Journal of Cardiology 61 (2013) 348–353

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Journal of Cardiology
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Original article

Association between sleep apnea and overnight hemodynamic changes in

hospitalized heart failure patients with and without paroxysmal nocturnal
dyspnea
Yoshimi Yagishita-Tagawa (MD), Dai Yumino (MD) ∗ , Atsushi Takagi (MD, FJCC),
Naoki Serizawa (MD), Nobuhisa Hagiwara (MD, FJCC)
Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Paroxysmal nocturnal dyspnea (PND) is a common symptom for patients with acute decom-
Received 28 June 2012 pensated heart failure (ADHF). Some symptoms of PND are similar to those of sleep apnea (SA) which
Received in revised form 4 November 2012 might be associated with overnight worsening hemodynamics in failing hearts. However, the associa-
Accepted 17 December 2012
tion between PND, SA, and overnight change in hemodynamics in patients with heart failure remains
Available online 16 March 2013
uncertain.
Methods: We studied 28 consecutive patients with reduced ejection fraction who were hospitalized with
Keywords:
ADHF. Plasma atrial natriuretic peptide (ANP) levels were measured before and after overnight sleep
Acute decompensated heart failure
Atrial natriuretic peptide
study. PND was defined as having an episode of PND prior to hospitalization for ADHF.
Central sleep apnea Results: Ten (36%) patients had a history of PND. Respiratory disturbance index (the frequency and severity
Obstructive sleep apnea of sleep apnea) was an independent factor associated with a history of PND (odds ratio 1.24, 95% con-
fidence interval 1.05–1.47, p = 0.011). In those without PND, plasma ANP levels decreased from before
sleep to after waking, whereas in those with PND it increased (p = 0.011). In addition, overnight change
in plasma ANP levels was independently associated with respiratory disturbance index (p = 0.035).
Conclusion: These results thus suggest that in patients with ADHF, SA might be a predisposing cause of
PND in association with overnight worsening hemodynamics.
© 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction lead to improved quality of life and be important as a therapeutic

Acute decompensated heart failure (ADHF) is a common and
growing medical problem associated with major morbidity and
mortality [1]. The difficulties surrounding treatment begin with a
lack of clear definitions. Because of the heterogeneous nature of
ADHF, no single finding is definitive for diagnosis, and instead a
broad array of signs and symptoms are associated with the condi-
tion. Of the associated symptoms in patients with ADHF, dyspnea on
exertion is the most sensitive, whereas paroxysmal nocturnal dys-
pnea (PND) is the most specific [2], and is characterized by “patient
awakens, often quite suddenly and with a feeling of severe anxiety
and suffocation, sits bolt upright, and gasps for breath” [3]. Thus,
PND is a common symptom among patients with ADHF. Relieving a
typical symptom as a focus of treatment for heart failure (HF) could
∗ Corresponding author at: Department of Cardiology, Tokyo Women’s Medical
University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666,
Japan. Tel.: +81 3 3353 8111; fax: +81 3 3356 0441.
E-mail addresses: dai.yumino@gmail.com,
yumino@mvj.biglobe.ne.jp (D. Yumino).
target. However, the pathophysiology of PND remains unknown.
It is therefore important to achieve a better understanding of PND
which might contribute to improving the clinical course. Coexisting
sleep apnea (SA) may be a factor in PND.
Some symptoms of PND are similar to those of SA. SA is more
common in patients with fluid retention such as in HF than in those
without [4,5]. A previous study showed the possibility that rostral
fluid displacement from edematous legs to the neck and lung upon
assuming the recumbent position could predispose to obstructive
and central apnea during sleep [6]. In addition, pulmonary capil-
lary wedge pressure (PCWP) in patients with HF is associated with
central apnea [7]. Therefore, excess fluid volume and worsening
hemodynamics could be important factors coexisting with SA in
patients with HF. On the other hand, SA is characterized by recur-
rent hypoxia, arousal, and the generation of exaggerated negative
intrathoracic pressure during sleep, which increases sympathetic
nervous system activity, reduces cardiac parasympathetic activity,
and causes repetitive surges in heart rate, blood pressure, and left
ventricular preload and afterload. The mechanical loading of the
myocardium can also increase myocardial oxygen demand in the
face of a reduced supply, causing a decrease in cardiac output in

