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1
Division of Cardiology,
Healthcare System Gangnam
Center, Seoul National
University Hospital, Seoul, Korea
2
Department of Cardiology,
Asan Medical Center, University
of Ulsan College of Medicine,
Seoul, Korea
3
Division of Cardiology,
Department of Internal
Medicine, Seoul National
University Hospital, Seoul, Korea
4
Department of Cardiology,
Cardiovascular Center, Seoul
National University Bundang
Hospital, Seongnam, Korea
5
Division of Cardiology,
Department of Internal
Medicine, Heart Vascular
Stroke Institute, Samsung
Medical Center, Sungkyunkwan
University School of Medicine,
Seoul, Korea
Correspondence to
Dr Sang Eun Lee, Department
of Cardiology, Asan Medical
Center, University of Ulsan
College of Medicine, 88
Olympic-ro 43-gil, Songpa-
gu, Seoul 138-736, Korea; ​
sangeunlee.​md@​gmail.c​ om
Received 30 June 2017
Revised 5 October 2017
Accepted 5 October 2017
To cite: Lee H, Lee SE,
Park CS, et al. Heart
Published Online First:
[please include Day Month
Year]. doi:10.1136/
heartjnl-2017-312084
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Heart failure and cardiomyopathies
Original research article
Hyponatraemia and its prognosis in acute heart
failure is related to right ventricular dysfunction
Heesun Lee,1 Sang Eun Lee,2 Chan Soon Park,3 Jin Joo Park,4 Ga Yeon Lee,5
Min-Seok Kim,2 Jin-Oh Choi,5 Hyun-jai Cho,3 Hae-Young Lee,3 Dong-Ju Choi,4
Eun-Seok Jeon,5 Jae-Joong Kim,2 Byung-Hee Oh3
ABSTRACT
Objectives  Hyponatraemia is a well-known predictor
of clinical outcomes in heart failure (HF). However,
the mechanism remains poorly understood. Previous
reports suggest that hyponatraemia is related to right
HF. We sought to evaluate the association between right
ventricular (RV) dysfunction and hyponatraemia, and the
impact of this relationship on the prognosis of patients
with acute heart failure (AHF).
Methods  This is a nested case–control study of the
Korean Acute Heart Failure registry. Among 2935 AHF
patients enrolled prospectively and consecutively at
four tertiary hospitals in Korea from 2011 to 2014, 116
patients with severe persistent hyponatraemia, defined
as serum sodium level <130 mmol/L at admission and
<135 mmol/L before discharge, were matched with 232
controls, based on propensity scores for hyponatraemia.
RV function was assessed with fractional area change
(FAC) by echocardiography.
Results  RV dysfunction (FAC <35%) was more
prevalent in patients with severe persistent
hyponatraemia than in those without (81.0% vs 33.6%,
p<0.001). Hyponatraemia was strongly associated
with RV dysfunction (adjusted OR 8.00, 95% CI 4.50
to 14.22, p<0.001), but not with left ventricular
dysfunction (adjusted OR 1.21, 95% CI 0.74 to
1.50, p=0.308). RV dysfunction was an independent
predictor of all-cause mortality, after adjustment for
hyponatraemia (adjusted HR 2.20, 95% CI 1.53 to 3.15,
p<0.001), while hyponatraemia was not (adjusted HR
1.33, 95% CI 0.94 to 1.87, p=0.108).
Conclusions  In patients with AHF, hyponatraemia was
more common with RV dysfunction. RV dysfunction,
rather than hyponatraemia, was more significantly
related with patients’ prognosis. Thus, the utility of RV
dysfunction instead of hyponatraemia per se should be
considered in HF risk models.
Trial registration number  Korean Acute Heart Failure
registryNCT01389843;Results.
Introduction
Hyponatraemia, the most common electrolyte
imbalance in heart failure (HF), occurs in 20%–25%
of patients1 2; it is as a surrogate marker of advanced
disease and a significant predictor of poor outcomes
in acute and chronic HF.1–5 Although the non-os-
motic release of arginine vasopressin (AVP) due to
arterial underfilling may be associated with hypona-
traemia, the mechanism underpinning deleterious
effects and the clinical features of hyponatraemia in
Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
HF remain unknown.1 3 5 In our previous study of
patients hospitalised for acute heart failure (AHF),
an improvement of hyponatraemia was not asso-
ciated with a better clinical outcome.6 Further,
vasopressin antagonist therapy fails to improve
survival in HF patients.7 These findings suggest
that increased release of AVP and consequent hypo-
natraemia may not determine a poor prognosis
in HF; rather, the causative factor responsible for
both AVP and hyponatraemia is likely implicated.
Right ventricular (RV) function is a strong predictor
of mortality in various cardiac diseases, including
HF.8 9 Several prior studies have propounded an
association between hyponatraemia and RV func-
tion. An experiment in dogs showed indicated
that hyponatraemia predominated in those with
right HF.10 Two prospective studies with pulmo-
nary arterial hypertension demonstrated similar
results, noting that hyponatraemia was associated
with right HF.11 12 Similarly, in the Korean Acute
Heart Failure (KorAHF) registry, the prevalence of
hyponatraemia was significantly higher in patients
with isolated right HF than in those with other HF
subtypes (27.1% vs 20.9%, p=0.002).13 Here, we
hypothesised that hyponatraemia might be asso-
ciated with RV dysfunction in patients with AHF,
which accounts for the poor prognosis.
Methods
Study population
This was a nested case–control study from the
KorAHF registry, which is a prospective multicentre
cohort study designed to describe the characteris-
tics and clinical outcomes of patients hospitalised
for AHF in Korea.13 14 We enrolled 2935 patients
(52.2%) from four hospitals whose echocardio-
graphic data were available. Among them, 122
patients (4.2%) showed severe persistent hypona-
traemia, defined as serum sodium concentration
(sNa) <130 mmol/L at admission and <135 mmol/L
before discharge. After excluding six patients on
dialysis, 116 patients were allocated as cases. To
assess the independent relationship between hypo-
natraemia and RV dysfunction by reducing selec-
tion bias and statistical inferences of confounders
related with hyponatraemia, we matched controls
