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nutrients
Review
Sodium Intake as a Cardiovascular Risk Factor:
A Narrative Review
David A. Jaques 1, * , Gregoire Wuerzner 2and Belen Ponte 1
Citation: Jaques, D.A.; Wuerzner, G.;
Ponte, B. Sodium Intake as a
Cardiovascular Risk Factor: A
Narrative Review. Nutrients 2021,13,
3177. https://doi.org/10.3390/
nu13093177
Academic Editor: Hirofumi Tanaka
Received: 8 August 2021
Accepted: 10 September 2021
Published: 12 September 2021
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1Division of Nephrology and Hypertension, Department of Medicine, Geneva University Hospitals,
1205 Geneva, Switzerland; belen.ponte@hcuge.ch
2Division of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospitals,
1011 Lausanne, Switzerland; gregoire.wuerzner@chuv.ch
*Correspondence: David.Jaques@hcuge.ch
Abstract:
While sodium is essential for human homeostasis, current salt consumption far exceeds
physiological needs. Strong evidence suggests a direct causal relationship between sodium intake
and blood pressure (BP) and a modest reduction in salt consumption is associated with a meaningful
reduction in BP in hypertensive as well as normotensive individuals. Moreover, while long-term
randomized controlled trials are still lacking, it is reasonable to assume a direct relationship between
sodium intake and cardiovascular outcomes. However, a consensus has yet to be reached on the
effectiveness, safety and feasibility of sodium intake reduction on an individual level. Beyond indirect
BP-mediated effects, detrimental consequences of high sodium intake are manifold and pathways
involving vascular damage, oxidative stress, hormonal alterations, the immune system and the
gut microbiome have been described. Globally, while individual response to salt intake is variable,
sodium should be perceived as a cardiovascular risk factor when consumed in excess. Reduction
of sodium intake on a population level thus presents a potential strategy to reduce the burden of
cardiovascular disease worldwide. In this review, we provide an update on the consequences of
salt intake on human health, focusing on BP and cardiovascular outcomes as well as underlying
pathophysiological hypotheses.
Keywords: salt; sodium; blood pressure; hypertension; cardiovascular
1. Introduction
Sodium (Na+), contained in dietary salt, is essential for human homeostasis. For
millions of years, our ancestors ate less than 0.25 g of salt per day, while the current
average daily consumption approaches 10 g in most countries [
1
,
2
]. Such an increase
over a comparatively modest time span imposes a significant physiological challenge in
evolutionary terms. Excessive sodium intake is thought to adversely affect our health
through effects on blood pressure (BP) and cardiovascular damages. Consequently, three
million deaths were attributed to high salt intake in 2017 [
3
]. Given that the majority
of cardiovascular burden affects individuals with high-normal BP or mild hypertension,
dietary and lifestyle programs including salt reduction constitute attractive and simple
public health measures [
4
]. Despite general agreement that excessive sodium consumption
is globally harmful, controversies still exist on the net benefit of sodium intake reduction
on a population level and the levels that should be targeted [
5
]. Moreover, far from a
simplistic cause–effect relationship, pathophysiological mechanisms linking sodium intake
and cardiovascular outcomes are diverse and intricate.
In this paper, we review the available evidence on the association between sodium
intake, BP and cardiovascular diseases. We more specifically discuss major pathophysio-
logical hypotheses underlying this relationship.
Nutrients 2021,13, 3177. https://doi.org/10.3390/nu13093177 https://www.mdpi.com/journal/nutrients
Nutrients 2021,13, 3177 2 of 15
2. Sodium Intake, Blood Pressure and Cardiovascular Outcomes
2.1. Blood Pressure
Convincing evidence suggest a direct and positive association between sodium intake
and BP regulation. At the population level, the INTERSALT (International Study of Sodium,
Potassium and Blood Pressure) study was the first international study to look at this
association [
6
]. This cross-sectional analysis described the relationship between sodium
intake based on 24-h urine collection and BP in over 10,000 participants aged 20 to 50 from
39 countries. The authors reported a significant association between sodium excretion and
BP at the individual level. Furthermore, sodium intake was also associated with age-related
hypertension, suggesting that sodium could also have a long-term impact in addition
to its immediate effect on BP regulation. More recently, the PURE (Prospective Urban
Rural Epidemiology) study, a large international report including more than 100,000 adult
participants from 18 countries, was published [
7
]. A positive curvilinear relationship
between sodium intake and BP was described. In line with INTERSALT, this relationship
was stronger in older individuals and those consuming low potassium diets. The UK
Biobank study is the largest report to date with urinary electrolyte data and BP measurements
in more than 450,000 adult subjects [
8
]. Authors found a positive linear association between
urinary sodium excretion and BP. On top of those cross-sectional data, longitudinal studies
are also available. In the EPOGH (European Project on Genes in Hypertension) study,
investigators followed a group of 1499 participants without cardiovascular disease over
6.1 years [
9
]. Compared to baseline values, increased sodium intake was associated with
an increase in BP after adjusting for potential confounders. In such observational studies, a
systolic blood pressure increase of 2 to 3 mmHg for each 1 g/day increment in estimated
sodium excretion was generally reported [7,8].
