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Sleep apnea in patients with exacerbated heart failure and overweight
Petar Kalaydzhiev
a
,
b
,
*
, Nikolay Poroyliev
a
,
b
, Desislava Somleva
a
,
b
, Radostina Ilieva
a
,
b
,
Dimitar Markov
a
,
b
, Elena Kinova
a
,
b
, Asen Goudev
a
,
b
a
Medical University, Sofia, Bulgaria
b
University Hospital “Tsaritsa Yoanna eISUL”, Byalo More St N8, Clinical of Cardiology, Sofia, Bulgaria
article info
Article history:
Received 7 December 2022
Received in revised form
8 February 2023
Accepted 24 February 2023
Available online 28 February 2023
Keywords:
Exacerbated heart failure
Obstructive sleep apnea
Central sleep apnea
abstract
Sleep disorders are a common concomitant comorbidity in patients with heart failure. The aims of our
study are to determine the incidence and phenotypic characteristics of sleep apnea in overweight pa-
tients with exacerbated heart failure and to assess the degree of involvement of systolic and diastolic
function impairment in the individual group. From 100 screened patients with heart failure in our
department from 2015 to 2017, 61 met the inclusion criteria and participated in the study. 82% (n ¼50) of
the patients had obstructive sleep apnea (OSA), and 18% (n ¼11) had central sleep apnea (CSA). The CSA
group had a significantly lower left ventricular ejection fraction (LVEF) than the OSA group (EF%
49.6 ±8.5 vs 41.8 ±11.4; p ¼0.013). A negative correlation was found between LVEF and the number of
central apnea events (r ¼0.52; p <0.001). More frequent hospitalizations for heart failure (HF) and
higher mortality rate were found in the CSA group. Screening for sleep apnea in patients with exacer-
bated heart failure and obesity is necessary for the complex treatment of these patients.
©2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
1. Introduction
Sleep apnea is more common in patients with heart failure (HF)
than in the general population. There are two main types of sleep
apnea. Obstructive sleep apnea is caused by an obstruction of the
upper airway, while central sleep apnea is caused by a lack of signal
from the central nervous system to the respiratory muscles. The
comorbidity rate in patients with OSA and heart failure is high. The
frequency varies from 11 to 38% in different studies. In patients with
CSA, this percentage is even higher 28e82% [1]. This statistic raises
the question of the diagnosis and treatment of these comorbidities.
In these patients, hospitalization due to exacerbation of HF is a
more frequent phenomenon compared to patients without sleep
apnea [2]. Treatment options are being explored, and currently
positive results are reported only in the obstructive type, while in
the case of central apnea, the studies have not reported definite
benefits [3]. The high comorbidity rate may be due to the fact that
the two disorders, sleep apnea and heart failure, share common risk
factors [4,5]. There is a lack of sufficient data on the type of sleep
apnea that prevails during hospitalization for exacerbated heart
failure. It is not established whether there is an association between
high NTproBNP (N-Terminal Fragment of the Prohormone Brain-
Type Natriuretic Peptide - NT-proBNP) and Apnea-Hypopnea In-
dex (AHI) and whether it can be used as a predictive value for the
severity of sleep apnea in these patients, which we will seek an
answer in the present study. Our study aims to differentiate the
frequency and type of sleep apnea in patients with overweight and
exacerbated heart failure, evaluate the systolic and diastolic func-
tion in the individual groups, and determine whether there is a
correlation between the severity of heart failure and the type of
sleep apnea.
2. Materials and methods
We conducted a single-centre, prospective cohort study in
which patients hospitalized in the Cardiology Clinic of UMHAT
“Tsaritsa Joanna - ISUL”took part from 2015 to 2017. In 100
consecutive patients with clinical and laboratory evidence of
exacerbated heart failure - New York Heart Association (NYHA)
class II/III and Body mass index (BMI) >25 kg/m2, additional lab-
oratory methods were used to assess the degree of heart failure
using NTproBNP. Measurements were conducted on a Point of Care
- Roche Cobas h 232 System. Patients with NTproBNP
values >300 pg/ml were included. The screening for sleep apnea
was conducted using the Epworth Sleepiness Scale (ESS) and an
*Corresponding author.
E-mail address: pkalaidjiev@gmail.com (P. Kalaydzhiev).
