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The association between serum sodium concentration, hypertension and

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Article  in  Journal of Human Hypertension · January 2019

DOI: 10.1038/s41371-018-0115-5

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 Journal of Human Hypertension
https://doi.org/10.1038/s41371-018-0115-5

ARTICLE

The association between serum sodium concentration, hypertension

and primary cardiovascular events: a retrospective cohort study
Nicholas I. Cole 1 Rebecca J. Suckling1 Pauline A. Swift1 Feng J. He2 Graham A. MacGregor2 William Hinton3
● ● ● ● ● ●

Jeremy van Vlymen3 Nicholas Hayward3 Simon Jones3,4 Simon de Lusignan 3

● ● ●

Received: 10 May 2018 / Revised: 7 August 2018 / Accepted: 24 August 2018

© Springer Nature Limited 2018

Abstract
The mechanisms underlying the adverse cardiovascular effects of increased salt intake are incompletely understood, but
parallel increases in serum sodium concentration may be of importance. The aim of this retrospective cohort study was to
investigate the relationship between serum sodium, hypertension and incident cardiovascular disease (CVD). Routinely
collected primary care data from the Royal College of General Practitioners Research and Surveillance Centre were
analysed. A total of 231,545 individuals with a measurement of serum sodium concentration at baseline were included.
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Exclusion criteria were: age < 40 years; abnormal serum sodium; diabetes mellitus; prior CVD event; stage 5 chronic kidney
disease; and liver cirrhosis. The primary outcome was incident CVD (myocardial infarction, acute coronary syndrome,
coronary revascularisation, stroke, transient ischaemic attack or new heart failure diagnosis) over 5 years. There was a
‘J-shaped’ relationship between serum sodium concentration and primary cardiovascular events that was independent of
established risk factors, medications and other serum electrolytes. The lowest cardiovascular risk was found with a serum
sodium between 141 and 143 mmol/l. Higher serum sodium was associated with increased risk in hypertensive individuals,
whereas lower concentrations were associated with increased risk in all individuals. Therefore, alterations in serum sodium
concentration may be a useful indicator of CVD risk. Higher serum sodium could have a direct effect on the vasculature,
particularly in hypertensive individuals. Lower serum sodium may be a reflection of complex volume and neuroendocrine
changes.

Introduction The mechanisms underlying this relationship are incom-

pletely understood, but it has been proposed that changes in
Excessive dietary salt consumption increases blood pressure serum sodium concentration could be important [3, 4]. In
and is a risk factor for cardiovascular disease (CVD) [1, 2]. randomised-controlled trials, higher salt intake is associated
with small increases in serum sodium sustained over several
days [3–5]. Furthermore, cross-sectional studies have
demonstrated a positive association between serum sodium
Electronic supplementary material The online version of this article
and blood pressure [6–8]. One hypothesis is that an increase
(https://doi.org/10.1038/s41371-018-0115-5) contains supplementary
material, which is available to authorised users. in serum sodium elevates blood pressure by stimulating
thirst and antidiuresis, thus expanding extracellular volume.
* Nicholas I. Cole However, studies in both animals and humans receiving
nicholascole@nhs.net
dialysis have shown that there is a positive relationship
1
Renal Department, Epsom and St Helier University Hospitals NHS between serum sodium and blood pressure, independent of
Trust, London, UK extracellular volume status [9–11]. Additionally, a number
2
Wolfson Institute of Preventative Medicine, Queen Mary of animal and in vitro studies suggest a direct effect of
University of London, London, UK serum sodium concentration on the blood vessels: higher
3
Department of Clinical and Experimental Medicine, University of serum sodium stiffens the vascular endothelium by inhi-
Surrey, Guildford, UK biting nitric oxide release and promotes hypertrophy of
4
Division of Healthcare Delivery Science, New York University, vascular smooth muscle cells [12, 13].
New York, NY, USA