In addition to epidemiological studies, numerous randomized controlled trials have
confirmed the impact of dietary sodium on BP values and control of hypertension (
Table 1
).
The DASH-sodium (Dietary Approaches to Stop Hypertension) study included around
400 pre-hypertensive individuals [
10
]. Authors evaluated the impact on BP control of three
different diets with various sodium intake (1.5 g/day, 2.4 g/day and 3.3 g/day) consumed
for 30 days. On average, systolic BP values decreased by 2.1 mmHg when comparing
3.3 g/day to 2.4 g/day diets. An additional 4.6 mmHg decrease was reported when com-
paring 2.4 g/day to 1.5 g/day diets, highlighting a dose-dependent relationship between
sodium consumption and BP regulation. In the TOHP-II (Trial of Hypertension Prevention)
study, investigators evaluated the impact of long-term sodium intake reduction and weight
loss on blood pressure in 2382 individuals not taking antihypertensive medications using
a factorial design [
11
]. Despite a sodium intake target below 1.8 g/day, mean sodium
intake was 3.1 g/day and 3.2 g/day at 18 and 36 months, respectively. In comparison,
mean sodium intake was 4.0 g/day at 36 months in the control group. Consequently, the
improvement in BP values and hypertension prevalence achieved in the intervention group
decreased over time. As such, the primary efficacy endpoint, defined as the mean decrease
in diastolic BP, was not significant at 36 months. The TONE (Trial of Nonpharmacological
Intervention in the Elderly) trial also tested the impact of sodium reduction and weight loss
on BP control and cardiovascular events in 975 treated hypertensive adults aged between
60 and 80 [
12
]. As in the TOHP-II study, the sodium intake target in the intervention
group was 1.8 g/day. At 3-months follow-up, a 3.4 mmHg reduction in systolic BP was
achieved in the intervention group. Thirty months later, a higher proportion of patients
were withdrawn from antihypertensive medication in the intervention group compared to
the control group.
Nutrients 2021,13, 3177 3 of 15
Table 1. Selected RCTs on sodium intake, blood pressure and cardiovascular outcomes.
Study Population Intervention Outcome
Sodium intake and blood pressure
DASH-sodium
n= 412
Pre-HT; Age 47;
Male 41%; White 40%
Sodium intakes of 3.3, 2.4 and
1.5 g/day
SBP reduction of 2.1 mmHg (3.3 vs 2.4 g/day)
and 4.6 mmHg (2.4 vs 1.5 g/day) (p< 0.001)
TOHP-II
n= 2382
Not HT; Age 43.9;
Male 65.7%; White 79.3%
Sodium intake reduction to
80 mmol/day DBP reduction of 0.7 mmHg (p= 0.10)
TONE
n= 975
Treated HT; Age 65.8;
Male 53%; White 76%
Sodium intake reduction to
80 mmol/day SBP reduction of 3.4 mmHg (p< 0.001)
Sodium intake and cardiovascular outcomes a
Morgan et al.
n= 77
Untreated HT; Age 57.1;
Male 100%; White NA
Sodium intake reduction to
70–100 mmol/day Relative risk of CV event: 1.16 (0.39–3.45)
TOHP-I
n= 744
Not HT; Age 43.4;
Male 71.4%; White 77.2%
Sodium intake reduction to
80 mmol/day Relative risk of CV event: 0.51 (0.29–0.91)
TOHP-II
n= 2382
Not HT; Age 43.9;
Male 65.7%; White 79.3%
Sodium intake reduction to
80 mmol/day Relative risk of CV event: 0.88 (0.65–1.20)
TONE
n= 975
Treated HT; Age 65.8;
Male 53%; White 76%
Sodium intake reduction to
80 mmol/day Relative risk of CV event: 0.80 (0.53–1.21)
Abbreviations: RCT, randomized controlled trial; HT, hypertension; SBP systolic blood pressure: DBP, diastolic blood pressure; CV,
cardiovascular. Age is expressed as mean.
a
: Represented by follow-up studies including individuals who previously participated in RCT
of sodium intake reduction. Data from Taylor et al. meta-analysis.
Finally, meta-analyses of interventional trials globally confirmed an antihypertensive
effect of sodium reduction. A first meta-analysis, which included 36 randomized controlled
trials and 6736 adult individuals showed that reduced sodium intake was associated with a
decrease in BP of 3.39/1.54 mmHg without an adverse effect on renal function, or metabolic
or endocrine profile [
13
]. Of note, in sensitivity analyses, taking into account the study’s
duration, the authors reported a decrease in this beneficial effect with longer follow-up.
A second meta-analysis included randomized controlled trials investigating a modest
reduction in sodium intake with a minimum follow-up of four weeks [
14
]. A total of
34 trials and 3230 participants were identified. Investigators showed that a sodium intake
reduction of 4.4 g/day decreased BP of 5.4/2.8 mmHg in hypertensive individuals and
2.4/1.0 mmHg in normotensive individuals.