0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jjcc.2012.12.010
 Y. Yagishita-Tagawa et al. / Journal of Cardiology 61 (2013) 348–353
patients with HF [8,9]. Therefore, the failing heart could also be
susceptible to the adverse hemodynamic consequences of SA.
Thus, it is likely that the pathophysiology of PND may be asso-
ciated with SA through worsening hemodynamics during sleep in
patients with HF. However, the relationship among PND, SA, and
overnight change in hemodynamics in patients with HF remains
uncertain. A number of studies have shown that plasma atrial natri-
uretic peptide (ANP) levels are elevated in patients with HF, which
are positively correlated with right atrial pressure (RAP) or PCWP,
or both [10,11]. Therefore, plasma ANP levels could be useful as a
cardiac biomarker predicting overnight changes in general hemo-
dynamics in patients with HF. We hypothesized that coexisting SA
in patients referred for ADHF might be associated with PND accom-
panied by increased plasma ANP levels at baseline and its overnight
increment during pathologic sleep disturbance.
Methods
Patients and study design
We prospectively recruited consecutive HF patients with
reduced ejection fraction who were hospitalized with ADHF in
our institute between May 1, 2006 and October 30, 2006. After
their conditions had been improved by medical treatment and their
HF had been stabilized [New York Heart Association (NYHA) class
II and III], each patient underwent complete assessment during
overnight sleep. Plasma ANP levels were measured before and after
the overnight sleep study.
Inclusion criteria were: (1) age 18 years or older and (2)
left ventricular ejection fraction (LVEF) ≤ 40% as confirmed by
echocardiography. Exclusion criteria included: (1) unstable status,
including unstable angina, NYHA class IV, receiving any intravenous
drip infusions, oxygen supplementation, or positive airway pres-
sure treatment; (2) hospitalization with acute coronary syndrome;
(3) congenital heart disease; and (4) having renal dysfunction
defined as an estimated glomerular filtration rate < 60 ml/min,
because renal function directly contributes to elevated natriuretic
peptide levels [12]. No patients were selected on the basis of possi-
ble underlying SA. The study was approved by the local institutional
review boards and all patients gave written informed consent for
participation in the study.
Data collection
Data on demographic characteristics, medical history, and
medication use were obtained with the use of a standardized ques-
tionnaire and patient medical records obtained by a physician at
the time of the sleep study. PND was defined as having an episode
that ‘patient suddenly awakens with a feeling of suffocation or a
gasp for breath’ prior to hospitalization for ADHF. Atrial fibrillation
was defined by its presence on the continuous electrocardiographic
recording during the sleep study. LVEF was determined using Simp-
son’s method with echocardiography in the stable condition. Right
catheterization was performed by experienced cardiologists on the
day of the sleep study.
Plasma ANP levels were determined in samples obtained at
22:00 (before sleep) and 06:00 (after waking). The patients lay qui-
etly for at least 30 min before the baseline samples were collected
before sleep. At the end of the sleep study, samples were collected
immediately after the patients awoke, but before they arose from
bed. Blood was first collected in a heparinized plastic syringe to
clear the tubing volume. Thereafter, the blood samples collected
for the determination of ANP were transferred to chilled disposable
tubes containing aprotinin and ethylenediaminetetraacetic acid
and immediately centrifuged. The plasma was then frozen at −20 ◦ C
349
and stored until quantitative ANP analysis was performed. Plasma
ANP levels were measured using a standard peptide radioim-
munoassay kit (Shionogi ANP kit, Shionogi & Co., Ltd., Osaka, Japan).
Sleep study
The overnight sleep study was performed using a cardiopul-
monary monitoring device (Morpheus, Teijin Inc., Tokyo, Japan)
consisting of a pressure sensor for nasal flow, two stress-sensitive
belts for the ribcage and abdomen, respectively, and a continuous
pulse oximeter. An episode of apnea was defined as the com-
plete cessation of the sum of thoracoabdominal movements and
air flow for ≥10 s. An episode of hypopnea was defined as a ≥50%
decrease in the sum of thoracoabdominal movements and air flow
lasting for ≥10 s, followed by a reduction in SaO2 of at least 4%.
Apnea was classified as obstructive or central in the presence or
absence of flow and thoracoabdominal motion, respectively, and
hypopnea as obstructive or central in the presence or absence
of out-of-phase thoracoabdominal motion, respectively [13]. The
total respiratory disturbance index (RDI) was quantified as the total
frequency of apnea and hypopnea per hour of time in bed and sub-
classified into either central-RDI or obstructive-RDI based on the
above definitions. The sleep study was manually analyzed by an
expert technician who was blinded to the patients’ baseline clinical
characteristics.
Statistical analysis
Comparisons between the two groups were performed using
Student’s t-test for continuous variables that were normally dis-
tributed and the Mann–Whitney U-test for variables that were
not normally distributed. The chi-square or Fisher’s exact test
was used to compare nominally scaled variables. To evaluate
the independent factors associated with PND, multivariate anal-
ysis was performed using the logistic regression model with the
best subset variable selection method including older age, male
sex, body mass index, LVEF, atrial fibrillation, ischemic etiology,
and total RDI. To determine the independent factors associated
with RDI, multivariate analysis was performed using the gen-
eralized linear regression model with the best subset variable
selection method including older age, male sex, body mass index,
LVEF, atrial fibrillation, ischemic etiology, plasma ANP level before
sleep, and overnight change in plasma ANP level. Odds ratios
(ORs) and regression coefficients are reported with 95% confi-
dence intervals (CIs). The best cutoff values for variables predicting
increasing plasma ANP levels during overnight sleep were iden-
tified based on receiver operating characteristic (ROC) curves
at regular intervals as the value that minimized the expression
[(1 − sensitivity)2 + (1 − specificity)2 ] [14]. Data are presented as
mean ± SD or SEM unless indicated otherwise. The influence of
profile, linearity, interaction, and collinearity was assessed in all
models by regression diagnostic analysis. A two-tailed p-value of
less than 0.05 was considered to indicate a statistically significant
difference. The analyses were performed using Statistical Analysis
System ver. 9.1 software (SAS Institute Inc., Cary, NC, USA).
Results
Of 50 consecutive hospitalized patients with ADHF, 23 patients
were excluded from the study: 2 patients died, 15 patients had
normal ejection fraction, 1 had congenital heart disease, 4 had renal
dysfunction, and 1 was receiving supplemental oxygen. Thus, a total
of 28 patients hospitalized for ADHF were included in the final anal-
ysis. There were 15 (54%) men and 13 (46%) women, whose ages
ranged from 33 to 77 years (mean 59 ± 12 years), and whose body
mass index was 22.5 ± 2.9 kg/m2 . Ten (36%) patients had a history
350 Y. Yagishita-Tagawa et al. / Journal of Cardiology 61 (2013) 348–353