without hyponatraemia to cases according to a
propensity score (PS). The PS, as a predicted prob-
ability for severe persistent hyponatraemia, was
derived for each patient with logistic regression.15
Twelve variables that significantly differed included
  1
 Downloaded from http://heart.bmj.com/ on October 29, 2017 - Published by group.bmj.com
Heart failure and cardiomyopathies
Figure 1  Flow chart of the study population. KorAHF, Korean Acute Heart Failure.
to estimate the PS: alcohol, body mass index, history of hyper-
tension, de novo HF, systolic and diastolic blood pressure, pulse
rate, haemoglobin, renin-angiotensin system (RAS) blockers,
beta-blockers, aldosterone antagonists and loop diuretics. We
used a 1:2 nearest-neighbour-matching method without replace-
ment, with no interactions included.16 Finally, we matched 116
patients with severe persistent hyponatraemia and 232 controls
on the logit of PSs (figure 1). The protocol conformed to the
Declaration of Helsinki, and was approved by the institutional
review board of all hospitals with a waiver of written informed
consent.
Clinical data and follow-up
We collected clinical information, laboratory results, electro-
cardiography, echocardiography and outcomes at admission,
discharge and during follow-up (30 days, 90 days, 180 days,
and 1 to 5 years, annually). Serial sNa values were collected
according to the attending physician’s clinical decision, without
a fixed interval. Detailed information regarding data collection
has been described previously.13 14 All information was ascer-
tained from patients by attending physicians. The mortality data
were collected from national insurance data or death records.
Echocardiographic evaluation
All patients underwent a comprehensive echocardiographic
examination at admission by certified cardiologists using commer-
cially available equipment with second-harmonic imaging and
a 3.5 MHz transducer. Echocardiographic evaluation was
conducted according to current guidelines.16 17 Left ventric-
ular ejection fraction (LVEF) was calculated from apical four-
chamber and two-chamber views using the modified Simpson’s
biplane method. If technically impossible, EF was evaluated with
M-mode or visual estimation by experienced cardiologists. RV
function was evaluated by the fractional area change (FAC) from
an RV-optimised apical four-chamber view by tracing endocar-
dial borders at end-diastole and end-systole.17 RV dysfunction
was defined as FAC <35%. To minimise measurement bias, RV
FAC was measured by two independent cardiologists, with final
values decided by agreement. Tricuspid regurgitation (TR) was
graded as 0 (nil) to 4 (severe), based on synthetic information
regarding valve morphology, vena contracta width, proximal
flow convergence radius and hepatic venous flow pattern.17
The diameter of the inferior vena cava (IVC) and its respiratory
variation were measured 10–20 mm from the junction with the
right atrium in the subcostal view, with an IVC size ≥20 mm and
failure to collapse ≥50% during inspiration defined as dilatation
and plethora, respectively.18 Pulmonary artery systolic pressure
2 Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
(PASP) was estimated by adding right atrial pressure to peak
trans-tricuspid pressure gradient at systole.19
Reproducibility
Intraobserver and interobserver variabilities for RV FAC value
were assessed. Measurement of RV FAC was repeated twice
within 2 weeks to assess the intraobserver variability. Interob-
server variability was evaluated by comparing the value from two
separate observers. Reproducibility was assessed using Bland-Al-
tman analysis and intraclass correlation coefficient.
Statistical analysis
Descriptive statistics were used for clinical and echocardio-
graphic characteristics, prevalence of RV dysfunction and
death according to hyponatraemia. A p<0.05 was considered
statistically significant. Data were presented as numbers and
percentages for categorical variables, and mean±SD for contin-
uous variables. Differences between continuous variables were
compared using Student’s t-test or Wilcoxon rank sum test for
independent samples, while those between categorical variables
were analysed by the χ2 test or Fisher’s exact test, as appropriate.
PS matching was performed to adjust the differences in baseline
characteristics of the study population. All of the standardised
differences for each of the baseline variables were <0.10 after
matching. The predictive ability of our PS matching was assessed
by the c-statistic (0.658) and p value of Hosmer and Lemeshow
Goodness-of-Fit Test was 0.872, indicating good discrimination
between the groups (χ2=3.835, df=8). In PS-matched cohort,
associations of echocardiographic parameters with severe
persistent hyponatraemia were derived from univariable and
multivariable analyses with stepwise selection, and expressed
as OR and corresponding 95% CI. Survival was determined
using Kaplan-Meier analysis with the generalised Wilcoxon test
to give greater weight to survival differences occurring at the
early period of the study, since the proportional hazard assump-
tion was not satisfied (p=0.034). Cox regression analyses were
employed to determine significant predictors of survival during
follow-up, including severe persistent hyponatraemia and RV
dysfunction. The risk of all-cause death was expressed as an HR
and corresponding 95% CI from univariable and multivariable
analyses with stepwise selection. Sequential Cox analysis using
four nested models ((1) significant clinical risk factors according
to univariable analysis; (2) clinical risk factors+severe persistent
hyponatraemia; (3) clinical risk factors+severe persistent hypo-
natraemia+left  ventricular (LV)  dysfunction; and (4) clinical
risk factors+severe persistent hyponatraemia+RV dysfunction)
was used to evaluate independent predictors and to compare
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Heart failure and cardiomyopathies