Although the beneficial effect on BP is clear, it has been previously suggested that
sodium intake reduction could potentially lead to harmful consequences. A meta-analysis
of 167 trials randomizing patients to low versus high sodium diets concluded that sodium
reduction resulted in an increase in renin, aldosterone, catecholamine and cholesterol
levels [
15
]. However, this report included studies involving large reductions in sodium
intake over a very short period of time. Such an abrupt decrease in sodium consumption
is expected to enhance several compensatory mechanisms, in contrast to what has been
described with a modest reduction over longer periods [
16
]. Second, a dose-response
relationship between sodium intake and BP has consistently been shown across obser-
vational as well as interventional trials, suggesting that benefits of sodium reduction
could extend to very low values [
6
,
10
,
17
,
18
]. Third, studies have generally shown that
sodium reduction allowed a significantly greater BP fall in older, hypertensive and Afro-
American individuals [
6
,
12
]. Such findings can be linked to varying sensitivities of the
renin–angiotensin–aldosterone system (RAAS) regulation in different populations [
19
,
20
].
Finally, sodium reduction has synergistic effects with pharmacological and conservative
measures on BP control. The DASH-sodium trial showed that a combination of low sodium
and a healthy diet has a greater effect on BP reduction than individual measures [
10
]. The
TONE and TOHP-II trials reported similar additive effects of sodium reduction with weight
reduction [
11
,
12
]. Taking into account such compensatory mechanism, a randomized
Nutrients 2021,13, 3177 4 of 15
controlled trial showed that sodium reduction allowed for a further reduction of BP in
hypertensive individuals treated with captopril as compared to normal sodium intake [
21
].
Sodium intake has varying effects on different subjects. In its simplest definition
“salt sensitivity” is a physiological trait by which BP exhibits changes parallel to sodium
intake [
22
]. Conversely, in “salt resistant” individuals, BP does not vary according to salt
loading. In humans, salt sensitivity is a continuous, normally distributed, quantitative
characteristic and any distinction between salt sensitive and salt resistant individuals is,
thus, somewhat arbitrary [
23
]. Although the definition and identification of salt sensitivity
lacks uniformity, it is suggested that up to 50% of hypertensive and 25% of normotensive in-
dividuals are salt sensitive [
24
]. Overall, the elderly, women and those with Afro-American
ethnicity, as well as patients suffering from chronic kidney disease, diabetes and primary
aldosteronism, are more prone to salt sensitivity [
25
–
27
]. Given the pathophysiological
complexity of hypertension, identification of genetic factors associated with salt sensi-
tivity is an intensive field of research [
28
]. Gene–environment interactions have been
characterized where polymorphisms in RAAS genes modified the effect of sodium intake
on BP in Japanese workers [
29
]. Such considerations could partially explain heteroge-
neous findings in clinical studies as well as facilitate personalized approaches to sodium
intake recommendations.
Globally, the causal relationship between sodium intake and BP control is, thus, well
established, and modest reduction in salt consumption is associated with a meaningful
reduction in BP on a population level. However, as the full effect of sodium intake reduction
on BP control is not reached until several weeks, results of interventional trials could have
underestimated the magnitude of this effect as most studies lasted a few weeks only [
14
,
30
].
On the other hand, the few existing long-term interventional trials showed that maintaining
a lower salt intake on a prolonged time period is challenging from an individual perspective
given the societal food environment [11,31].
2.2. Cardiovascular Outcomes
As sodium intake reduction lowers BP in normotensive and hypertensive individuals,
it could also be expected to improve cardiovascular outcomes. However, evidence from
large, long-term, randomized controlled trials on an individual level is currently lacking.
Over the years, numerous cohort studies have been published exploring the rela-
tionship between sodium intake and cardiovascular outcomes. Several meta-analyses
have pooled those studies and come to the conclusion that salt consumption directly and
negatively impacts cardiovascular prognosis [
13
,
32
,
33
]. Interestingly, several independent
cohort studies have reported a U-shaped association where both low and high sodium
consumption increased the risk of cardiovascular events and mortality when compared
with moderate intake [
34
–
37
]. Despite this, major potential confounding factors impede
definite conclusions and a causative association between low sodium intake and increased
cardiovascular risk for several reasons. First, reverse causality likely introduces a signifi-
cant bias as those studies included subjects at high cardiovascular risk, probably already
advised to lower their salt consumption. The increased morbidity associated with de-
creased sodium intake might therefore represent the confounding effect of underlying
cardiovascular diseases. Second, most of those studies relied on a single morning fasting
urine sample to estimate 24 h sodium consumption. Kawasaki’s formula is usually used in
such circumstances, including parameters such as age, gender, height and weight [
38
]. As
these variables are themselves potentially associated with the adverse prognosis, this could
further confound the association between sodium intake and the considered outcomes. As
such, 24 h urinary collection should be considered the gold standard to reliably estimate
sodium intake in such a setting. Globally, cohort studies that relied on multiple 24 h urinary
collections universally reported a direct positive linear relationship between sodium intake
and cardiovascular events [
39
–
42
]. Moreover, post hoc analysis of the data from the TOHP
trial has shown that the association between mortality and sodium intake was J or U-shaped
only when using formula-derived spot estimates but linear when measured on 24 h urine
Nutrients 2021,13, 3177 5 of 15
collections [
43
]. In agreement with these reports, an observational study recently showed
that 24 h estimates of sodium consumption derived from formulae based on spot urine
measurement overestimated sodium consumption at lower levels and underestimated
sodium consumption at higher levels when compared to directly measured 24 h sodium
urinary excretion [
44
]. Consequently, while a linear association existed between systolic
BP and measured 24 h sodium excretion, formula-derived estimates resulted in a J-shaped
association, thus altering the true relationship between dietary sodium and BP.