Table 1
Patient characteristics in the presence and absence of PND.

Variable PND p-Value

No (N = 18) Yes (N = 10)

Age (years) 56 ± 13 64 ± 9 p = 0.118

Male (%) 9 (50) 6 (60) p = 0.627
Body mass index (kg/m2 ) 21.8 ± 2.3 23.7 ± 3.6 p = 0.100
Left ventricular ejection fraction (%) 30.2 ± 11.5 21.6 ± 9.5 p = 0.056
Left ventricular diastolic diameter (mm) 62.1 ± 11.2 67.6 ± 9.5 p = 0.201
Atrial fibrillation (%) 7 (39) 5 (50) p = 0.586
Ischemic heart disease (%) 1 (6) 4 (40) p = 0.022
Medications
Thiazide or loop diuretics (%) 15 (83) 9 (90) p = 0.644
ACE inhibitors and/or ARB (%) 16 (89) 10 (100) p = 0.291
Beta-blockers (%) 17 (94) 10 (100) p = 0.467
Total RDI (no./h) 9.6 ± 7.7 24.4 ± 8.9 p < 0.001
Obstructive-RDI (no./h) 7.1 ± 6.2 8.8 ± 9.6 p = 0.570
Central-RDI (no./h) 2.5 ± 3.4 15.5 ± 12.6 p < 0.001
Lowest SaO2 (%) 86.4 ± 5.3 80.3 ± 5.1 p = 0.006

Values are expressed as mean ± SD or number (%).