Evidence for a potential relationship between serum
sodium concentration and the development of CVD is
limited. This is in stark contrast to the well-established
association between hyponatraemia and adverse outcomes
in those with existing CVD, in whom hyponatraemia is
often of consequence of decompensated disease or phar-
macological therapy [14–17]. Previous studies have
demonstrated a positive association between increased
serum sodium and estimated coronary heart disease risk, as
well as surrogate markers of hypertensive heart disease in
chronic kidney disease (CKD) [18, 19]. A small cohort
study in older men has reported higher serum sodium to be
predictive of cardiovascular events, as well as lower serum
sodium [20]. However, an important confounding factor
may have been diuretic therapy. Therefore, the present
study further investigated the relationship between serum
sodium concentration and incident CVD in a large
community-based cohort. The primary hypothesis was that
increased serum sodium, within the normal physiological
range, is a risk factor for primary cardiovascular events.
Subjects and methods
Study design and cohort
This was a retrospective cohort study using data from the
Royal College of General Practitioners (RCGP) Research
and Surveillance Centre (RSC) network. This is a database
of coded primary care data from over 100 General Practi-
tioner (GP) practices across England, comprising of around
1.8 million patients. The study protocol was approved by
the Proportionate Review Sub-committee of the London—
Stanmore Research Ethics Committee (REC reference: 15/
LO/1865).
Routine data collected over a 10-year period between
April 2005 and March 2015 were extracted using Read
(version 2) and Egton Medical Information Systems (EMIS)
codes. Data recorded between April 2005 and March 2010
were used to determine the baseline characteristics of study
population, and the follow-up period was between April
2010 and March 2015. The study cohort comprised of a
sub-population of individuals who were at least 40 years old
at baseline, who had at least one measurement of serum
sodium concentration during the baseline period and who
were registered for the duration follow-up (unless they
died). Exclusion criteria were: an abnormal serum sodium at
baseline (defined as < 135 or > 146 mmol/l); diabetes mel-
litus or decompensated liver disease at any stage; stage 5
CKD or a cardiovascular event prior to the follow-up per-
iod. Individuals with diabetes were excluded due to the
confounding effect of blood glucose on serum sodium
concentration.
N. I. Cole et al.
Outcomes
The primary outcome was incident CVD. This was a
composite outcome comprising of the following cardio-
vascular events: myocardial infarction (MI); acute coronary
syndrome (ACS); coronary revascularisation procedure;
stroke; transient ischaemic attack (TIA); or a new diagnosis
of heart failure. Cardiovascular deaths were not included as
an outcome due to the limitations of mortality coding in this
database.
Predictors
Initial variable selection was based on traditional cardio-
vascular risk factors, associations with serum sodium
identified by previous studies and other potential sources of
confounding considered by the authors [20, 21]. Baseline
data were established for each study participant: age, sex,
race and smoking status were established using routinely
collected registration data; deprivation quintile was
assigned by matching postcodes to area scores of the United
Kingdom Index of Multiple Deprivation (IMD) 2015 [22];
the most recent measurements of office blood pressure,
height and weight for each individual were extracted and
used to determine the baseline blood pressure and body
mass index (BMI); prescription data were obtained from the
latest prescription during the baseline period using electro-
nic prescription data (EMIS codes); and hypertension was
defined by diagnostic code or the prescription of an anti-
hypertensive medication.
Laboratory data were derived from samples collected
routinely in general practice, with the most recent results
during the baseline period used for comparison. Extreme
values beyond physiological limits were excluded as
inputting errors. In order to limit the influence of acute
alterations in serum sodium and creatinine, a penultimate
result was also extracted. This was defined as the second
most recent result during the baseline period that was at
least 90 days prior to the first. The mean of the latest and
penultimate serum sodium concentration was then calcu-
lated and rounded-up to the nearest integer. Creatinine
values were used to calculate estimated glomerular filtration
rate (eGFR) using the CKD Epidemiology Collaboration
(CKD-EPI) formula, with the maximum estimation for each
individual used as the baseline [23].
Statistical analysis
The study data were analysed using the statistical package R
(version 3.4.1), with a P-value of < 0.05 being regarded as
statistically significant. Continuous variables were analysed as
grouped categorical variables to adjust for non-linear associa-
tions, with missing data included as unknown: equally spaced
The association between serum sodium concentration, hypertension and primary cardiovascular events: a. . .
A B
Females Males
Agebands
Proportion of population
Fig. 1 Cohort demographics and baseline serum sodium concentration:
a Age-sex distribution of the RCGP RSC cohort. The black line
represents age-sex distribution of the general population in England
and clinically relevant ranges were used for categorisation, with
the exception of BMI, eGFR and glycated haemoglobin
(HbA1c) that were grouped using conventional cut-offs (Sup-
plemental Table). Differences between groups at baseline were
determined using the chi-squared test for categorical variables,
one-way analysis of variance (ANOVA) for normally dis-
tributed continuous variables and the Kruskal–Wallis test for
non-parametric data. A binary logistic regression model was
then used to evaluate the association between serum sodium
concentration and cardiovascular events after adjustment for
confounding variables. A restricted cubic spline plot with four
knots (at the 5th, 35th, 65th and 95th percentiles) was used to
explore the relationship between serum sodium concentration,
as a continuous variable, and the primary outcome [24]. The
cohort was subsequently categorised into serum sodium
groups, based on 3 mmol/l increments, for further subgroup
analysis.
The primary multivariable model included the following
variables, employing a forced-entry method: age; sex; race;
BMI; smoking status; IMD quintile; CKD stage; high-density
and low-density lipoprotein (HDL and LDL) cholesterol;
haemoglobin; packed cell volume (PCV); HbA1c; potassium;
corrected calcium; phosphate; albumin; C-reactive peptide
(CRP); and cardiovascular medications (anti-platelets agents,
lipid-lowering therapy, diuretics, renin–angiotensin system
(RAS) antagonists, beta-blockers, other antihypertensives).
No significant multicollinearity was detected (variance infla-
tion factor < 5 for all variables). Blood pressure was not
included in the primary model because we hypothesised it to
be a mediator of the relationship between serum sodium and
cardiovascular outcomes. It was analysed separately using
one-way ANOVA, to compare the mean blood pressure
according to serum sodium, and linear regression models.
and Wales (from 2011 National Census data); b Histogram of baseline
serum sodium concentration of the RCGP RSC cohort
Results
Cohort description
The distribution of serum sodium in the population showed
a slight negative skew, and deviated from normal: the
median concentration at baseline was 140 mmol/l (inter-
quartile range (IQR) 139–142). The study cohort consisted
of 231,545 individuals with a serum sodium within the
normal physiological range (between 135 and 146 mmol/l).
The median age was 58 years (IQR 49–67), 131,990
(57.0%) were female and 11,922 (5.1%) were identified as
non-white race. Male patients, particularly those < 60 years
old, were under-represented compared with the general
population of England and Wales (Fig. 1). The median time
from the most recent serum sodium measurement to the start
of the follow-up period was 10 months (IQR 4–22).
In total, 97,616 (42.2%) individuals met the study criteria
for hypertension. Of these, 47,535 (48.7%) were prescribed
a diuretic and 51,423 (52.7%) were prescribed a RAS
inhibitor. In all, 5852 (6.0%) individuals with a diagnostic
code for hypertension were not prescribed an anti-
hypertensive medication.
Baseline analysis
Table 1 outlines the baseline characteristics of the study
population by serum sodium concentration. Due to the large
sample size, testing for differences in baseline character-
istics was statistically significant for all variables. Notably,
lower serum sodium was associated with female gender and
lower deprivation. These individuals were more likely to be
prescribed cardiovascular medications, including diuretics.
 N. I. Cole et al.