As patients with chronic kidney disease are at increased risk of cardiovascular events
compared with the general population, the effect of sodium consumption in this specific
sub-group is of pivotal importance. To answer this question, a prospective cohort study
included more than 3700 participants with chronic kidney disease and evaluated the as-
sociation between urinary sodium excretion and clinical cardiovascular events with a
median follow-up of 6.8 years [
41
]. Higher sodium consumption was associated with
increased risk of cardiovascular events in this population. Patients suffering from heart
disease also constitute a sub-group of special relevance. Left ventricular hypertrophy
is considered a major predictor of cardiovascular prognosis and, since left ventricular
hypertrophy is directly caused by hypertension, it could be expected that salt consumption
would indirectly induce ventricular remodelling through raised BP [
45
]. However, there
exists increasing evidence suggesting that sodium intake may directly induce left ven-
tricular hypertrophy, independent of BP [
46
,
47
]. A review of nine cross-sectional studies
described a strong correlation between sodium intake as assessed by 24 h urinary collection
and left ventricular mass, independent of relevant confounders as well as BP [
48
]. In a
prospective cohort study including more than 10,000 participants, higher salt consumption
was associated with increased risk of developing heart failure over a follow-up of almost
20 years [
49
]. This association was, however, significant in overweight individuals only.
Conversely, a low salt diet is a mainstay of congestive heart failure management. As such,
in a cohort of 443 patients with preserved ejection fraction, those who were recommended
a sodium-restricted diet had lower risk of death and hospital readmission at 30 days [50].
Estimation of sodium consumption on a population level is more reliable than at an
individual level [51]. Overall, evidence derived from public health interventions describe
a robust relationship between sodium intake and cardiovascular outcomes. For example,
Finland, and more recently the UK, have led salt reduction campaigns in an effort to
improve national health and both were successful at significantly reducing BP and car-
diovascular burden over the course of several years [
52
,
53
]. In Finland, salt consumption
decreased from 14 g/day in 1972 to 9 g/day in 2002 [
53
]. During this time period, mean
systolic and diastolic BP decreased by 10 mmHg and cardiovascular mortality by 75%.
While other factors could have played a role, obesity and alcohol consumption have both
increased during this time period suggesting a pivotal impact of sodium restriction. In
the UK, salt consumption decreased from 9.5 g/day in 2003 to 8.1 g/day in 2011 [
52
] and
a mean decrease in systolic BP of 2.7 mmHg was reported after adjustment for potential
confounders, while stroke and ischemic heart disease mortality decreased by 36%.
Finally, in a cluster randomized controlled trial including five veteran’s retirement
homes in Taiwan [
54
], sodium intake was reduced from 5.2 to 3.8 g/day in the intervention
group in combination with increased potassium, resulting in a reduction in cardiovascular
mortality. Follow-up studies have also been conducted including individuals who previ-
ously participated in randomized controlled trials of sodium intake reduction (
Table 1
),
later aggregated in meta-analyses. Despite including seven studies pooling 6489 partici-
pants with or without hypertension, the first study found no significant association between
reduced sodium intake and cardiovascular events [
55
]. Authors concluded that there is
insufficient power to exclude a clinically important effect of reduced sodium consumption
on cardiovascular morbidity and called for future, large, long-term, randomized controlled
trials focusing on clinical outcomes. According to their own calculation, 2500 cardiovascu-
lar events would be needed to achieve sufficient power to detect a clinically meaningful
effect. Such a trial would require thousands of participants adhering to specific sodium
Nutrients 2021,13, 3177 6 of 15
diets over several years. Imposing a high salt diet on a large scale for an extended pe-
riod would raise serious ethical and methodological concerns, rendering such a study
unlikely to ever be conducted. A second meta-analysis conducted by another group later
reanalysed the same dataset in with a slightly different methodology [
56
]. Indeed, one
study was excluded from the pooled analysis as it involved heart failure patients who
were likely to be sodium depleted before randomization as they had already been treated
with furosemide, spironolactone, captopril and fluid restriction [
57
]. Then, instead of
considering two distinct groups of patients, normotensive and hypertensive individuals
were analysed collectively, thereby increasing statistical power. By implementing those
methodological modifications, authors showed that reduced sodium intake was associated
with a significant decrease in cardiovascular events and a non-significant trend toward
lower mortality.