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; PND,
paroxysmal nocturnal dyspnea; RDI, respiratory disturbance index.

of PND. All patients had NYHA class II and III, and mean LVEF was
27.1 ± 11.5%. There was a history of hypertension in 21% of patients
and diabetes in 11%. The etiology of HF was ischemic in 18%. At
the time of assessment, 93% were taking angiotensin-converting
enzyme (ACE) inhibitors and/or angiotensin receptor blockers, 96%
beta-blockers, and 86% thiazide or loop diuretics. The period from
hospitalization to the sleep study ranged from 4 to 36 days (mean
14 ± 6 days). RDI ranged from 0.4 to 37.7/h (mean 14.9 ± 10.8/h).
The characteristics of the patients with and without PND are
shown in Table 1. Patients with PND had a significantly higher per-
centage of ischemic etiology, higher total RDI and central-RDI, and
lower SaO2 than those without PND. Patients with PND tended Fig. 1. Plasma atrial natriuretic peptide (ANP) levels before sleep and after waking
to be older, have a higher body mass index, and have a lower (panel A), and overnight change in plasma ANP levels (panel B) in patients with and
without paroxysmal nocturnal dyspnea (PND).
LVEF compared with those without PND. There were no differences
in the proportion of male sex, atrial fibrillation, and medication
use between the two groups. In multivariate analysis using the Both plasma ANP levels obtained before sleep and after waking
logistic regression model with the best subset variable selection were more than two-fold higher in patients with PND than in those
method including older age, male sex, body mass index, LVEF, atrial without (Fig. 1A). In addition, in the non-PND group, plasma ANP
fibrillation, ischemic etiology, and total RDI, only total RDI was levels decreased from before sleep to after waking, whereas in the
an independent factor associated with a history of PND (per one PND group it increased (Fig. 1B).
event/h increase, OR 1.24, 95% CI 1.05–1.47, p = 0.011). The ROC On univariate analysis, older age, male sex, ischemic heart
curve demonstrating the sensitivity and specificity of total RDI in disease, plasma ANP level at baseline, and overnight change
patients with HF shows that the best total RDI cutoff value to pre- in plasma ANP levels were positively associated with RDI. On
dict for PND was ≥20/h (area under the curve 0.88 ± 0.07, p < 0.001, multivariate analysis, male sex, plasma ANP level before sleep,
sensitivity 90.0%, specificity 88.9%). and overnight change in plasma ANP levels were independently
Of the 28 patients analyzed, 20 underwent right catheterization associated with RDI (Table 2). In addition, when total RDI was sub-
before sleep study. Plasma ANP levels at baseline (before sleep) classified into central- and obstructive-RDI, plasma ANP levels at
significantly correlated with RAP (y = 0.04x + 1.8, R = 0.55, p = 0.026) baseline associated with central-RDI (R = 0.52, p = 0.005), but not
and PCWP (y = 0.09x + 4.5, R = 0.71, p = 0.002). with obstructive-RDI (R = 0.08, p = 0.690). And overnight change

Table 2
Univariate and multivariate analyses of factors associated with respiratory disturbance index.

Variable Univariate Multivariate

Coefficient (95% CI) p-Value Coefficient (95% CI) p-Value

Older age (per 10-yr increase) 4.72 (1.73–7.70) 0.003

Male sex 11.70 (4.54–18.85) 0.002 10.45 (4.40–16.50) 0.002
Body mass index (kg/m2 ) 1.30 (–0.09–2.68) 0.065
Left ventricular ejection fraction (%) –0.15 (–0.52–0.23) 0.428
Atrial fibrillation 4.89 (–3.52–13.29) 0.243
Ischemic heart disease 6.23 (0.80–12.43) 0.048
ANP before sleep (per 10-pg/ml increase) 0.71 (0.10–1.33) 0.025 0.58 (0.09–1.06) 0.021
Overnight change in ANP (per 10-pg/ml increase) 0.81 (0.13–1.49) 0.021 0.59 (0.05–1.12) 0.035