Table 1 Baseline characteristics of study cohort

Serum sodium concentration at baseline (mmol/l)
135–137 138–140 141–143 144–146 All
(n = 21,888) (n = 103,528) (n = 92,319) (n = 13,810) (n = 231,545)

Age, years (median, 59 (48–71) 57 (48–66) 59 (50–68) 61 (52–69) 58 (49–67)

IQR)
Female sex (n, %) 14,019 (64.0) 59,701 (57.7) 50,719 (54.9) 7551 (54.7) 131,990
(57.0)
Blood pressure
Systolic, mmHg 133.2 ± 16.2 132.4 ± 15.5 133.1 ± 15.4 133.7 ± 15.2 132.9 ± 15.5
Diastolic, mmHg 78.5 ± 9.6 79.0 ± 9.4 79.1 ± 9.3 79.3 ± 9.2 79.0 ± 9.3
Race (n, %)
White 15,878 (72.5) 75,226 (72.7) 66,161 (71.8) 9337 (67.6) 166,602
(72.0)
Asian 496 (2.3) 2467 (2.4) 2535 (2.7) 543 (3.9) 6041 (2.6)
Black 164 (0.7) 1319 (1.3) 1924 (2.1) 518 (3.8) 3925 (1.7)
Other 101 (0.5) 855 (0.8) 849 (0.9) 151 (1.1) 1956 (0.8)
Not known 5249 (24.0) 23,661 (22.9) 20,850 (22.6) 3261 (23.6) 53,021 (22.9)
Smoking status (n, %)
Never smoked 8888 (40.6) 41,945 (40.5) 38,318 (41.5) 5642 (40.9) 94,793 (40.9)
Current 3614 (16.5) 16,121 (15.6) 13,239 (14.3) 2038 (14.8) 35,012 (15.1)
Ex-smoker 7689 (35.1) 37,327 (36.1) 34,034 (36.9) 5106 (37.0) 84,156 (36.3)
Not known 1697 (7.8) 8135 (7.9) 6728 (7.3) 1024 (7.4) 17,584 (7.6)
Deprivation quintile
(n, %)
Least deprived 6950 (31.8) 31,506 (30.4) 26,420 (28.6) 3625 (26.2) 68,501 (29.6)
Most deprived 2236 (10.2) 11,824 (11.4) 12,329 (13.4) 2362 (17.1) 28,751 (12.4)
BMI (median, IQR) 26.3 27.1 27.3 27.3 27.1
(23.4–29.9) (24.2–30.7) (24.4–30.9) (24.4–30.8) (24.2–30.7)
Laboratory results
Potassium, mmol/l 4.4 ± 0.4 4.4 ± 0.4 4.4 ± 0.4 4.4 ± 0.5 4.4 ± 0.4
eGFR, ml/min/ 81.8 ± 17.7 82.1 ± 16.6 80.9 ± 16.1 80.7 ± 16.1 81.5 ± 16.5
1.73 m2
Haemoglobin, g/l 136.3 ± 14.0 139.3 ± 13.5 140.7 ± 13.1 141.2 ± 12.9 139.7 ± 13.4
Packed cell volume, 40.5 ± 3.8 41.4 ± 3.7 42.0 ± 3.6 42.2 ± 3.6 41.6 ± 3.7
%
Albumin, g/l 41.6 ± 3.8 42.4 ± 3.5 43.2 ± 3.4 44.1 ± 3.3 42.7 ± 3.5
Corrected calcium, 2.3 ± 0.2 2.3 ± 0.1 2.3 ± 0.1 2.3 ± 0.2 2.3 ± 0.1
mmol/l
Phosphate, mmol/l 1.1 ± 0.2 1.1 ± 0.2 1.1 ± 0.2 1.1 ± 0.2 1.1 ± 0.2
HDL cholesterol, 1.5 ± 0.5 1.5 ± 0.4 1.5 ± 0.4 1.5 ± 0.4 1.5 ± 0.4
mmol/l
LDL cholesterol, 3.2 ± 1.0 3.3 ± 0.9 3.2 ± 0.9 3.2 ± 0.9 3.2 ± 0.9
mmol/l
CRP, mg/l (median, 5.0 (2.0–8.0) 4.7 (2.0–6.8) 5.0 (2.0–6.0) 5.0 (2.0–7.0) 5.0 (2.0–6.7)
IQR)
HbA1c, mmol/mol 38.8 38.8 38.8 38.8 38.8
(median, IQR) (35.5–41.0) (35.5–42.1) (36.0–42.1) (36.6–42.1) (35.5–42.1)
Prescriptions (n, %)
Diuretics 6078 (27.8) 20,221 (19.5) 18,338 (19.9) 2898 (21.0) 47,535 (20.5)
RAS inhibitors 5988 (27.4) 22,586 (21.8) 19,890 (21.5) 2959 (21.4) 51,423 (22.2)
Beta-blockers 3989 (18.2) 15,793 (15.3) 14,437 (15.6) 2220 (16.1) 36,439 (15.7)
The association between serum sodium concentration, hypertension and primary cardiovascular events: a. . .

