported by the following grants which have also contributed to some of the original work cited here: NIH P20 GM113125; NIH R01 HL128388; NIH R01 HL104106.

ABBREVIATIONS

AHA

American heart association

BMD

Bone mineral density

BP

Blood pressure

BPV

Blood pressure variability

CKD

Chronic kidney disease

CV

Cardiovascular

CVD

Cardiovascular disease

eGFR

Estimated glomerular filtration rate

ENaC

Epithelial sodium channel

eNOS

Endothelial nitric oxide synthase

FMD

Flow-mediated dilation

fMRI

Functional magnetic resonance imaging

OH

Orthostatic hypotension

LV

Left ventricle

mRNA

Messenger ribonucleic acid

NaCl

Salt

NADPH

Nicotinamide adenine dinucleotide phosphate

NKCC2

Na-K-2Cl co-transporter

NO

Nitric oxide

O2−

Superoxide

POTS

Postural orthostatic tachycardia syndrome

PWV

Pulse wave velocity

ROS

Reactive oxygen species

TGF-B1

Transforming growth factor beta 1

VEGF

Vascular endothelial growth factor

Footnotes

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