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Heart Online First, published on October 27, 2017 as 10.1136/heartjnl-2017-312084
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- (PASP) was estimated by adding right atrial pressure to peak
tension, de novo HF, systolic and diastolic blood pressure, pulse trans-tricuspid pressure gradient at systole.19
rate, haemoglobin, renin-angiotensin system (RAS) blockers,
beta-blockers, aldosterone antagonists and loop diuretics. We Reproducibility
used a 1:2 nearest-neighbour-matching method without replace- Intraobserver and interobserver variabilities for RV FAC value
ment, with no interactions included.16 Finally, we matched 116 were assessed. Measurement of RV FAC was repeated twice
patients with severe persistent hyponatraemia and 232 controls within 2 weeks to assess the intraobserver variability. Interob-
on the logit of PSs (figure 1). The protocol conformed to the server variability was evaluated by comparing the value from two
Declaration of Helsinki, and was approved by the institutional separate observers. Reproducibility was assessed using Bland-Al-
review board of all hospitals with a waiver of written informed tman analysis and intraclass correlation coefficient.
consent.
Statistical analysis
Clinical data and follow-up Descriptive statistics were used for clinical and echocardio-
We collected clinical information, laboratory results, electro- graphic characteristics, prevalence of RV dysfunction and
cardiography, echocardiography and outcomes at admission, death according to hyponatraemia. A p<0.05 was considered
discharge and during follow-up (30 days, 90 days, 180 days, statistically significant. Data were presented as numbers and
and 1 to 5 years, annually). Serial sNa values were collected percentages for categorical variables, and mean±SD for contin-
according to the attending physician’s clinical decision, without uous variables. Differences between continuous variables were
a fixed interval. Detailed information regarding data collection compared using Student’s t-test or Wilcoxon rank sum test for
has been described previously.13 14 All information was ascer- independent samples, while those between categorical variables
tained from patients by attending physicians. The mortality data were analysed by the χ2 test or Fisher’s exact test, as appropriate.
were collected from national insurance data or death records. PS matching was performed to adjust the differences in baseline
characteristics of the study population. All of the standardised
Echocardiographic evaluation differences for each of the baseline variables were <0.10 after
All patients underwent a comprehensive echocardiographic matching. The predictive ability of our PS matching was assessed
examination at admission by certified cardiologists using commer- by the c-statistic (0.658) and p value of Hosmer and Lemeshow
cially available equipment with second-harmonic imaging and Goodness-of-Fit Test was 0.872, indicating good discrimination
a 3.5 MHz transducer. Echocardiographic evaluation was between the groups (χ2=3.835, df=8). In PS-matched cohort,
conducted according to current guidelines.16 17 Left ventric- associations of echocardiographic parameters with severe
ular ejection fraction (LVEF) was calculated from apical four- persistent hyponatraemia were derived from univariable and
chamber and two-chamber views using the modified Simpson’s multivariable analyses with stepwise selection, and expressed
biplane method. If technically impossible, EF was evaluated with as OR and corresponding 95% CI. Survival was determined
M-mode or visual estimation by experienced cardiologists. RV using Kaplan-Meier analysis with the generalised Wilcoxon test
function was evaluated by the fractional area change (FAC) from to give greater weight to survival differences occurring at the
an RV-optimised apical four-chamber view by tracing endocar- early period of the study, since the proportional hazard assump-
dial borders at end-diastole and end-systole.17 RV dysfunction tion was not satisfied (p=0.034). Cox regression analyses were
was defined as FAC <35%. To minimise measurement bias, RV employed to determine significant predictors of survival during
FAC was measured by two independent cardiologists, with final follow-up, including severe persistent hyponatraemia and RV
values decided by agreement. Tricuspid regurgitation (TR) was dysfunction. The risk of all-cause death was expressed as an HR
graded as 0 (nil) to 4 (severe), based on synthetic information and corresponding 95% CI from univariable and multivariable
regarding valve morphology, vena contracta width, proximal analyses with stepwise selection. Sequential Cox analysis using
flow convergence radius and hepatic venous flow pattern.17 four nested models ((1) significant clinical risk factors according
The diameter of the inferior vena cava (IVC) and its respiratory to univariable analysis; (2) clinical risk factors+severe persistent
variation were measured 10–20 mm from the junction with the hyponatraemia; (3) clinical risk factors+severe persistent hypo-
right atrium in the subcostal view, with an IVC size ≥20 mm and natraemia+left ventricular (LV) dysfunction; and (4) clinical
failure to collapse ≥50% during inspiration defined as dilatation risk factors+severe persistent hyponatraemia+RV dysfunction)
and plethora, respectively.18 Pulmonary artery systolic pressure was used to evaluate independent predictors and to compare
2 Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
Downloaded from http://heart.bmj.com/ on October 29, 2017 - Published by group.bmj.com
the prognostic value among hyponatraemia per se, LV dysfunc- patients, 116 patients with severe persistent hyponatraemia were
tion and RV dysfunction. Subgroup analysis according to LVEF compared with 232 PS-matched equivalents. No differences in
was performed to determine the effect of LV function on the baseline characteristics were noted. Matched patients (n=348;
relationship between hyponatraemia and RV dysfunction. All 116 with persistent hyponatraemia and 232 controls) had a mean
analyses were performed using SPSS V.22.0 (SPSS, Chicago, Illi- age of 69.5±14.3 years, and 57.8% were male. The percent-
nois, USA) and the MatchIt R package (R Development Core ages of hypertension, diabetes mellitus and atrial fibrillation
Team, Ho et al, 2011). were 45.4%, 34.8% and 39.1%, respectively. The most frequent
cause of HF was ischaemia (40.0%). Approximately one-third
Results of these patients presented with de novo HF (37.4%), and half
Baseline clinical characteristics were classified as New York Heart Association (NYHA) class IV
Among all patients (n=2935, age 67.8±14.9 years, male (48.0%). Prior evidence-based medical therapies included RAS
55.7%), hyponatraemia (sNa <135 mmol/L) was present in 697 blockers (50.0%), beta-blockers (23.6%) and aldosterone antag-
(23.7%) patients, of which 122 (4.2%) had severe persistent onists (44.8%) (table 2).