Table 1 (continued)
Serum sodium concentration at baseline (mmol/l)
135–137 138–140 141–143 144–146 All
(n = 21,888) (n = 103,528) (n = 92,319) (n = 13,810) (n = 231,545)

Other 4658 (21.3) 18,399 (17.8) 18,204 (19.7) 2986 (21.6) 44,247 (19.1)
antihypertensives
Antiplatelet agents 3173 (14.5) 12,310 (11.9) 12,228 (13.2) 2068 (15.0) 29,779 (12.9)
Lipid-lowering 4163 (19.0) 20,226 (19.5) 21,888 (23.7) 3653 (26.5) 49,930 (21.6)
therapy
Data are shown as mean ± standard deviation unless otherwise specified. Differences between groups were statistically significant for all variables
(P = 0.04 for HbA1c, P < 0.001 for all other variables)
n number of patients, BMI body mass index, eGFR estimated glomerular filtration rate (CKD-EPI equation), HDL high-density lipoprotein, LDL
low-density lipoprotein, CRP C-reactive protein, HbA1c glycated haemoglobin, RAS renin–angiotensin system, IQR interquartile range

A higher serum sodium was associated with a higher BMI

and non-white race: this was particularly the case for those
of black race (n = 3925), in whom the sodium distribution
curve was shifted to the right by 1 mmol/l. Also of note,
positive linear relationships were observed between serum
sodium and a number of laboratory variables at baseline: a
1 mmol/l increase in serum sodium was associated with a
0.64 g/l increase in haemoglobin (P < 0.001), a 0.23%
increase in PCV (P < 0.001) and a 0.31 g/L increase in
albumin (P < 0.001). In contrast, serum potassium was
comparable between the groups.

Relationship between serum sodium and blood

pressure

The unadjusted relationship between baseline serum sodium

concentration and blood pressure is shown in Fig. 2. In
normotensive individuals, there was a positive association
between a serum sodium ≥ 137 mmol/l and blood pressure
(0.28/0.07 mmHg higher for every 1 mmol/l increase in
serum sodium, P < 0.001). However, no relationship was
present after adjustment for age, sex, race, smoking, BMI
and eGFR. In hypertensives, the majority of whom were
prescribed antihypertensive medication, a serum sodium ≥
137 mmol/l was significantly associated with systolic blood
pressure only (0.10 mmHg higher for every 1 mmol/l
increase in serum sodium, P < 0.001). However, this was no
longer significant following multivariable adjustment. A
serum sodium lower than 137 mmol/l was associated with
higher systolic blood pressure in all individuals, and lower
diastolic blood pressure in hypertensives.