Considering the available evidence, it is reasonable to assume a direct and continuous
relationship between sodium intake, BP control and cardiovascular outcomes from a popu-
lation standpoint. However, as definite evidence from long-term randomized controlled
trials is still lacking, a consensus has yet to be reached on the effectiveness, safety and
feasibility of sodium intake reduction on an individual level. Until then, it seems judicious
to routinely evaluate sodium intake in patients at high cardio-renal risk and recommend
adherence to low sodium diet as part of a multifaceted treatment approach in an effort to
reduce morbidity and mortality in those patients [58,59].
3. Pathophysiological Considerations
3.1. Basic Principles
Multiple mechanisms are responsible for the association between sodium intake and
BP. The key role of the kidney in this relationship has been clearly demonstrated in several
transplant experiments [
60
,
61
]. Guyton formalized the basic principle of kidney BP reg-
ulation as the pressure natriuresis response [
62
]. In its simplest form, this concept states
that when BP increases, the excess pressure causes the kidney to excrete more sodium and
water. This, subsequently, decreases extracellular blood volume and, thus, preload as well
as cardiac output, thereby restoring BP to lower levels. On the other hand, variations in
sodium intake induce parallel changes in plasma sodium content, both in hypertensive and
normotensive individuals [
63
,
64
]. A rise in plasma sodium increases osmolarity, thus induc-
ing a fluid shift from the intracellular to the extracellular compartment. A small increase
in plasma osmolarity also stimulates vasopressin secretion, thus resulting in water reten-
tion. Both these mechanisms restore plasma sodium to its original level but also increase
extracellular fluid volume thereby increasing BP [
65
]. Importantly, evidence exists that a
variation in plasma sodium can influence BP regulation independently of blood volume
variation [
66
]. Such additive effects could be mediated by the direct influence of plasma
sodium on the hypothalamus; the vasculature as well as the immune system [67–69].
3.2. Organ Damage and Cardiovascular Impact
Sodium intake indirectly affects target organs via its effect on BP. Hypertension is
associated with endothelial dysfunction and platelet activation eventually resulting in
microvascular as well as macrovascular disease and target organ damage [
70
]. However,
evidence also points towards direct adverse consequences of sodium load on cardiovascular
prognosis independent of BP (Figure 1). In this section, we review the main mechanisms
involved in this pathophysiological process.
Nutrients 2021,13, 3177 7 of 15
Nutrients 2021, 13, x FOR PEER REVIEW 7 of 16
Figure 1. Pathophysiological pathways linking sodium intake to target organ damage independently of BP-mediated ef-
fects.
Excessive sodium has been shown to be involved in different pathways such as ox-
idative stress, inflammation and fibrosis, which are determinant in target organs being
damaged. In patients with non-diabetic chronic kidney disease, sodium restriction in-
creases the concentration of anti-inflammatory and anti-fibrotic peptides on top of RAAS
blockade, providing pathophysiological insights into the synergistic benefit of sodium
reduction and RAAS blockade [71]. Animal studies confirmed a direct pro-fibrotic effect
of sodium on glomeruli mediated via an increased local expression of transforming
growth factor (TGF) β [72,73]. Additionally, sodium intake directly influences nitric oxide
(NO) generation and local oxidative stress in rats’ kidneys [74,75]. Thus, in middle-aged
hypertensive adults, dietary sodium restriction largely reversed macro- and microvas-
cular endothelial dysfunction by enhancing NO bioavailability and decreasing oxidative
stress, thus supporting a direct vascular protective effect of sodium restriction beyond
any influence on BP regulation [76].
Some evidence suggests that sodium is involved in cellular senescence as a high
NaCl environment inhibits the activity of key components of the classical DNA damage
response, such as Mre11 exonuclease in cell culture [77,78]. Exposure to NaCl was also
associated, both in cell culture as well as in vivo, with increased senescence-associated
β-galactosidase activity and p16
INK4
expression as well as reduced levels of Hsp70, all of
which are indicative of cellular senescence [79]. High salt intake is also associated with
cell death in animal experiments as cytosolic accumulation of caspase-independent
apoptotic factors, such as apoptosis-induced factor (AIF) and HtrA2/Omi, was described
in response to sodium loading [80]. Finally, apoptosis signal-regulating kinase 1 (ASK1)
has been involved in sodium-induced organ damage in animal models. ASK1 deficiency
abolished sodium-induced cardiac and vascular pathological alterations in normotensive
mice [81]. In a second experimental study, ASK1 deficiency also improved aldoste-
rone/salt-induced cardiac inflammation and fibrosis. Furthermore, the enhancement of
NADPH oxidase-induced cardiac oxidative stress caused by aldosterone and sodium
was notably decreased by ASK1 deficiency [82]. A schematic representation of potential
pathways involved in sodium-induced cellular injury is given in Figure 2.
Figure 1.
Pathophysiological pathways linking sodium intake to target organ damage independently
of BP-mediated effects.