Contents lists available at ScienceDirect
Sleep Medicine: X
journal homepage: www.elsevier.com/locate/sleep
https://doi.org/10.1016/j.sleepx.2023.100065
2590-1427/©2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sleep Medicine: X 5 (2023) 100065
ApneaLink™somnographic screening system, which was attached
to patients on the first night of their stay in the unit. The number
and type of apneas and hypopneas per hour were measured -
Apnea-Hypopnea Index (AHI). The somnographic recordings were
analysed with ApneaLink™Reporting Software to determine the
sleep apnea phenotype. All patients with ESS >6 pts and AHI >5
were included. Two-dimensional (2D) echocardiography was used
to assess systolic and diastolic function. To assess systolic function,
measurement of the left ventricular ejection fraction using the
Simpson method was used, and to measure diastolic function, the
ratio E/e'm (the ration of the wave of early diastolic filling of the
mitral inflow- E and the tissue Doppler velocity of the medial mitral
annulus-e'm) was used. Exclusion criteria were: acute respiratory
failure, acute coronary syndrome, severe renal or hepatic failure,
and chronic lung diseases (COPD). Sixty-one patients met the in-
clusion criteria. They were divided into two groups according to the
type of sleep apnea - with CSA and with OSA. Patients were fol-
lowed up for HF hospitalizations and mortality rate over a two-year
period. The statistical analysis was performed by SPSS 22.0 (Chi-
cago, Illinois). Statistical methods for comparison using Pearson's
chi-squared test and Student's t-test as appropriate. Correlation
analysis for linear dependence were used. Simple linear regression
was performed to test significantly predicted value. The Kaplan-
Meier method was used to analyze the survival rate and first HF
hospitalization. The comparison between the two groups was
performed using the Log Rank (Mantel-Cox) test. Data with a p-
value <0.05 were considered significant.
3. Results
From 100 screened consecutive patients, sleep apnea was found
in 61% of them (n ¼61). Of these, 82% (n ¼50) had obstructive sleep
apnea, and 18% (n ¼11) had central sleep apnea. Regarding the
demographic indicators of age and gender, no significant differ-
ences were found in the individual groups.
When comparing the ejection fraction (EF%) of the left ventricle
between the two groups, significantly lower values of EF were
recorded in the group with central sleep apnea compared to the
group with OSA (LVEF % 49.6 ±8.5 vs 41.8 ±11.4; p ¼0.013).
There is also a difference in the diastolic dysfunction indicators,
with the E/e'm ratio in the CSA group being significantly higher (E/
e'm-17.1 ±3.7 vs 20.9 ±2.5; p ¼0.002). The NTproBNP values also
support this data, patients with CSA have significantly higher
values compared to patients with OSA (2857.36 ±1090.90 pg/ml vs
1359.12 ±740.64 pg/ml, p ¼0.001).
Regarding BMI, significantly higher values were found in the
OSA group compared to the patients with CSA (BMI 38.5 ±7.1 v s
31.9 ±4.5; p ¼0.005).
No significant difference was registered in the degree of severity
regarding sleep disorder. Comparison of AHI between the two
groups showed no difference (OSA 41.8 ±23.2 vs CSA 37.7 ±12.6;
p¼0.575). The data summary is presented in Table 1.
Standard heart failure therapy during the study period included
angiotensin converting enzyme inhibitors or angiotensin receptor
blockers (ACEi or ARB), Sacubitril/Valsartan, beta blockers and di-
uretics. Patients in both groups were on standard heart failure
therapy. The percentage distribution is shown in Table 2. There was
no significant difference in therapy between the two groups.
After conducting a correlation analysis, a strong negative cor-
relation was found between the number of central apnea events
(apneas and hypopneas) and the left ventricular ejection fraction
r¼0.52, p <0.001. The distribution and data are presented in
Fig. 1.
Simple linear regression was used to test if the left ventricular
ejection fraction significantly predicted the number of central
apnea events. The overall regression was statistically significant
(R
2
¼0.32, F(1, 59) ¼28.26, p <0.000). It was found that the left
ventricular ejection fraction significantly predicted the number of
central apnea events (
b
¼-1.829, p <0.000).
A strong correlation was also found between BMI and the degree
of daytime sleepiness based on the ESS (r ¼0.649; p <0.001).
Simple linear regression was used. It was found that the BMI
significantly predicted the ESS (
b
¼0.27, p <0.000).
No correlation was found between AHI and NTproBNP
(r ¼0.038; p ¼0.770).