Primary analysis
The primary composite cardiovascular outcome occurred in
9070 (3.9%) individuals during the 5 years of follow-up:
MI, ACS or a coronary revascularization was recorded in
3689 (1.6%) individuals; stroke or TIA occurred in 4118
Fig. 2 Unadjusted relationship between blood pressure and serum
sodium concentration at baseline in 125,010 normotensive individuals
and 97,168 hypertensive individuals: a systolic blood pressure;
b diastolic blood pressure

Events (n) 1,077 3,972 3,420 601
Number at risk 21,888 103,528 92,319 13,810
Fig. 3 Restricted cubic spline plot demonstrating the association
between serum sodium concentration and incident cardiovascular
events over 5 years. Knots were located at serum sodium values of
137, 140, 141 and 144 mmol/l, corresponding to the 5th, 35th, 65th
and 95th percentiles. The analyses were adjusted for age, sex, race,
BMI, smoking status, deprivation quintile, CKD stage, HDL and LDL
cholesterol, haemoglobin, PCV, HbA1c, potassium, albumin, cor-
rected calcium, phosphate, CRP and cardiovascular medications
(antiplatelet agents, lipid-lowering therapy, diuretics, RAS antagonists,
beta-blockers, other antihypertensives)
(1.8%); and new heart failure was diagnosed in 1880
(0.8%). The mean time from time zero was 31.0 months
(SD 17.5). Univariable associations with the primary out-
come and the multivariable analysis are displayed in
the Supplemental Table.
There was a ‘J-shaped’ relationship between serum
sodium and primary cardiovascular events (Fig. 3). Indivi-
duals with a serum sodium concentration between 141 and
143 mmol/l had the lowest risk of a cardiovascular event
and were used as the reference category for subgroup ana-
lysis (Table 2). After multivariable adjustment, a serum
sodium ≤ 140 mmol/l and ≥ 144 mmol/l were both asso-
ciated with an increased risk of the primary cardiovascular
outcome. The relationship between lower and higher serum
sodium and incident cardiovascular events remained sig-
nificant after the exclusion of heart failure from the com-
posite outcome.
On further subgroup analysis, the relationship between
increased serum sodium and cardiovascular events was
observed in hypertensives, but not in normotensives
(Table 2). In the 97,616 individuals with hypertension, a
serum sodium of ≥ 144 mmol/l was associated with a 16%
higher risk of the primary outcome compared with a serum
sodium between 141 and 143 mmol/l (OR 1.16; 95%
CI 1.03, 1.30). In comparison, there was a significant
inverse relationship between serum sodium concentrations ≤
140 mmol/l and cardiovascular events in all individuals. This
included the 133,929 individuals without hypertension, none
N. I. Cole et al.
of whom were prescribed antihypertensive medication at
baseline (including diuretics). The inclusion of blood pres-
sure in the primary model did not affect these results.
Discussion
This study investigated the relationship between serum
sodium concentration and primary cardiovascular events in
a community-based cohort. We found there to be a sig-
nificant ‘J-shaped’ association that was independent of
established risk factors, medications and other serum elec-
trolytes. Serum sodium concentrations ≥ 144 mmol/l were
associated with greater cardiovascular risk in hypertensive
individuals, whereas concentrations ≤ 140 mmol/l were
associated with greater risk in hypertensive and normoten-
sive individuals. Serum sodium is usually tightly controlled
and so it is notable that one or two measurements in this
analysis were predictive of events over 5 years in this
analysis. Other studies have demonstrated there to be sig-
nificant individuality in serum sodium over long periods,
and so the importance of small inter-individual differences
may have been underestimated [25, 26].
The cardiovascular risk associated with higher
serum sodium
It has been proposed that the adverse cardiovascular effects
of dietary salt intake could be mediated through small
increases in serum sodium concentration [3, 4]. We found
that higher serum sodium at baseline was associated with
male sex, non-white race and greater deprivation. This is in
keeping with cross-sectional data in England that has shown
greater salt intake in these groups [27, 28]. It is also of
interest that the relationship between higher serum sodium
and cardiovascular events was significant only in those with
hypertension. These individuals exhibit a greater blood
pressure response to alterations in dietary salt intake com-
pared with normotensive individuals, but it is unknown if
there is also heterogeneity in the physiological response to
serum sodium concentration [2].
However, although these findings support the primary
hypothesis, we did not find convincing evidence for a
relationship between serum sodium and blood pressure. It is
possible that this was obscured by antihypertensive medi-
cation and the inaccuracy of single blood pressure readings
in primary care [29]. Alternatively, serum sodium con-
centration may influence cardiovascular risk independent of
blood pressure: in mice, higher serum sodium is associated
with endothelial activation, as well as the release of von
Willebrand factor and inflammatory markers that promote
thrombogenesis and atherogenesis [18, 30, 31]; although
not observed in the present study, a positive association
The association between serum sodium concentration, hypertension and primary cardiovascular events: a. . .