The above variables were all evaluated using the generalized linear regression model with the best subset variable selection method.
ANP, atrial natriuretic peptide; 95% CI, 95% confidence interval.
 Y. Yagishita-Tagawa et al. / Journal of Cardiology 61 (2013) 348–353
Fig. 2. Plasma atrial natriuretic peptide (ANP) levels before sleep and after waking
(panel A), and overnight change in plasma ANP levels (panel B) in patients with
respiratory disturbance index (RDI) < 20 and RDI ≥ 20/h.
in plasma ANP levels was associated with central-RDI (R = 0.54,
p = 0.004).
Plasma ANP levels were higher in the RDI ≥ 20 group than in
the RDI < 20 group regardless of the sampling time point (Fig. 2A).
In addition, in the RDI < 20 group, the overnight change in plasma
ANP levels showed a decreasing pattern, whereas in the RDI ≥ 20
group it increased (Fig. 2B).
Discussion
This observational study yielded several novel observations.
First, in patients referred for ADHF, the frequency and severity
of SA (total RDI) was an independent factor associated with the
presence of prior PND. Second, patients with PND had increased
ANP levels at baseline and overnight increases in ANP; con-
versely, those without PND did not. Third, we found that increased
ANP at baseline and increasing overnight change in ANP were
independent factors associated with RDI. To the best of our
knowledge, this is the first study that determined the rela-
tionship between PND and SA with a surrogate hemodynamic
marker.
The relationship between PND and SA was described in the
1930s by Harrison et al., who reported that the hyperpneic phase of
central apnea could produce dyspnea [15]. On the other hand, Mon-
tuschi reported four HF cases in which the symptoms of PND were
alleviated by volume reduction using diuretics [16]. Our results
351
provided further support for a direct link between PND, SA, and
overnight change in hemodynamics. In patients with HF, venous
return to the right heart at bedtime when moving from the upright
to the recumbent position is increased and this might lead to a
further worsening of hemodynamics including increased RAP and
PCWP [17,18]. Their conditions might predispose to central apnea
due to the stimulation of pulmonary irritant receptors that can
cause hyperventilation, which might then lead to PND. Indeed, a
previous study showed that in patients with HF, overnight ros-
tral fluid displacement from the legs did not only contribute to
the pathogenesis of both obstructive and central SA, but also with
progressively greater overnight rostral fluid shift, and there was
a gradation from no sleep apnea to obstructive SA to central SA
[6]. Solin et al. showed that PCWP and pulmonary artery pressure
were markedly higher in the central-predominant SA group than in
the obstructive-predominant SA and no SA groups when compar-
ing hemodynamics via right heart catheterization [7]. In addition,
positive airway pressure treatment and cardiac resynchronization
therapy reduced plasma ANP levels and the frequency and sever-
ity of SA through improvement of cardiac function in patients with
central SA [19,20]. Furthermore, a recent study showed that ANP
levels are increased among patients with HF and central SA com-
pared with those without CSA [21]. Our results were consistent
with those in the previous studies. The frequency and severity of
SA were positively correlated with plasma ANP levels at baseline
in central-RDI. Therefore, central apnea more likely arises as a con-
sequence of poor hemodynamics in HF than obstructive apnea. A
key factor predisposing to CSA is hyperventilation, setting eupneic
PaCO2 close to the apnea threshold. Hemodynamic congestion is
a significant factor triggering hyperventilation and CSA. And other
factors, including impaired cerebral blood flow, prolongation of cir-
culation time, metabolic alkalosis, low functional residual capacity,
upper airway instability, and hypoxia, may further contribute to
respiratory instability and CSA.
On the other hand, SA itself might contribute to deteriorating
cardiac hemodynamics overnight in patients with HF. To our
knowledge, there has been no previous study of overnight changes
in hemodynamics among HF patients with and without SA. Nev-
ertheless, during obstructive apnea, the generation of exaggerated
negative intrathoracic pressure against the occluded upper airway,
hypoxia and hypercapnea, and sympathetic nerve activation leads
to increased right ventricular preload and increased left ventric-
ular afterload, both of which increase myocardial oxygen demand
[9,22], thereby causing distention of the right atrium and ventricle.
This distention also shifts the interventricular septum, impairs left