Patients from both groups were followed up regarding first
hospitalization for heart failure and mortality over a period of 24
months. Mortality in the OSA group for 2 years was 38% (n ¼19),
and 63.6% (n ¼7) in the CSA group.
First hospitalization in patients with CSA occurs significantly
sooner than in patients with OSA. The average number of months
without hospitalization for HF in patients with CSA was 5.3 months
versus 12.8 months in patients with OSA (Log Rank (Mental-Cox)
p¼0.009). Refer to Fig. 2.
The OSA group had a median survival of 18.7 months versus
13.09 months in the CSA group. The data approached but did not
exceed the limit of significance (p ¼0.063). The survival curve is
presented in Fig. 3.
4. Discussion
For the first time in Bulgaria, a prospective cohort study is being
conducted on sleep apnea and exacerbated heart failure and over-
weight. In our study we found that 61% of tested patients have sleep
apnea. 82% (n ¼50) of patients had OSA, and 18% (n ¼11) had CSA.
On a global scale, a study on this topic was conducted by Schulz R
et al. [6]. Two hundred and three patients with exacerbated heart
failure were studied, of whom 145 (71%) had sleep apnea. The dis-
tribution of the OSA and CSA percentage is also at the expense of
OSA, without obesity being an inclusion criterion. The percentage of
patients with central sleep apnea in the study by Sin and coworkers
was significantly higher which may be due to the larger number of
patients studied [7]. In 2017 Arzt M et al. performed an extensive
analysis of patients in the German registry SchlaHF for patients with
reduced systolic function. A high rate of CSA was also found in their
study [8]. The high repeatability of the data confirms the need to
screen heart failure patients for sleep apnea.
We found significant differences between patients with
Table 1
Summary of demographic, echocardiographic and sleep parameters.
OSA group (n ¼50) CSA group (n ¼11) P Value
Age, yr 66.2 ±9,1 66.1 ±11.9 0.991
Sex, m% m 52% m 54% 0.878
ESS 12.1 ±2.9 10,6 ±3.2 0.144
LVEF, % 49.6 ±8.5 41.8 ±11.4 0.013
AHI 41.8 ±23.2 37.7 ±12.6 0.575
BMI 38.5 ±7.1 31.9 ±4.5 0.005
E/e'm 17.1 ±3.7 20.9 ±2.5 0.002
NTproBNP, pg/ml 1359.12 ±740.64 2857.36 ±1090.9 0.001
Av. Saturation, % 83.9 ±6.8 86.6 ±6.6 0.257
Low Saturation, % 65.3 ±12.7 67.6 ±12.8 0.590
Av. Pulse, bpm 75.5 ±11.1 76.4 ±11.7 0.825
Max. Pulse, bpm 131.1 ±42.5 121.4 ±51.2 0.511
N of Desaturation 381.1 ±212.6 397.5 ±184.4 0.813
Obstructive sleep apnea(OSA); Central sleep apnea(CSA); male %(m%); Epworth
Sleepiness Scale (ESS); Apnea-Hypopnea Index (AHI); The ration of the wave of early
diastolic filling of the mitral inflow- E and the tissue Doppler velocity of the medial
mitral annulus-e'm(E/e'm); Left ventricular ejection fraction in %(LVEF%); N-Ter-
minal Fragment of the Prohormone Brain-Type Natriuretic Peptide e(NT-proBNP);
beats per minute (bpm).
P. Kalaydzhiev, N. Poroyliev, D. Somleva et al. Sleep Medicine: X 5 (2023) 100065
2
obstructive sleep apnea and those with central sleep apnea in terms
of ejection fraction and diastolic function. Decreased systolic
function, elevated NTproBNP values, and increased left ventricular
filling pressures, increase the risk of central apnea events. A
possible pathophysiological explanation for this phenomenon is
that patients with reduced systolic function also have a lower left
ventricular filling pressure, as well as increased pulmonary
pressure, which increases the risk of hyperventilation and Cheyne-
Stokes breathing during sleep [8,9]. We used linear regression
analysis to demonstrate the strong correlation between the
occurrence of central apneas and decreased systolic function. Left
ventricular ejection fraction has a significant predictive value for
occurrence of Cheyne-Stokes breathing (R
2
¼0.32, F(1, 59) ¼28.26,
p<0.000).
BMI is a definite risk factor for both SA and heart failure [10,11].