Table 2 Association of serum

Serum sodium concentration at baseline (mmol/l)
sodium concentration with
primary cardiovascular events 135–137 138–140 141–143 144–146

All individuals (N = 231,545)

Number of individuals 21,888 103,528 92,319 13,810
Major cardiovascular event: 1077 (4.9%) 3972 (3.8%) 3420 (3.7%) 601 (4.4%)
Univariable analysis 1.35 (1.25, 1.04 (0.99, 1.00 1.18 (1.08,
1.44) 1.09) 1.29)
Multivariable analysis 1.22 (1.13, 1.10 (1.05, 1.00 1.13 (1.03,
1.32) 1.16) 1.23)
Cardiovascular event, excluding heart 880 (4.0%) 3396 (3.3%) 2869 (3.1%) 496 (3.6%)
failure:
Univariable analysis 1.31 (1.21, 1.06 (1.01, 1.00 1.16 (1.05,
1.41) 1.11) 1.28)
Multivariable analysis 1.24 (1.14, 1.13 (1.07, 1.00 1.11 (1.01,
1.34) 1.19) 1.22)
Hypertensive individuals (n = 97,616)
Number of individuals 10,199 42,221 39,242 5954
Major cardiovascular event: 759 (7.4%) 2413 (5.7%) 2124 (5.4%) 387 (6.5%)
Univariable analysis 1.41 (1.29, 1.06 (1.00, 1.00 1.21 (1.09,
1.53) 1.12) 1.36)
Multivariable analysis 1.20 (1.09, 1.06 (1.00, 1.00 1.16 (1.03,
1.31) 1.13) 1.30)
Normotensive individuals (n = 133,929)
Number of individuals 11,689 61,307 53,077 7856
Major cardiovascular event: 318 (2.7%) 1559 (2.5%) 1296 (2.4%) 214 (2.7%)
Univariable analysis 1.12 (0.99, 1.04 (0.97, 1.00 1.12 (0.97, 1.3)
1.27) 1.12)
Multivariable analysis 1.27 (1.12, 1.16 (1.08, 1.00 1.08 (0.93,
1.45) 1.26) 1.26)
Data represent odds ratios (95% confidence interval) or number of individuals, n (%). Major cardiovascular
events included myocardial infarction, acute coronary syndrome, coronary revascularisation procedures,
stroke, cerebral transient ischaemic attack and new heart failure. The primary model included age, sex, race,
BMI, smoking status, deprivation quintile, CKD stage, HDL cholesterol, LDL cholesterol, haemoglobin,
HbA1c, PCV, potassium, albumin, corrected calcium, phosphate, CRP, and prescription of cardiovascular
medications (diuretics, RAS antagonists, beta-blockers, other antihypertensives, antiplatelet agents, and
lipid-lowering therapy)

between serum sodium and cholesterol has been reported,
with increased sodium promoting lipid accumulation in
cultured adipocytes [26]; finally, higher serum sodium
concentrations may be associated with aldosterone excess,
which could moderate increased cardiovascular risk [7].
The cardiovascular risk associated with lower serum
sodium
The clear demonstration of a significant inverse relationship
between lower serum sodium and the risk of primary car-
diovascular events is in keeping with a number of studies
that have demonstrated a link between hyponatraemia and
mortality in those with established CVD, especially heart
failure [14–17]. It has been suggested that low serum
sodium is a marker of ‘neuroendocrine activation’ including
release of antidiuretic hormone, simulation of the sympa-
thetic nervous system and activity of the RAS [32, 33]. For
example, in heart failure, lower serum sodium is associated
with increased RAS activity and predicts a better response
to RAS inhibition [33]. However, our study cohort was
relatively healthy and excluded those with decompensated
disease or prior cardiovascular events. Therefore, the higher
cardiovascular risk associated with lower serum sodium
concentrations (well within the normal physiological range)
may warrant further explanation. Although some investi-
gators have associated low dietary salt intake with adverse
cardiovascular outcomes [34], lower serum sodium in this
cohort is unlikely to be representative of low salt intake
given that the average salt intake in the United Kingdom is
8 g/day [28]. Experimental evidence implicates higher
serum sodium with adverse vascular effects and so lower