Excessive sodium has been shown to be involved in different pathways such as ox-
idative stress, inflammation and fibrosis, which are determinant in target organs being
damaged. In patients with non-diabetic chronic kidney disease, sodium restriction in-
creases the concentration of anti-inflammatory and anti-fibrotic peptides on top of RAAS
blockade, providing pathophysiological insights into the synergistic benefit of sodium
reduction and RAAS blockade [
71
]. Animal studies confirmed a direct pro-fibrotic ef-
fect of sodium on glomeruli mediated via an increased local expression of transforming
growth factor (TGF)
β
[
72
,
73
]. Additionally, sodium intake directly influences nitric oxide
(NO) generation and local oxidative stress in rats’ kidneys [
74
,
75
]. Thus, in middle-aged
hypertensive adults, dietary sodium restriction largely reversed macro- and microvascu-
lar endothelial dysfunction by enhancing NO bioavailability and decreasing oxidative
stress, thus supporting a direct vascular protective effect of sodium restriction beyond any
influence on BP regulation [76].
Some evidence suggests that sodium is involved in cellular senescence as a high
NaCl environment inhibits the activity of key components of the classical DNA damage
response, such as Mre11 exonuclease in cell culture [
77
,
78
]. Exposure to NaCl was also
associated, both in cell culture as well as
in vivo
, with increased senescence-associated
β
-galactosidase activity and p16
INK4
expression as well as reduced levels of Hsp70, all of
which are indicative of cellular senescence [
79
]. High salt intake is also associated with cell
death in animal experiments as cytosolic accumulation of caspase-independent apoptotic
factors, such as apoptosis-induced factor (AIF) and HtrA2/Omi, was described in response
to sodium loading [
80
]. Finally, apoptosis signal-regulating kinase 1 (ASK1) has been
involved in sodium-induced organ damage in animal models. ASK1 deficiency abolished
sodium-induced cardiac and vascular pathological alterations in normotensive mice [
81
].
In a second experimental study, ASK1 deficiency also improved aldosterone/salt-induced
cardiac inflammation and fibrosis. Furthermore, the enhancement of NADPH oxidase-
induced cardiac oxidative stress caused by aldosterone and sodium was notably decreased
by ASK1 deficiency [
82
]. A schematic representation of potential pathways involved in
sodium-induced cellular injury is given in Figure 2.
Nutrients 2021,13, 3177 8 of 15
Nutrients 2021, 13, x FOR PEER REVIEW 8 of 16
Figure 2. Schematic representation of potential pathways involved in sodium-induced cellular in-
jury. SA-beta-gal, senescence-associated β-galactosidase; AIF, apoptosis-induced factor; Nox,
NADPH oxidase; ASK1, apoptosis signal-regulating kinase 1.
In healthy adults, endothelial function, as measured by flow-mediated dilatation
and arterial stiffness, was negatively impacted by high sodium intake [83,84], and re-
ducing sodium intake had the opposite effect [85]. Importantly, the adverse influence of
sodium on vascular function was unequivocally found to be independent of BP [86–88].
Sodium intake was also positively and independently associated with renal resistive in-
dex (RRI) in an adult general population [89]. As RRI could represent systemic vascular
damage and correlates with adverse cardiovascular outcomes, this suggests that sodium
consumption impacts renal hemodynamic as a reflection of a broader systemic alteration
[90,91]. An effect of sodium intake on systemic vascular properties independent of BP has
been confirmed in other studies. High sodium consumption was associated with in-
creased arterial stiffness as measured by pulse wave velocity after adjustment for BP in
Chinese communities [92]. The same group showed that pulse wave velocity was de-
creased in Australian normotensive subjects adhering to a low sodium diet compared
with age and BP matched controls [93]. More recently, a meta-analysis comprising 11
randomized controlled trials and 14 independent cohorts reported a positive association
between sodium intake and pulse wave velocity beyond BP control. Globally, those
findings are all the more important in that the severity of endothelial dysfunction relates
to the global cardiovascular risk [94]. On a cellular level, dietary salt has direct effects on
vascular endothelium NO production [95]. In bovine aortic endothelial cells, sodium
exposure caused a significant decrease in NO synthase (NOS) activity in a
dose-dependent manner, thereby explaining a salt-induced reduction in endothelial NO
generation [96]. High salt intake led to increased superoxide production and decreased
NO bioavailability in mice aortas [97]. Furthermore, a high salt diet impaired aortic ring
endothelium-dependent relaxation via reduced NO levels and increased superoxide
production in rat aorta [98]. In spontaneously hypertensive rats, excessive dietary salt
decreased cyclic GMP production in the aorta, leading to the impairment of
NO-mediated vascular relaxation despite increased NO production [99]. Such alterations
Figure 2.
Schematic representation of potential pathways involved in sodium-induced cellular injury.
SA-beta-gal, senescence-associated
β
-galactosidase; AIF, apoptosis-induced factor; Nox, NADPH
oxidase; ASK1, apoptosis signal-regulating kinase 1.