Sin DD et al. studied 450 patients with congestive heart failure,
with obesity being the leading risk factor for concomitant sleep
disorder. Similar results were published by Lee SJ et al., who found a
strong correlation between BMI and daytime sleepiness (ESS) [12].
In our research, we also confirm this dependence.
To support the diagnosis of exacerbated heart failure, we addi-
tionally used NTproBNP tests. As expected, they were significantly
higher in the CSA group, corresponding to the lower systolic
function in these patients. We found no correlation between AHI
and NTproBNP. A similar comparison was also conducted by Hüb-
ner RH et al. in the study of 60 patients with obstructive sleep
apnea and heart failure [13]. This shows us that NTproBNP can't
help us with the degree of severity of sleep apnea as well as its type.
In our study, we found that patients with central sleep apnea
had significantly more frequent hospitalization for heart failure
than patients with obstructive sleep apnea (Log Rank (Mental-Cox)
p¼0.009) Fig. 2. This conclusion was also reached by Khayat R et al.
in their study [14]. Similar to us, they followed up patients with
exacerbated heart failure and sleep disorders, and rehospitalization
for heart failure in the CSA group was significantly higher than that
in the OSA group. The lower systolic function and higher percent-
age of hospitalizations in the CSA group determines the worse
quality of life in these patients. Although both groups were on
standard heart failure therapy, lower systolic function in the CSA
Table 2
Distribution of used medications.
Medication OSA group (n ¼50) CSA group (n ¼11) P Value
Beta blockers (%) 92% 82% 0.294
ACEi or ARB or Sacubitril/Valsartan (%) 84% 64% 0.133
Mineralocorticoid blockers (%) 70% 82% 0.350
Loop and thiazide diuretics (%) 62% 82% 0.185
Obstructive sleep apnea(OSA); Central sleep apnea(CSA); angiotensin converting enzyme inhibitors (ACEi); angiotensin receptor blockers (ARB).
Fig. 1. Correlation analysis of the relationship between ejection fraction and number of
central sleep apnea events. EF% - ejection fraction %.
Fig. 2. Survival Functions Kaplan-Meier method for time to first hospitalization for
Heart Failure (HF) in months Obstructive sleep disease (OSD); Central sleep disease
(CSD).
Fig. 3. Survival Functions Kaplan-Meier method survival in months. Obstructive sleep
disease (OSD); Central sleep disease (CSD).
P. Kalaydzhiev, N. Poroyliev, D. Somleva et al. Sleep Medicine: X 5 (2023) 100065
3
group was an independent risk factor for higher rehospitalization
and higher mortality [15].
Mortality in the CSA group was higher, approaching but not
reaching significance. In another of their publications, Khayat and
coworkers discuss the increased mortality rate in patients with CSA
and acute heart failure [16].
Timely diagnosis could help the addition of adjunctive therapy
to patients with sleep disorders and exacerbated heart failure,
which would improve the prognosis especially in patients with low
systolic function [17].
One of the major limiting factors in our study is the low number
of patients in the CSA group. Analyzing the cohort in more recruited
patients would allow the conclusions drawn to be confirmed or
rejected. Studies in this field are highly limited due to the multi-
stage conduct of the studies, the hospitalization of the patients, and
the severe general condition of exacerbated symptoms of heart
failure. Globally, the main studies also have low numbers of
patients.
Due to economic constraints, continued positive airway pres-
sure (CPAP) therapy was not added to the patients with OSA, which
allowed the comparison between the two groups. Adding CPAP
therapy to the management of patients with OSA would undoubt-
edly improve the prognosis of these patients [18].
Since patient recruitment and follow-up, there have been sig-
nificant advances in heart failure therapy and the use of new classes
of medications such as SGLT2 inhibitors, which in our patients were
not included [19]. Which confirms the need for new studies in this
area.
5. Conclusion
Sleep apnea is a common comorbidity in patients with exacer-
bated heart failure and obesity. OSA occurs to a greater extent than
CSA. Patients with reduced systolic function are at higher risk of
central sleep apneas events. Low LVEF% can be used as a prognostic
factor regarding the occurrence of central sleep apnea events.
Controlling sleep apnea can reduce patient readmissions and
mortality. Large-scale, long-term randomized trials will be needed
to test the possibility of finding an effective therapy for central
sleep apnea would improve the prognosis of patients with exac-
erbated heart failure and overweight.
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