serum sodium concentration may occur secondary to other
factors involved in the development of CVD.
Limitations
A substantial strength of this study is that it involved a large
community-based sample of patients. However, there is
potential for selection bias because only individuals with a
serum sodium test were included: it is unknown whether
samples were taken as part of routine monitoring or due to
ill health, which could have influenced the results. Other
limitations include the observational nature of the analysis
and the possibility of missing or inaccurately coded data.
The duration of follow-up was also short and this may
increase the possibility of reverse causality. Furthermore,
variables not included in the multivariate model may be a
cause of residual confounding bias. This includes serum
chloride, which is infrequently measured in primary care
but has been reported to be associated with CVD inde-
pendently of serum sodium [35]. In addition, although we
included PCV to adjust for volume status, it is a crude
estimate. Alterations in extracellular volume often accom-
pany abnormalities of serum sodium and could have an
effect on cardiovascular risk.
Conclusion
Although this analysis does not establish causation, it is in
keeping with experimental evidence for direct effects of
increased serum sodium on the vasculature. Whether lower
serum sodium has a direct effect to moderate outcomes or is
a marker for other factors, including neuroendocrine activity
and volume status, is uncertain. Further investigation could
determine the utility of serum sodium as a marker of car-
diovascular risk, and whether it may enable individuals to
be identified that would benefit from specific primary
interventions.
Summary table
What is known about this topic
● Abnormalities of serum sodium concentration, particu-
larly hyponatraemia, are associated with adverse out-
comes in established cardiovascular disease.
● In contrast, the relationship between serum sodium and
primary cardiovascular events has yet to be established.
● Experiments have shown that small increases in
serum sodium raise blood pressure and have direct
effects on the vasculature that could increase cardio-
vascular risk.
N. I. Cole et al.
What this study adds
● There is a ‘J-shaped’ relationship between serum sodium
concentrations within the normal physiological range
and incident cardiovascular events.
● Higher serum sodium is associated with increased
cardiovascular risk in hypertensive individuals, but not
in normotensives.
● Lower serum sodium is associated with increased
cardiovascular risk in both normotensive and hyperten-
sive individuals.
Acknowledgements Patients and practices of the RCGP Research and
Surveillance Centre who allow their data to be used for surveillance
and research; EMIS, InPractice Computer Systems, TPP SystmOne
and other computerised medical record system vendors; Apollo
Medical Systems who facilitate data extraction; and Barbara Arrow-
smith, SQL Developer, for support with data extraction.
Compliance with ethical standards
Conflict of interest FJH is a member of Consensus Action on Salt &
Health (CASH) and World Action on Salt & Health (WASH). Both
CASH and WASH are non-profit charitable organisations and FJH
does not receive any financial support from CASH or WASH. GAM is
Chairman of Blood Pressure UK (BPUK), Chairman of CASH,
WASH and Action on Sugar (AoS). BPUK, CASH, WASH and AoS
are non-profit charitable organisations. GAM does not receive any
financial support from any of these organisations. SdeL is Director of
the RCGP RSC. The remaining authors declare that they have no
conflict of interest.
References
1. He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk:
meta-analysis of outcome trials. Lancet. 2011;378:380–2.
2. He FJ, Li J, Macgregor GA. Effect of longer term modest salt
reduction on blood pressure: Cochrane systematic review and
meta-analysis of randomised trials. BMJ. 2013;346:f1325.
3. He FJ, Markandu ND, Sagnella GA, de Wardener HE, MacGregor
GA. Plasma sodium: ignored and underestimated. Hypertension.
2005;45:98–102.
4. de Wardener HE, He FJ, MacGregor GA. Plasma sodium and
hypertension. Kidney Int. 2004;66:2454–66.
5. Suckling RJ, He FJ, Markandu ND, MacGregor GA. Dietary salt
influences postprandial plasma sodium concentration and systolic
blood pressure. Kidney Int. 2012;81:407–11.
6. Bulpitt CJ, Shipley MJ, Semmence A. Blood pressure and plasma
sodium and potassium. Clin Sci (Lond). 1981;61(suppl 7):85s–7s.
7. Komiya I, Yamada T, Takasu N, Asawa T, Akamine H, Yagi N,
et al. An abnormal sodium metabolism in Japanese patients with
essential hypertension, judged by serum sodium distribution, renal
function and the renin-aldosterone system. J Hypertens.
1997;15:65–72.
8. He FJ, Fan S, MacGregor GA, Yaqoob MM. Plasma sodium and
blood pressure in individuals on haemodialysis. J Hum Hypertens.
2013;27:85–9.
9. Norman RA Jr., Coleman TG, Wiley TL Jr., Manning RD Jr.,
Guyton AC. Separate roles of sodium ion concentration and fluid
The association between serum sodium concentration, hypertension and primary cardiovascular events: a. . .
volumes in salt-loading hypertension in sheep. Am J Physiol.
1975;229:1068–72.
10. Friedman SM, McIndoe RA, Tanaka M. The relation of blood
sodium concentration to blood pressure in the rat. J Hypertens.
