Sleep and Breathing
https://doi.org/10.1007/s11325-021-02382-4
SLEEP BREATHING PHYSIOLOGY AND DISORDERS • ORIGINAL ARTICLE
Endothelial dysfunction in obstructive sleep apnea patients
Michał Harańczyk1
· Małgorzata Konieczyńska1 · Wojciech Płazak2
Received: 17 November 2020 / Revised: 5 March 2021 / Accepted: 15 April 2021
© The Author(s) 2021
Abstract
Purpose Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular diseases. The aim of
the study was to assess the influence of OSAS on endothelial dysfunction and thrombosis biomarkers and to evaluate the
effect of treatment with continuous positive airway pressure (CPAP) on biomarker levels.
Methods NT-proBNP, sICAM-1, endothelin-1, von Willebrand factor, D-dimers, and thrombin-antithrombin complex (TAT)
were measured in 50 patients diagnosed with moderate-to-severe OSAS. All patients underwent transthoracic echocardiography, and 38 months after the inclusion, 16 CPAP users and 22 non-CPAP users were reassessed.
Results Sleep-related indices of apnea-hypopnea index (AHI) and mean SpO2 were associated with higher sICAM-1 levels
(AHI < 30: 7.3 ± 4.7 vs. AHI ≥ 30: 19.5 ± 19.4 mg/ml, p = 0.04; SpO2 ≥ 90%: 11.9 ± 9.3 vs. SpO2 < 90%: 23.6 ± 25.8, p = 0.04).
sICAM-1 levels were significantly higher in obese patients, particularly with BMI ≥ 40. Plasma levels of TAT were significantly correlated with the increased right ventricular size (right ventricular diameter ≤ 37 mm: 0.86 ± 0.70 vs. > 37 mm:
1.96 ± 1.20 ng/ml, p = 0.04). Endothelin-1 levels were higher in patients with decreased right ventricular function (right
ventricle TDI-derived S′ ≥ 12 cm/s: 11.5 ± 10.9 vs. < 12 cm/s: 26.0 ± 13.2 pg/ml, p = 0.04). An increase in NT-proBNP was
related to impaired parameters of the right ventricular contractile function. There were no correlations between long-term
CPAP therapy and the levels of biomarkers.
Conclusion Severe OSAS influences endothelial damage as manifested by an increase in sICAM-1 levels. Changes in right
ventricular structure and function, observed mainly in patients with higher TAT and endothelin-1 levels, are also manifested
by an increase in NT-proBNP levels. Long-term CPAP treatment does not seem to influence biomarkers in patients with
moderate-to-severe OSAS, which may help to explain the lack of influence of CPAP on cardiovascular risk reduction.
Keywords CPAP · Endothelin-1 · SICAM-1 · Von Willebrand factor · Thrombin-antithrombin complex
Introduction
Obstructive sleep apnea syndrome (OSAS) is considered an
epidemic disease in the modern world, affecting approximately 7% of men and 5% of women [1]. It is a chronic
disorder characterized by recurrent episodes of upper airway
collapse during sleep, resulting in hypoxia. Its effect on sleep
* Michał Harańczyk
m.haranczyk@szpitaljp2.krakow.pl
* Wojciech Płazak
wojciech.plazak@uj.edu.pl
1
Department of Diagnostic Medicine, John Paul 2Nd
Hospital, Prądnicka Str 80, 31-202 Kraków, Poland
2
Department of Cardiac and Vascular Diseases, John Paul
2Nd Hospital, Jagiellonian University Medical College,
Prądnicka Str 80, 31-202 Kraków, Poland
quality and daytime sleepiness is widely acknowledged, but
it has been also recognized as an independent risk factor
for cardiovascular diseases such as arterial hypertension
or stroke. Although the strong correlation between OSAS
and cardiovascular diseases is well recognized, the detailed
underlying mechanism remains unknown. Numerous possible mechanisms had been proposed to explain the association between OSAS and cardiovascular diseases, including
the inappropriate supply of oxygen, abnormal sympathetic
activity, increased circulating inflammatory mediators, or
an imbalance of the coagulation/fibrinolysis system [2–4].
Biomarkers have been evaluated for several applications in
patients with OSAS including diagnosis, prediction of disease
course, and therapeutic guidance. In addition, recent studies
have demonstrated a positive correlation between several biomarkers and severity of OSAS [5, 6]. Many potential OSAS
biomarkers have been proposed, with pro-inflammatory
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Sleep and Breathing
and procoagulant factors being the most frequently studied.