Table 1  Baseline characteristics in total patients before propensity score matching

Total patients Patients with severe persistent Patients without severe persistent
Variables (n=2935) hyponatraemia (n=122) hyponatraemia (n=2813) p
Demographics
 Age, year 67.8±14.9 70.1±13.8 67.7±14.9 0.062
  ≥65  years (%) 1929 (65.7) 88 (72.1) 1841 (65.4) 0.128
 Male (%) 1634 (55.7) 70 (57.4) 1564 (55.6) 0.699
 Current smoking (%) 521 (17.8) 15 (12.3) 506 (18.0) 0.107
 Alcohol (%) 1261 (43.0) 39 (32.0) 1222 (43.4) 0.012
 BMI, kg/m2 23.4±4.1 22.5±3.8 23.4±4.1 0.010
Medical history
 Hypertension (%) 1719 (58.6) 54 (44.3) 1665 (59.2) 0.001
 Diabetes mellitus (%) 1051 (35.8) 41 (33.6) 1010 (35.9) 0.604
 Chronic kidney disease (%) 465 (15.8) 18 (15.5) 447 (15.9) 0.917
 Ischaemic heart disease (%) 843 (28.7) 34 (27.9) 809 (28.8) 0.222
 Atrial fibrillation (%) 940 (32.0) 48 (39.3) 892 (31.7) 0.114
 Chronic obstructive lung disease (%) 477 (16.3) 19 (15.6) 458 (16.3) 0.836
Aetiology
 Ischaemic (%) 878 (29.9) 37 (30.3) 841 (29.9) 0.919
Clinical status on admission
 De novo heart failure (%) 1432 (48.8) 43 (35.2) 1389 (49.4) 0.002
 Systolic BP, mm Hg 130.7±44.2 118.3±28.2 131.2±44.7 0.002
 Diastolic BP, mm Hg 79.0±39.2 70.1±17.7 79.3±39.8 <0.001
 Pulse rate, beats/min 92.5±35.4 83.5±24.1 92.9±35.7 <0.001
 NYHA class ≥III (%) 2526 (86.1) 104 (85.2) 2422 (86.1) 0.790
 LV ejection fraction, % 37.8±15.5 38.3±16.5 37.8±15.5 0.708
  <40% 1253 (42.7) 57 (46.7) 1196 (42.5) 0.358
 Hb, g/dL 12.4±2.3 11.9±2.4 12.4±2.3 0.010
 sCr, mg/dL 1.6±1.7 1.7±1.7 1.6±1.7 0.353
Evidence-based medical therapy before admission
 RAS blocker (%) 1243 (42.4) 63 (51.6) 1180 (41.9) 0.034
 Beta-blocker (%) 940 (32.0) 29 (23.8) 911 (32.4) 0.046
 Aldosterone antagonist (%) 579 (19.7) 59 (48.4) 520 (18.5) <0.001
 Loop diuretics (%) 2660 (90.6) 116 (95.1) 2544 (90.4) 0.042
 Nitrate (%) 1939 (66.1) 75 (61.5) 1864 (66.3) 0.274
 Amiodarone (%) 525 (17.9) 26 (21.3) 499 (17.7) 0.313
 Digitalis (%) 1032 (35.2) 50 (41.0) 982 (34.9) 0.169
Outcome
 1-year mortality (%) 714 (24.3) 59 (48.4) 655 (23.3) <0.001
BMI, body mass index; BP, blood pressure; Hb, haemoglobin; LV, left ventricular; NYHA, New York Heart Association; RAS, renin angiotensin system; sCr, serum creatinine.