hyponatraemia. Patients with severe persistent hyponatraemia
(n=122, age 70.1±13.8 years, male 57.4%) were older, thinner, Echocardiographic characteristics
had a higher prevalence of alcohol history, hypertension and use The mean LV and RV systolic function, indicated by LVEF
of evidence-based medication and lower systolic/diastolic pres- and RV FAC, were 36.3% and 34.1%, respectively. RV FAC
sures and haemoglobin. Such patients exhibited higher 1-year was significantly lower in patients with severe persistent hypo-
mortality than those without (table 1). After excluding dialysis natraemia (28.2% vs 37.1%, p<0.001), whereas LVEF did
Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084 3
Downloaded from http://heart.bmj.com/ on October 29, 2017 - Published by group.bmj.com
not differ (38.1% vs 35.5%, p=0.149). In addition, patients 3 (unadjusted OR 1.80, 95% CI 1.10 to 2.95, p=0.020), IVC
with severe persistent hyponatraemia showed significant TR plethora (unadjusted OR 2.63, 95% CI 1.64 to 4.21, p<0.001)
(33.6% vs 22.0%, p=0.019), an estimated PASP of ≥40 mm and a PASP of ≥40 mm Hg (unadjusted OR 1.57, 95% CI 1.00 to
Hg (65.5% vs 54.7%, p=0.035), and IVC plethora (47.0% vs 2.49, p=0.049), suggesting a close correlation with RV dysfunc-
25.2%, p<0.001) more frequently (table 3). The measurement tion. In the multivariable logistic model, RV dysfunction, IVC
errors for RV FAC were small (differences within and between plethora and TR ≥grade 3 maintained independent associations
observers, –0.12%±3.95% and 0.10%±4.15%) (online supple- with severe persistent hyponatraemia, while LV dysfunction was
mentary figure). Reproducibility for RV FAC was good (intra- not statistically significant (table 4).
class correlation coefficients were 0.89 (intraobserver) and 0.80
(interobserver); p<0.001).
Survival according to severe persistent hyponatraemia and
Severe persistent hyponatraemia and RV systolic function RV systolic function
RV dysfunction was observed in 81.0% (94/116) of patients with During follow-up (median 24 months, IQR 6–36 months),
severe persistent hyponatraemia, and 33.6% (78/232) of patients 160 patients (46.0%) died in the matched cohort, two-thirds
without (χ2=69.6, p<0.001) (table 3). The strongest associa- of which occurred within 1 year (n=110, 31.6%). Sixty-nine
tion of severe persistent hyponatraemia was with RV dysfunc- deaths during follow-up occurred in patients with severe
tion (unadjusted OR 8.43, 95% CI 4.93 to 14.45, p<0.001); in persistent hyponatraemia, predominating in the subgroup
contrast, no significant relationship was noted with LV dysfunc- with concomitant RV dysfunction (61/94 with RV dysfunction
tion (unadjusted OR 1.22, 95% CI 0.96 to 1.51, p=0.091). vs 8/22 without RV dysfunction). In univariable Cox regres-
Severe persistent hyponatraemia was associated with TR ≥grade sion analysis, ageing, anaemia with haemoglobin <11 g/dL,
4 Lee H, et al. Heart 2017;0:1–8. doi:10.1136/heartjnl-2017-312084
Downloaded from http://heart.bmj.com/ on October 29, 2017 - Published by group.bmj.com
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.
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.
These include:
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Notes