Hypoxia as a result of cyclic apnea and hypopnea episodes
increases endothelin-1 levels and, as a consequence, causes
vasoconstriction. Intermittent hypoxia enhances also the
expression of adhesion molecules such as soluble form of
intracellular adhesion molecule-1 (sICAM-1). Cell adhesion
molecules enable the process of binding circulating leukocytes with the endothelial cells, which is supposed to be the
primary step in the pathogenesis of atherosclerosis. As OSAS
is associated with an increased cardiovascular risk and inflammation and is fundamental to the development of cardiovascular diseases, it is likely that the severity of OSAS will be
related to the levels of biomarkers. Moreover, the assessment
of circulating biomarkers of inflammation may become a
useful tool for identifying patients with high cardiovascular
risk. Consequently, it should be expected that the reduction of
elevated biomarker levels will be possible through the use of
effective OSAS treatment. Moreover, it has been documented
that repeated episodes of nocturnal hypoxia in OSAS patients
may result with a hypercoagulable state, and thus, it could be
an independent risk factor for cardiovascular and cerebrovascular episodes [7]. Some studies have suggested significant
correlations between OSAS and thrombin-antithrombin complex (TAT), D-dimers, and von Willebrand factor (vWF) [8,
9]. TAT is formed as a result of the inhibition of thrombin by
antithrombin. D-dimers are the final products of the plasminmediated degradation of fibrin. D-dimers and TAT are biomarkers of coagulation activation, enabling the diagnosis of
thrombotic events. vWF is synthesized in endothelial cells
and megakaryocytes. It is responsible for facilitating platelet
plug formation. Elevated plasma levels of vWF may indicate
endothelial dysfunction and are found in several cardiovascular diseases, e.g., as pulmonary artery hypertension.
Other biomarkers linking cardiovascular diseases with
OSAS are cardiac neurohormones. NT-proBNP is the firstline biomarker recommended for diagnosing heart failures,
but its value in the early detection of subclinical changes in
heart structures and contractility is also known [10]. NTproBNP has been also established as a prognostic marker in
heart failure, coronary artery disease, and cardiac hypertrophy [11, 12]. There are limited data about predicting OSASrelated cardiovascular events before the manifestation of
clinical and echocardiographic findings. Therefore, the use
of biomarkers for the detection of subclinical changes in the
heart and for risk stratification has gained importance.
Similarly, mechanisms responsible for the development of
structural and functional changes in the right ventricle (RV)
are still controversial. The right ventricle plays a pivotal
role in the morbidity and mortality of patients with cardiopulmonary disease. Several studies reported decreased RV
contractility in patients with severe OSAS [13, 14]. Repeated
oxygen desaturations lead to pulmonary vasoconstriction,
which results in pulmonary remodeling and dysfunction in
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patients with OSAS. It has been recently documented that
decreased RV function is independent of the presence of
pulmonary hypertension and independently related to sleep
apnea severity based on the apnea–hypopnea index (AHI)
[15]. Therefore, early determination of subclinical RV
dysfunction may be important in early diagnosis of heart
failures and administration of early treatment to improve
prognosis. Echocardiography is the leading method for the
heart evaluation and also a good non-invasive tool to measure the increased right-heart pressures [16]. The evaluation
of hemodynamics in OSAS is also clinically useful, since
the negative effects of pressure changes during apnea/hypopnea episodes result in flow disturbances. As chest pressure becomes highly negative during respiration in OSAS
patients, the decreased pressures according to the respiratory
cycle affect pulmonary and systemic hemodynamics, mainly
by increasing afterload [17].
For this reason, a group of biomarkers with a recognized
role in the assessment of pulmonary circulation and inflammatory processes was selected in order to establish their
levels in patients with newly diagnosed OSAS and during
the treatment of patients with CPAP.
The aim of the study was (1) to determine endothelial
function, thrombotic activation, and possible cardiac dysfunction in patients with newly diagnosed OSAS by means
of sICAM-1, endothelin-1, D-dimers, vWF, TAT, and NTproBNP concentrations examination; (2) to compare the
levels of these biomarkers with OSAS parameters and with
the structure and function of right heart assessed by echocardiography; and (3) to determine the possible changes in
endothelial function and thrombotic activation in patients
during CPAP treatment.
Material and methods
The study involved 77 consecutive patients admitted to hospital suffering from suspected OSAS. Men and women over
the age of 18 were included. The exclusion criteria were congestive heart failure, severe valvular heart disease, severe or
uncontrolled pulmonary disease (such as pulmonary hypertension, chronic obstructive pulmonary disease, or asthma),
active neoplasm, or any other uncontrolled internal diseases,
such as hypertension, hypothyroidism, or diabetes mellitus.
The study protocol is presented in Fig. 1.
Sleep test and CPAP adjustment
Seventy-seven patients underwent an overnight in-lab
recording using a sleep-monitoring system (Embletta MPR,
type III according to the American Academy of Sleep Medicine, AASM). Standard recommendations of sleep scoring
criteria were applied [18]. Electrocardiography, airflow
Sleep and Breathing
Fig. 1 Study protocol
analysis, and pulse oximetry were performed. Ventilatory
flows were measured with airflow cannulas fitted both over
the nose and the mouth. Respiratory movements were determined using inductive plethysmography belts. Body position
was monitored with the use of a built-in position sensor.