the prognostic value among hyponatraemia per se, LV dysfunc-
tion and RV dysfunction. Subgroup analysis according to LVEF
was performed to determine the effect of LV function on the
relationship between hyponatraemia and RV dysfunction. All
analyses were performed using SPSS V.22.0 (SPSS, Chicago, Illi-
nois, USA) and the MatchIt R package (R Development Core
Team, Ho et al, 2011).
Results
Baseline clinical characteristics
Among all patients (n=2935, age 67.8±14.9 years, male
55.7%), hyponatraemia (sNa <135 mmol/L) was present in 697
(23.7%) patients, of which 122 (4.2%) had severe persistent
hyponatraemia. Patients with severe persistent hyponatraemia
(n=122, age 70.1±13.8 years, male 57.4%) were older, thinner,
had a higher prevalence of alcohol history, hypertension and use
of evidence-based medication and lower systolic/diastolic pres-
sures and haemoglobin. Such patients exhibited higher 1-year
mortality than those without (table 1). After excluding dialysis
Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
patients, 116 patients with severe persistent hyponatraemia were
compared with 232 PS-matched equivalents. No differences in
baseline characteristics were noted. Matched patients (n=348;
116 with persistent hyponatraemia and 232 controls) had a mean
age of 69.5±14.3 years, and 57.8% were male. The percent-
ages of hypertension, diabetes mellitus and atrial fibrillation
were 45.4%, 34.8% and 39.1%, respectively. The most frequent
cause of HF was ischaemia (40.0%). Approximately one-third
of these patients presented with de novo HF (37.4%), and half
were classified as New York Heart Association (NYHA) class IV
(48.0%). Prior evidence-based medical therapies included RAS
blockers (50.0%), beta-blockers (23.6%) and aldosterone antag-
onists (44.8%) (table 2).
Echocardiographic characteristics
The mean LV and RV systolic function, indicated by LVEF
and RV FAC, were 36.3% and 34.1%, respectively. RV FAC
was significantly lower in patients with severe persistent hypo-
natraemia (28.2% vs 37.1%, p<0.001), whereas LVEF did
3
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Heart failure and cardiomyopathies

Table 2  Baseline characteristics in propensity score-matched patients

Total patients Patients with severe persistent Patients without severe persistent
Variables (n=348) hyponatraemia (n=116) hyponatraemia (n=232) p
Demographics
 Age, year 69.5±14.3 70.0±14.0 69.3±14.5 0.663
  ≥65  years (%) 240 (69.0) 84 (72.4) 156 (67.2) 0.326
 Male (%) 201 (57.8) 68 (58.6) 133 (57.3) 0.818
 Current smoking (%) 49 (14.1) 13 (11.2) 36 (15.5) 0.276
 Alcohol (%) 110 (31.6) 37 (31.9) 73 (31.5) 0.935
 BMI, kg/m2 22.6±3.7 22.6±3.8 22.6±3.6 0.815
  ≥25  kg/m2 (%) 78 (22.4) 26 (22.4) 52 (22.4) 0.999
Medical history
 Hypertension (%) 158 (45.4) 53 (45.7) 105 (45.3) 0.939
 Diabetes mellitus (%) 121 (34.8) 40 (34.5) 81 (34.9) 0.937
 Chronic kidney disease (%) 55 (15.8) 18 (15.5) 37 (15.9) 0.917
 Ischaemic heart disease (%) 80 (23.0) 29 (25.0) 51 (22.1) 0.542
 Atrial fibrillation (%) 136 (39.1) 48 (41.4) 88 (37.9) 0.534
 Chronic obstructive lung disease (%) 33 (9.5) 12 (10.3) 21 (9.1) 0.698
Aetiology
 Ischaemic (%) 139 (40.0) 39 (33.6) 100 (43.1) 0.069
Clinical status on admission
 De novo heart failure (%) 130 (37.4) 43 (37.1) 87 (37.5) 0.938
 Systolic BP, mm Hg 117.9±27.4 119.3±28.3 117.1±27.0 0.220
 Diastolic BP, mm Hg 71.2±17.4 70.1±17.9 71.7±17.1 0.578
 Pulse rate, beats/min 87.9±25.8 83.9±24.0 89.9±26.5 0.185
 NYHA class≥III (%) 301 (86.5) 100 (86.2) 201 (86.6) 0.912
 Hb, g/dL 11.8±2.4 11.9±2.3 11.8±2.5 0.900
 sCr, mg/dL 1.7±1.9 1.7±1.7 1.7±2.1 0.941
Evidence-based medical therapy before admission
 RAS blocker (%) 174 (50.0) 58 (50.0) 116 (50.0) 0.999
 Beta-blocker (%) 82 (23.6) 26 (22.4) 56 (24.1) 0.721
 Aldosterone antagonist (%) 156 (44.8) 54 (46.4) 102 (44.2) 0.672
 Loop diuretics (%) 323 (92.8) 110 (94.8) 213 (91.8) 0.304
 Nitrate (%) 215 (61.8) 72 (62.1) 143 (61.6) 0.938
 Amiodarone (%) 82 (23.6) 25 (21.6) 57 (24.6) 0.532
 Digitalis (%) 148 (42.5) 49 (42.2) 99 (42.7) 0.999
Outcome
 1-year mortality (%) 110 (31.6) 55 (47.4) 55 (23.7) <0.001
BMI, body mass index; BP, blood pressure; Hb, haemoglobin; LV, left ventricular; NYHA, New York Heart Association; RAS, renin angiotensin system; sCr, serum creatinine.