In healthy adults, endothelial function, as measured by flow-mediated dilatation and
arterial stiffness, was negatively impacted by high sodium intake [
83
,
84
], and reducing
sodium intake had the opposite effect [
85
]. Importantly, the adverse influence of sodium
on vascular function was unequivocally found to be independent of BP [
86
–
88
]. Sodium
intake was also positively and independently associated with renal resistive index (RRI)
in an adult general population [
89
]. As RRI could represent systemic vascular damage
and correlates with adverse cardiovascular outcomes, this suggests that sodium consump-
tion impacts renal hemodynamic as a reflection of a broader systemic alteration [
90
,
91
].
An effect of sodium intake on systemic vascular properties independent of BP has been
confirmed in other studies. High sodium consumption was associated with increased
arterial stiffness as measured by pulse wave velocity after adjustment for BP in Chinese
communities [
92
]. The same group showed that pulse wave velocity was decreased in
Australian normotensive subjects adhering to a low sodium diet compared with age and BP
matched controls [
93
]. More recently, a meta-analysis comprising 11 randomized controlled
trials and 14 independent cohorts reported a positive association between sodium intake
and pulse wave velocity beyond BP control. Globally, those findings are all the more
important in that the severity of endothelial dysfunction relates to the global cardiovascular
risk [
94
]. On a cellular level, dietary salt has direct effects on vascular endothelium NO
production [
95
]. In bovine aortic endothelial cells, sodium exposure caused a significant
decrease in NO synthase (NOS) activity in a dose-dependent manner, thereby explaining a
salt-induced reduction in endothelial NO generation [
96
]. High salt intake led to increased
superoxide production and decreased NO bioavailability in mice aortas [
97
]. Furthermore,
a high salt diet impaired aortic ring endothelium-dependent relaxation via reduced NO
levels and increased superoxide production in rat aorta [
98
]. In spontaneously hypertensive
rats, excessive dietary salt decreased cyclic GMP production in the aorta, leading to the im-
pairment of NO-mediated vascular relaxation despite increased NO production [
99
]. Such
alterations of the NO/cyclic GMP system were restored by dietary salt restriction but not by
Nutrients 2021,13, 3177 9 of 15
antihypertensive therapy in a later study [
100
]. Activation of vasopressor mechanisms were
also described, as a high salt diet increased the expression of cytochrome p450 4A enzymes
in rat mesenteric arteries, thus upregulating the production of 20-hydroxyeicosatetraenoic
acid (20-HETE) [
101
]. In turn, 20-HETE contributed to the vasoconstrictor response to
norepinephrine in those arteries [
101
]. A schematic representation of potential pathways
involved in sodium-induced vascular alterations is given in Figure 3.
Nutrients 2021, 13, x FOR PEER REVIEW 9 of 16
of the NO/cyclic GMP system were restored by dietary salt restriction but not by anti-
hypertensive therapy in a later study [100]. Activation of vasopressor mechanisms were
also described, as a high salt diet increased the expression of cytochrome p450 4A en-
zymes in rat mesenteric arteries, thus upregulating the production of
20-hydroxyeicosatetraenoic acid (20-HETE) [101]. In turn, 20-HETE contributed to the
vasoconstrictor response to norepinephrine in those arteries [101]. A schematic repre-
sentation of potential pathways involved in sodium-induced vascular alterations is given
in Figure 3.
Figure 3. Schematic representation of potential pathways involved in sodium-induced vascular
alterations. VSM, vascular smooth muscle; NOS, NO synthase; NO, nitric oxide; cGMP, cyclic
GMP; 20-HETE, 20-hydroxyeicosatetraenoic acid.
The adverse effect of sodium on target organs could be partially mediated by hor-
monal interactions. In a case-control study including 21 patients with primary aldoste-
ronism and 21 hypertensive control patients, 24 h sodium excretion was associated with
left ventricular mass and thickness only in patients with primary aldosteronism [102].
Aldosterone excess may thus play a permissive role in sodium induced target organ
damage. Another study prospectively investigated the influence of sodium intake on
cardiac outcomes of patients both before and after treatment of primary aldosteronism
[103]. Interestingly, sodium intake interacted with aldosterone in inducing cardiac
changes over time, while left ventricular mass was associated with both sodium intake
and aldosterone levels before treatment. The decrease in ventricular mass obtained after
treatment was greater in patients whose sodium intake also decreased. Change of ven-
tricular mass was also associated with sodium intake independently of BP and other po-
tential confounders. In another study including 90 adults with essential hypertension, left
ventricular mass was associated with plasma aldosterone level after, but not prior to, in-
travenous saline load, implying that a limited ability of sodium to supress aldosterone
production could contribute to organ damage [104]. Finally, in a longitudinal study, 182
adults with essential hypertension and left ventricular hypertrophy were treated with
RAAS blockade [105]. The observed decrease in left ventricular mass over time was cor-
Figure 3.
Schematic representation of potential pathways involved in sodium-induced vascular
alterations. VSM, vascular smooth muscle; NOS, NO synthase; NO, nitric oxide; cGMP, cyclic GMP;
20-HETE, 20-hydroxyeicosatetraenoic acid.