ventricular diastolic filling, and reduces stroke volume during each
apnea episode. Bradley et al. showed that during awake periods,
Mueller maneuvers were associated with significantly greater
reductions in cardiac index in patients with HF than in healthy
individuals [9]. In severe apnea cases, the cycles of apnea can recur
several hundred times each night and could worsen hemodynam-
ics during overnight sleep. Also, as a result of these vacillations,
atrial intragranular stores of ANP are released immediately due
to intrathoracic pressure swings that modify the atrial distention
pressure, as our results showed [23–25]. In addition, short-term
randomized trials demonstrated that treating obstructive SA with
positive airway pressure in HF patients reduced sympathetic
nervous system activity, blood pressure, and nocturnal ventricular
ectopy, increased vagal modulation of the heart rate, and improved
LVEF and the quality of life [26–29]. In contrast to obstructive
apnea, in which inspiratory efforts are made against the occluded
upper airway owing to the continued presence of respiratory drive,
no respiratory effort is generated during central apnea due to the
cessation of respiratory drive. Thus, unlike obstructive apnea, no
negative intrathoracic pressure is generated during central apnea.
Therefore, its impact on afterload might be less than in obstructive
352 Y. Yagishita-Tagawa et al. / Journal of Cardiology 61 (2013) 348–353
apnea. However, it remains uncertain whether central apnea con-
tributes to the deterioration of cardiac hemodynamics overnight.
From these viewpoints, we suggest that in HF patients poor
hemodynamics and a rostral fluid shift at bedtime are important
factors causing SA, which itself constitutes an additive adverse
affect on the worsening hemodynamics during sleep, and thus may
be closely associated with the predisposing to PND.
Our observations are subject to some limitations. First, the
present study examined PND in patients who were in a stable con-
dition after a mean 14 days of hospitalization for initial ADHF.
Nevertheless, previous studies showed that the severity and
types of SA remained unchanged between decompensated and sta-
ble HF status [30,31]. Second, the cardiorespiratory monitoring
device used in this study cannot record electroencephalograms,
unlike polysomnography. However, the Morpheus device can dis-
tinguish between obstructive and central apneas and hypopneas
and like polysomnography meets the recommendations for the
quality of evidence obtained using methods for measuring breath-
ing disorders during sleep [32]. In addition, several reports showed
a close correlation between data obtained with polysomnography
and this device [33]. Third, we only included patients with reduced
ejection fraction. Further research is needed to determine associ-
ation between PND and SA for patients with preserved ejection
fraction.
Clinical implications and conclusions
From a pathophysiologic viewpoint, it is likely that PND is asso-
ciated with coexisting SA and worsening hemodynamics in patients
with ADHF. From a therapeutic viewpoint, it may be inferred from
the present results that interventions aiming at reducing plasma
ANP levels and the frequency and severity of SA, independent of
specific treatment for cardiac hemodynamics, could help to relieve
symptoms in patients with HF [34]. Increased LV filling pressure
is the main reason for ADHF admission and readmission. The goal
of tailored therapy for ADHF has been to reduce RAP and PCWP
filling pressures [35]. Therefore, our results suggest that treatment
for SA appears more likely to have beneficial effects on symptoms
and quality of life in HF patients. The presence of SA should thus be
determined and treated as a target condition.
Author’s contribution
Y. Yagishita-Tagawa collected data and analyzed it, and assisted
in designing the study, and drafting and revising the manuscript.
D. Yumino, A. Takagi, and N. Serizawa collected data, assisted in
designing the study and revising the manuscript. N. Hagiwara pro-
vided collected data and assisted in its analysis, and assisted in
designing the study, and drafting and revising the manuscript.
Funding source and disclosure
There were no funding source and relationship to disclose.
Acknowledgments
The authors thank Katsunori Shimada (STATZ Institute Inc.,
Tokyo, Japan) for expert statistical assistance. The authors are
indebted to Koichi Takeuchi and Reiko Ohnishi for their excellent
technical assistance.
The institutional review board name and approval number:
Tokyo Women’s Medical University No. 1488.
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