not differ (38.1% vs 35.5%, p=0.149). In addition, patients
with severe persistent hyponatraemia showed significant TR
(33.6% vs 22.0%, p=0.019), an estimated PASP of ≥40 mm
Hg (65.5% vs 54.7%, p=0.035), and IVC plethora (47.0% vs
25.2%, p<0.001) more frequently (table 3). The measurement
errors for RV FAC were small (differences within and between
observers, –0.12%±3.95% and 0.10%±4.15%) (online supple-
mentary figure). Reproducibility for RV FAC was good (intra-
class correlation coefficients were 0.89 (intraobserver) and 0.80
(interobserver); p<0.001).
Severe persistent hyponatraemia and RV systolic function
RV dysfunction was observed in 81.0% (94/116) of patients with
severe persistent hyponatraemia, and 33.6% (78/232) of patients
without (χ2=69.6, p<0.001) (table 3). The strongest associa-
tion of severe persistent hyponatraemia was with RV dysfunc-
tion (unadjusted OR 8.43, 95% CI 4.93 to 14.45, p<0.001); in
contrast, no significant relationship was noted with LV dysfunc-
tion (unadjusted OR 1.22, 95% CI 0.96 to 1.51, p=0.091).
Severe persistent hyponatraemia was associated with TR ≥grade
4 Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
3 (unadjusted OR 1.80, 95% CI 1.10 to 2.95, p=0.020), IVC
plethora (unadjusted OR 2.63, 95% CI 1.64 to 4.21, p<0.001)
and a PASP of ≥40 mm Hg (unadjusted OR 1.57, 95% CI 1.00 to
2.49, p=0.049), suggesting a close correlation with RV dysfunc-
tion. In the multivariable logistic model, RV dysfunction, IVC
plethora and TR ≥grade 3 maintained independent associations
with severe persistent hyponatraemia, while LV dysfunction was
not statistically significant (table 4).
Survival according to severe persistent hyponatraemia and
RV systolic function
During follow-up (median 24 months, IQR 6–36 months),
160 patients (46.0%) died in the matched cohort, two-thirds
of which occurred within 1 year (n=110, 31.6%). Sixty-nine
deaths during follow-up occurred in patients with severe
persistent hyponatraemia, predominating in the subgroup
with concomitant RV dysfunction (61/94 with RV dysfunction
vs 8/22 without RV dysfunction). In univariable Cox regres-
sion analysis, ageing, anaemia with haemoglobin <11  g/dL,
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Heart failure and cardiomyopathies

Table 3  Echocardiographic characteristics in propensity score-matched patients

Patients with severe persistent Patients without severe persistent
Variables Total patients (n=348) hyponatraemia (n=116) hyponatraemia (n=232) p
LV ejection fraction, % 36.3±15.9 38.1±16.8 35.5±15.3 0.149
 <40% (%) 224 (64.4) 68 (58.6) 156 (67.8) 0.091
RVEDA, cm2 28.5±12.1 31.8±12.2 33.0±12.1 0.383
RVESA, cm2 19.1±9.3 24.3±10.0 22.5±8.7 0.088
RV fractional area change, % 34.1±10.4 28.2±10.2 37.1±9.1 <0.001
 <35% 172 (49.7) 94 (81.0) 78 (33.6) <0.001
Tricupid regurgitation, grade 1.9±1.0 2.1±1.0 1.8±0.9 0.002
 ≥grade 3 (%) 90 (25.9) 39 (33.6) 51 (22.0) 0.019
Estimated PASP, mmHg 45.0±16.1 47.6±17.2 43.5±15.5 0.030
 ≥40 mm Hg (%) 203 (58.3) 76 (65.5) 127 (54.7) 0.035
Size of inferior vena cava (IVC), mm 21.5±5.9 21.9±5.3 21.2±6.2 0.319
IVC dilatation≥20 mm (%) 82 (23.6) 33 (28.7) 49 (21.8) 0.181
IVC plethora (%) 112 (32.2) 54 (47.0) 58 (25.2) <0.001
LV, left ventricular; PASP, pulmonary artery systolic pressure; RV, right ventricle; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area.