The adverse effect of sodium on target organs could be partially mediated by hormonal
interactions. In a case-control study including 21 patients with primary aldosteronism and
21 hypertensive control patients, 24 h sodium excretion was associated with left ventricular
mass and thickness only in patients with primary aldosteronism [
102
]. Aldosterone excess
may thus play a permissive role in sodium induced target organ damage. Another study
prospectively investigated the influence of sodium intake on cardiac outcomes of patients
both before and after treatment of primary aldosteronism [
103
]. Interestingly, sodium intake
interacted with aldosterone in inducing cardiac changes over time, while left ventricular
mass was associated with both sodium intake and aldosterone levels before treatment.
The decrease in ventricular mass obtained after treatment was greater in patients whose
sodium intake also decreased. Change of ventricular mass was also associated with
sodium intake independently of BP and other potential confounders. In another study
including 90 adults with essential hypertension, left ventricular mass was associated with
plasma aldosterone level after, but not prior to, intravenous saline load, implying that
a limited ability of sodium to supress aldosterone production could contribute to organ
damage [
104
]. Finally, in a longitudinal study, 182 adults with essential hypertension
and left ventricular hypertrophy were treated with RAAS blockade [
105
]. The observed
decrease in left ventricular mass over time was correlated with change in BP, 24-h sodium
urinary excretion and plasma aldosterone concentration. At the end of the follow-up,
the combination of high sodium intake and high aldosterone levels was associated with
Nutrients 2021,13, 3177 10 of 15
increased left ventricular mass. In contrast, in patients with low sodium intake, no influence
of aldosterone levels was detected. These results together suggest that persistence of organ
damage despite adequate BP control may result from the combined effect of excessive
sodium intake and breakthrough of aldosterone despite pharmacological blockage. Basic
research studies also support the interplay between sodium and aldosterone in organ
damage physiopathology as aldosterone-induced superoxide over-production and vascular
smooth muscle hypertrophy in cell culture, a phenomenon synergistically augmented with
sodium chloride [106].
Finally, sodium could impact cardiovascular prognosis via other less studied path-
ways. Evidence suggests that sodium has immunomodulatory properties as interleukin-17
producing T lymphocytes are highly pro-inflammatory cells whose differentiation was
enhanced
in vitro
and
in vivo
by a modest sodium load [
107
]. Extensive renal T cell infil-
tration has otherwise been described in numerous
in vivo
experiments under a high salt
diet [
108
,
109
]. In parallel, interleukin-17 was reported to decrease nitric oxide bioavail-
ability in smooth muscle cells and fibroblast, thereby promoting endothelial dysfunction
and arterial stiffness [
67
]. The impact of dietary salt intake on the immune response has
also been described in humans in a post-hoc analysis of a controlled simulated spaceflight
program termed Mras520 [
110
]. Authors described an increase in inflammatory cytokines
(IL-6 and IL-23) as well as a decrease in anti-inflammatory cytokines (IL-10) in the plasma
of subjects submitted to high salt intake as compared to low salt intake. Recently, the gut
microbiome has been proposed as a potential intermediary between sodium intake and
clinical outcomes. The impact of a high sodium diet on gut microbial composition has been
illustrated in various animal models [
111
,
112
]. In mice, chronic high sodium load induced
qualitative and quantitative alterations in intestinal flora [
113
]. This study also revealed
that sodium altered intestinal immunological gene expression and enhanced gut perme-
ability as well as enteric bacterial translocation to the kidney. Excessive dietary sodium led
to expansion of interleukin-17 producing T cells in the small intestine of mice, resulting
in increased levels of circulating interleukin-17 [
114
]. High sodium intake affected mice
gut microbiome by depleting Lactobacillus murinus in another study [
115
]. Consequently,
treatment of those mice with L. murinus prevented salt-induced hypertension by modulat-
ing interleukin-17 producing T cells. Differences in gut microbial composition have been
shown between salt-sensitive and salt-resistant Dahl rats and faecal transplantation from
one strain to the other was able to change the BP pattern [116].
Altogether, the available evidence suggests that sodium not only affects target organs
via its indirect effect on BP but, clearly, also through complex interconnected pathways
involving oxidative, inflammatory, endocrine, immune and microbiological mechanisms.
4. Conclusions
The available evidence points toward a causal role of sodium intake on BP and
cardiovascular prognosis. While the pathophysiological link between hypertension and
cardiovascular events is relatively straightforward, a large body of data now suggests
that sodium directly damages target organs independently of BP control via multiple
intricate pathways. Although gaps in knowledge still exist, reduction in sodium intake
on a population level represents a feasible strategy to reduce the burden of cardiovascular
morbidity and mortality worldwide.
Author Contributions:
D.A.J. wrote the manuscript. G.W. and B.P. revised the manuscript and
gave final approval for publication. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Nutrients 2021,13, 3177 11 of 15
Acknowledgments:
We thank Eric Feraille (Department of Cellular Physiology and Metabolism,
University of Geneva) for the insights in the molecular pathways of sodium–cell interaction. We
also thank Jack Galliford (Department of Nephrology, North Bristol NHS Trust) for proofreading
the manuscript.
Conflicts of Interest: Authors declare no conflict of interest.
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