1990;8:61–6.
11. Suckling RJ, Swift PA, He FJ, Markandu ND, MacGregor GA.
Altering plasma sodium concentration rapidly changes blood
pressure during haemodialysis. Nephrol Dial Transplant.
2013;28:2181–6.
12. Oberleithner H, Riethmuller C, Schillers H, MacGregor GA, de
Wardener HE, Hausberg M. Plasma sodium stiffens vascular
endothelium and reduces nitric oxide release. Proc Natl Acad Sci
USA. 2007;104:16281–86.
13. Gu JW, Anand V, Shek EW, Moore MC, Brady AL, Kelly WC,
et al. Sodium induces hypertrophy of cultured myocardial myo-
blasts and vascular smooth muscle cells. Hypertension.
1998;31:1083–87.
14. Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W,
Greenberg BH, O’Connor CM, et al. Relationship between
admission serum sodium concentration and clinical outcomes in
patients hospitalized for heart failure: an analysis from the
OPTIMIZE-HF registry. Eur Heart J. 2007;28:980–8.
15. Rusinaru D, Tribouilloy C, Berry C, Richards AM, Whalley GA,
Earle N, et al. Relationship of serum sodium concentration to
mortality in a wide spectrum of heart failure patients with
preserved and with reduced ejection fraction: an individual
patient data meta-analysis(dagger): meta-analysis global group in
chronic heart failure (MAGGIC). Eur J Heart Fail. 2012;14:
1139–46.
16. Goldberg A, Hammerman H, Petcherski S, Zdorovyak A, Yalo-
netsky S, Kapeliovich M, et al. Prognostic importance of hypo-
natremia in acute ST-elevation myocardial infarction. Am J Med.
2004;117:242–8.
17. Rodrigues B, Staff I, Fortunato G, McCullough LD. Hypona-
tremia in the prognosis of acute ischemic stroke. J Stroke Cere-
brovasc Dis. 2014;23:850–4.
18. Dmitrieva NI, Burg MB. Elevated sodium and dehydration sti-
mulate inflammatory signaling in endothelial cells and promote
atherosclerosis. PLoS ONE. 2015;10:e0128870.
19. Wang AYM, Lu Y, Cheung S, Chan IHS, Lam CWK. Plasma
sodium and subclinical left atrial enlargement in chronic kidney
disease. Nephrol Dial Transplant. 2013;28:2319–28.
20. Wannamethee SG, Shaper AG, Lennon L, Papacosta O, Whincup
P. Mild hyponatremia, hypernatremia and incident cardiovascular
disease and mortality in older men: a population-based cohort
study. Nutr Metab Cardiovasc Dis. 2016;26:12–9.
21. Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Minhas
R, Sheikh A, et al. Predicting cardiovascular risk in England and
Wales: prospective derivation and validation of QRISK2. BMJ .
2008;336:1475.
View publication stats
22. Department for Communities and Local Government. English
indices of deprivation. https://www.gov.uk/government/collections/
english-indices-of-deprivation. Accessed 19 Sept 2018.
23. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd,
et al. A new equation to estimate glomerular filtration rate. Ann
Intern Med. 2009;150:604–12.
24. Harrell Jr FE. Regression modelling strategies with applications to
linear models, logistic regression, and survival analysis. 1st ed.
New York: Springer-Verlag Publishers; 2001.
25. Zhang Z, Duckart J, Slatore CG, Fu Y, Petrik AF, Thorp ML,
et al. Individuality of the plasma sodium concentration. Am J
Physiol Ren Physiol. 2014;306:F1534–43.
26. Gao S, Xiangqin C, Wang X, Burg MB, Dmitrieva NI. Cross-
sectional positive association of serum lipids and blood pressure
with serum sodium within the normal reference range of 135-145
mmol/L. Arterioscler Thromb Vasc Biol. 2017;37:598–606.
27. Millett C, Laverty AA, Stylianou N, Bibbins-Domingo K, Pape UJ.
Impacts of a national strategy to reduce population salt intake in
England: serial cross sectional study. PLoS ONE. 2012;7:e29836.
28. Public Health England. National Diet and Nutrition Survey:
assessment of dietary sodium. Adults (19 to 64 years) in England,
2014. https://www.gov.uk/government/statistics/national-diet-a
nd-nutrition-survey-assessment-of-dietary-sodium-in-adults-in-
england-2014. Accessed 19 Sept 2018.
29. Alsanjari ON, de Lusignan S, van Vlymen J, Gallagher H, Millett
C, Harris J, et al. Trends and transient change in end-digit pre-
ference in blood pressure recording: studies of sequential and
longitudinal collected primary care data. Int J Clin Pract.
2012;66:37–43.
30. Dmitrieva NI, Burg MB. Secretion of von Willebrand factor by
endothelial cells links sodium to hypercoagulability and throm-
bosis. Proc Natl Acad Sci USA. 2014;111:6485–90.
31. Wild J, Soehnlein O, Dietel B, Urschel K, Garlichs CD, Cicha I.
Rubbing salt into wounded endothelium: sodium potentiates
proatherogenic effects of TNF-alpha under non-uniform shear
stress. Thromb Haemost. 2014;112:183–195.
32. Lilly LS, Dzau VJ, Williams GH, Rydstedt L, Hollenberg NK.
Hyponatremia in congestive heart failure: implications for neu-
rohumoral activation and responses to orthostasis. J Clin Endo-
crinol Metab. 1984;59:924–30.
33. Lee WH, Packer M. Prognostic importance of serum sodium
concentration and its modification by converting-enzyme inhibi-
tion in patients with severe chronic heart failure. Circulation .
1986;73:257–67.
34. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X,
Liu L, et al. Urinary sodium and potassium excretion, mortality,
and cardiovascular events. N Engl J Med. 2014;371:612–23.
35. De Bacquer D, De Backer G, De Buyzere M, Kornitzer M. Is low
serum chloride level a risk factor for cardiovascular mortality? J
Cardiovasc Risk. 1998;5:177–84.