severe persistent hyponatraemia, prior use of beta-blockers and patients regardless of hyponatraemia (p=0.014 and p=0.004)
decreasing RV FAC were significant predictors for all-cause death (figure 2B, C).
(online supplementary table 1). Severe persistent hyponatraemia
increased the risk of death by approximately 90% (unadjusted
HR 1.91, p<0.001). RV dysfunction showed more than twofold Subgroup analysis according to LV systolic function
hazard increase for death (unadjusted HR 2.28, p<0.001), To assess the influence of LV function on developing severe
whereas LV dysfunction failed to show any such association persistent hyponatraemia in patients with AHF, subgroup
(unadjusted HR 1.02, p=0.700). In multivariable Cox models, analysis according to LVEF (≤40% and>40%) was performed
severe persistent hyponatraemia was independently associated (online supplementary table 2). No difference in the prevalence
with poor clinical outcome (adjusted HR 1.86, 95% CI 1.35 of severe persistent hyponatraemia was observed (33.5% vs
to 2.54, p<0.001) after adjusting for age, haemoglobin <11 g/ 39.3%, p=0.096). Severe persistent hyponatraemia was strongly
dL and prior use of beta-blockers (model 2). The independent associated with RV dysfunction regardless of LVEF (≤40%:
association between death and severe persistent hyponatraemia adjusted OR 7.15, 95% CI 3.55 to 14.41, p<0.001;>40%:
disappeared following inclusion of RV dysfunction in the model adjusted OR 11.59, 95% CI 7.81 to 19.67, p<0.001). It alludes
(model 4); conversely, statistical significance for severe persistent that RV function, rather than LV function, is significant in the
hyponatraemia remained regardless of LV dysfunction (model development of hyponatraemia.
3). RV dysfunction exhibited the strongest prognostic value for
death, even after adjustment for other significant predictors,
including severe persistent hyponatraemia (adjusted HR 2.20, Table 5  Multivariable Cox regression models for all-cause death
95% CI 1.53 to 3.15, p<0.001) (table 5). When we categorised Models Adjusted HR (95% CI) p
patients into four groups according to sNa and RV FAC, clin- Model 1
ical outcome was dependent on the presence of RV dysfunc-  Age 1.02 (1.01 to 1.03) 0.005
tion. Kaplan-Meier survival curves revealed patients with severe  Hb at admission <11 g/dL 1.49 (1.09 to 2.04) 0.015
persistent hyponatraemia and RV dysfunction had the worst  Prior use of beta-blocker 0.64 (0.42 to 0.96) 0.030
prognosis, followed by those with RV dysfunction without Model 2
hyponatraemia and those without RV dysfunction (p<0.001)  Age 1.02 (1.01 to 1.03) 0.006
(figure 2A). However, hyponatraemia was not associated with
 Hb at admission <11 g/dL 1.45 (1.03 to 1.94) 0.032
the clinical prognosis in patients without RV dysfunction. RV
 Prior use of beta-blocker 0.63 (0.42 to 0.94) 0.025
dysfunction was consistently associated with worse survival in
 Severe persistent hyponatraemia 1.86 (1.35 to 2.54) <0.001
Model 3
Table 4  Univariable and multivariable analysis for the association  Age 1.02 (1.01 to 1.03) 0.004
with severe persistent hyponatraemia  Hb at admission <11 g/dL 1.42 (1.03 to 1.95) 0.023
Unadjusted OR Adjusted OR  Prior use of beta-blocker 0.63 (0.42 to 0.94) 0.026
Variables (95% CI) p (95% CI) p  Severe persistent hyponatraemia 1.86 (1.36 to 2.55) <0.001
LV ejection 1.22 (0.96 to 1.51) 0.091 1.21 (0.74 to 1.50) 0.308  LVEF <40% 1.26 (0.90 to 1.76) 0.175
fraction<40% Model 4
RV FAC<35% 8.43 (4.93 to 14.45) <0.001 8.00 (4.50 to 14.22) <0.001  Age 1.02 (1.01 to 1.03) 0.001
IVC dilatation 1.50 (0.90 to 2.50) 0.124 – –  Hb at admission <11 g/dL 1.56 (1.13 to 2.15) 0.006
IVC plethora 2.63 (1.64 to 4.21) <0.001 1.52 (1.08 to 2.64) 0.033  Prior use of beta-blocker 0.71 (0.47 to 1.07) 0.104
TR of ≥grade 3 1.80 (1.10 to 2.95) 0.020 1.14 (1.04 to 2.04) 0.046  Severe persistent hyponatraemia 1.33 (0.94 to 1.87) 0.108
PASP≥40 mm Hg 1.57 (1.00 to 2.49) 0.049 1.18 (0.68 to 2.04) 0.558  RV FAC<35% 2.20 (1.53 to 3.15) <0.001
LV, left ventricular; FAC, fractional area change; IVC, inferior vena cava; PASP, Hb, haemoglobin; FAC, fractional area change;LVEF, left ventricular ejection fraction;
pulmonary artery systolic pressure; RV, right ventricle; TR, tricuspid regurgitation. RV, right ventricular.

Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084 5

 Downloaded from http://heart.bmj.com/ on October 29, 2017 - Published by group.bmj.com

Heart failure and cardiomyopathies

Figure 2  Kaplan-Meier survival curves according to combination of serum sodium and right ventricular (RV) fractional area change (FAC). (A)
Curves stratified according to presence of persistent hyponatraemia or RV dysfunction (RVD). Patients with persistent hyponatraemia/with RVD had
the worst prognosis of all subgroups. (B) In patients with persistent hyponatraemia, RVD could stratify the risk of event-free survival. (C) In patients
without persistent hyponatraemia, RVD could also provide risk stratification for long-term clinical outcome. 

Discussion RV dysfunction as a key feature of hyponatraemia in HF

The main findings of this study are as follows: (1) in AHF,
severe persistent hyponatraemia was significantly and inde-
pendently associated with RV dysfunction; (2) both severe
persistent hyponatraemia and RV dysfunction were significant
predictors of all-cause mortality during follow-up; (3) severe
persistent hyponatraemia was not independently associated
with death after adjusting for RV dysfunction, but main-
tained independence regardless of LV dysfunction; and (4)
RV dysfunction improved risk prediction in patients with and
without severe persistent hyponatraemia.
6 Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
Although prior studies have evaluated hyponatraemia in HF
patients,1 3–7 the nature of hyponatraemia and subsequent poor
prognosis in HF remains unknown.20 Indeed, LV dysfunction alone
cannot account for the aetiopathogenesis or clinical features of
hyponatraemia.20–22 In an American cohort of 8862 ambulatory
patients with HF (6185 with reduced LVEF and 2704 with preserved
LVEF), hyponatraemia was prevalent at a similar frequency (>10%)
and was an independent predictor in both patients regardless of
LVEF.21 Rusinaru et al22 reported that hyponatraemia on admission
was observed in 25.4% of patients with HF with preserved EF, an
 Downloaded from http://heart.bmj.com/ on October 29, 2017 - Published by group.bmj.com
incidence at least equivalent to that observed in large registries of
HF with reduced EF.1 2 In agreement with previous findings, our
analysis demonstrated that the prevalence of severe persistent hypo-
natraemia did not differ between patients with LVEF <40% and
≥40% (3.9% vs 4.5%; p=0.400). Additionally, LV dysfunction was
not significantly associated with severe persistent hyponatraemia
in the PS matched cohort (p=0.308). In contrast, RV dysfunction
was highly prevalent, and had more than eightfold increased risk
in patients with severe persistent hyponatraemia. Furthermore,
severe persistent hyponatraemia was associated with IVC plethora
and significant TR, congruent with RV dysfunction. These results
provide the first evidence of a strong association between hypona-
traemia and RV function in HF and a different viewpoint on the
pathophysiological mechanism of hyponatraemia in HF.
Mechanism of hyponatraemia and RV dysfunction in HF
Though the pathogenesis of hyponatraemia in HF is multifactorial,
it is generally assumed that hyponatraemia develops due to non-os-
motic release of AVP resulting from a decrease in arterial barore-
ceptor stretch during low cardiac output in HF.23 24 However, low
cardiac output can develop earlier in cases of RV dysfunction, due
to decreased LV preload and ventricular interdependence, while LV
dysfunction can mitigate the low cardiac output phenomenon by
compensatory chamber dilatation.25 This is prominent in cardio-
genic shock from RV infarction. Non-osmotic AVP can be also
released by systemic arterial vasodilation during portal hyperten-
sion, which is frequently caused by liver cirrhosis but also occasion-
ally by right HF.24 26 In some patients with severe and progressive
RV failure, pulmonary arterial pressure and left atrial (LA) pressure
may decrease as a consequence of small RV stroke volume.25 Baro-
receptors in the LA inhibit AVP release and encourage water excre-
tion in response to any increase in atrial pressure, a phenomenon
known as the Henry-Gauer reflex.27 Theoretically, low LA pres-
sure induced by severe RV dysfunction could weaken the Henry-
Gauer reflex, and consequently disturb inhibition of AVP release.
However, since the role of the RV in HF has been relatively over-
looked until recently,25 further study regarding RV dysfunction and
hyponatraemia is needed.
RV dysfunction as a key player of poor prognosis
RV dysfunction was the strongest independent predictor of long-
term prognosis regardless of sNa status in this study, while the
predictive power of hyponatraemia was attenuated by adjustment
with RV dysfunction. In the multivariable Cox regression model, a
10% decrease in RV FAC was associated with >30% increase in the
risk of death; indeed, only RV dysfunction significantly increased
long-term mortality more than twofold, even after adjustment for
hyponatraemia. Such results are consistent with previous studies
demonstrating the independent prognostic value of RV function in
advanced HF.9 28–30 Di Salvo et al noted that RV FAC ≥35% was a
more powerful predictor of survival in HF than LVEF or exercise
capacity.30 In prior research by our group,6 improvement of hypo-
natraemia during hospitalisation revealed no significant associa-
tion with a better prognosis in patients with AHF, except for those
having elevated blood urea nitrogen (BUN). Hyponatraemia may
indirectly reflect the severity of RV dysfunction in patients with
AHF, given that BUN elevation could indicate systemic congestion.
This implies that the role of hyponatraemia as a predictor of long-
term poor prognosis might derive from concomitant RV dysfunc-
tion and it is necessary to consider close monitoring and intensive
treatment in AHF patients with RV dysfunction. Furthermore,
RV dysfunction might be a therapeutic target in HF patients with
hyponatraemia.
Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
Heart failure and cardiomyopathies
Study limitations
First, as this study was an observational study from a prospective
AHF registry, unmeasured confounding variables may have been
present. Second, our definition of severe persistent hyponatraemia
was arbitrary; however, severe persistent hyponatraemia as a
metric is more suitable for assessment of relationships between RV
dysfunction and hyponatraemia than instantaneous measurements
since sNa can change temporally and dynamically with medication
and fluid changes, rather than disease activity. Third, RV function
was evaluated by 2D FAC only, which could be insufficient to
accurately assess RV. However, as RV-focused apical four-chamber
view was successfully obtained in all participants, and interobserver
variability for RV FAC was good. Lastly, the study population was
enrolled from an AHF registry in Korea; therefore, further inter-
national studies are needed to validate and generalise our results.
Key messages
What is already known on this subject?
►► Hyponatraemia is the most common electrolyte imbalance in
heart failure (HF). It is one of the strongest prognostic factors
of poor clinical outcome in patients with HF.
►► Previous reports have suggested that hyponatraemia is
related with right HF.
What might this study add?
►► This study provides the first evidence that the development of
hyponatraemia by right ventricular (RV) dysfunction (adjusted
OR 8.00, 95% CI 4.50 to 14.22, p<0.001) in acute HF.
Furthermore, RV dysfunction was an independent predictor
of all-cause mortality (adjusted HR 2.20, 95% CI 1.53 to 3.15,
p<0.001), while hyponatraemia was not (adjusted HR 1.33,
95% CI 0.94 to 1.87, p=0.108).
How might this impact on clinical practice?
►► This study helps us understand the role of RV dysfunction in
the development of hyponatraemia and its clinical relevance
in HF. These findings can potentially improve HF management
and clinical outcomes via identification of a novel therapeutic
target. It also highlights the importance of considering the
utility of RV dysfunction, instead of hyponatraemia, in HF risk
models.
Contributors  Conception and design, HL, SEL, HJC, HYL, BHO; data acquisition,
HL, SEL, CSP, JJP, GYL, MK; data analysis and interpretation, HL, SEL, CSP; statistical
analysis, HL, SEL; drafting and finalising the article, HL, SEL, BHO; critical revision of
the article for important intellectual content, HL, SEL, JJP, GYL, HJC, HYL, DJC, JOC,
ESJ, JJK.
Funding  This work was supported by grants from the Research of Korea Centres for
Disease Controland Prevention [2010-E63003-00, 2011-E63002-00, 2012-E63005-
00, 2013-E63003-00,2013-E63003-01, 2013-E63003-02, and 2016-ER6303-00].
Competing interests  None declared.
Patient consent  Obtained.
Ethics approval  Seoul National University Hospital, Asan Medical Center, Seoul
National University Bundang Hospital, Samsung Medical Center.
Provenance and peer review  Not commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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 Downloaded from http://heart.bmj.com/ on October 29, 2017 - Published by group.bmj.com

Hyponatraemia and its prognosis in acute

heart failure is related to right ventricular
dysfunction
Heesun Lee, Sang Eun Lee, Chan Soon Park, Jin Joo Park, Ga Yeon
Lee, Min-Seok Kim, Jin-Oh Choi, Hyun-jai Cho, Hae-Young Lee, Dong-Ju
Choi, Eun-Seok Jeon, Jae-Joong Kim and Byung-Hee Oh

Heart published online October 27, 2017

Updated information and services can be found at:

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