Arterial oxygen saturation (SpO2) was measured transcutaneously with a finger pulse oximeter.
Respiratory events were scored using the 2012 AASM
criteria [19]. Obstructive apnea (OA) was scored in the
event of absence or reduction of the baseline airflow with
continued respiratory effort to less than 10% lasting 10 s
or longer. Hypopnea (H) was defined as a 30–89% reduction in the respiratory airflow amplitude lasting at least 10
s and accompanied by a decrease of at least 3% in oxygen
saturation. Central apnea (CA) was scored as an absence
or reduction to less than 10% of baseline airflow without
continued respiratory effort, lasting 10 s or longer. When
an event met apnea criteria and was associated with absent
inspiratory effort in the initial part of the event, followed
by resumption of inspiratory effort in the second part of
the event, it was scored as a mixed apnea (MIX). The AHI
was defined as the average number of episodes of apnea
and hypopnea per hour. OSAS was defined as an AHI of
> 5 per hour in the presence of symptoms such as daytime
sleepiness. A decrease in the SpO2 of 3% or more from the
baseline was defined as desaturation. Oxygen desaturation
index (ODI) was calculated as the total number of desaturation episodes per hour.
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Sleep and Breathing
Moderate-to-severe OSAS (AHI ≥ 15/h) was diagnosed in
50 out of 77 patients who underwent the sleep study. CPAP
was recommended to all patients with AHI ≥ 30 or when
the AHI was between 15 and 30 and the patient complained
about severe daytime sleepiness. Therefore, CPAP therapy
was not initiated in 4 patients due to the presence of moderate OSAS and the absence of significant clinical symptoms.
Nine patients declined the proposed CPAP therapy or did not
initiate therapy after the titration. Four patients discontinued
treatment as a result of poor tolerance during CPAP titration, and 4 patients discontinued CPAP therapy after a few
months due to poor treatment tolerance. The final analysis
of CPAP parameters was based on the data obtained from
16 patients who had been treated with CPAP therapy during the study period. The following devices were applied:
RESMED AutoSet S9 (ResMed, Bella Vista, Australia) and
REMstar Auto (Philips-Respironics, Murraysville, USA)
with the initial pressure set around 7–13 cmH2O, and initial
“ramp” time, expiratory pressure relief, and a facial mask
were individually adjusted. In CPAP users, all available
data were downloaded from patients’ CPAP machines at
the follow-up visit.
Echocardiography
A day before the CPAP titration, the entire group of 50
patients had undergone a complete standardized two-dimensional (2-D) transthoracic echocardiography study using
the Philips IE33 device (transducer X5-1; 1.3 to 4.2 MHz).
Measurements of cardiac chambers and transvalvular flows
were made according to the established criteria [20]. For
assessment of the right atrium and ventricle, the RV-focused
4-chamber view was preferred, and mid-cavity RV (RVD)
dimensions were acquired. Right ventricular systolic pressure (RVSP) was estimated using standard Doppler practices, but several views were used to determine the maximal velocity. M-mode technique was used to assess the
maximum systolic excursion of the lateral tricuspid annulus
(TAPSE) in an apical 4-chamber view. Tissue Doppler imaging (TDI) was performed to obtain peak systolic (S′) velocity
and peak early (E′) diastolic tricuspid annular velocity.
Laboratory methods
Endothelin-1 and sICAM-1 levels were determined using
Nori® Human ICAM-1 ELISA Kit (Genorise Scientific,
USA) by quantitative ELISA (enzyme-linked immunosorbent assay) in the blood serum. According to the manufacturer’s recommendations, the plasma for sICAM-1 was
diluted three times. Thrombin–antithrombin complexes
were assessed in citrate plasma, using AssayMax™ Human
Thrombin-Antithrombin Complex ELISA Kit (Assaypro,
USA). Readings were taken at a wavelength of 450 nm using
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an absorbance microplate reader ELx 800 (BioTek Instruments, Vinooski, VT, USA). Values were converted to concentration units of the studied parameters on the basis of
the calibration curve made by KC Junior software (Bio Tek
Instruments). NT-proBNP levels were determined using the
Cobas e601 module (Roche Diagnostics, Risch-Rotkreuz,
Swiss). Von Willebrand factor and D-dimers were determined using BCS® XP System (Siemens, Cardiff, Wales).
Fasting blood samples were taken in the morning following
the sleep recordings, a day before the CPAP titration started.
For the second time, samples were taken during the followup visit.
All procedures were followed in accordance with the ethical standards of the Declaration of Helsinki, and all subjects
gave their informed consent. The trial was approved by the
local ethics committee (approval number 112.6120.2.2016).
Statistical analysis
Continuous variables are presented as mean and standard
deviations (SD). The Shapiro–Wilk test was used to determine if the variables were not normally distributed. Student
t-test for continuous variables was conducted to evaluate
differences between the study groups. The p-value of < 0.05
was considered statistically significant threshold.
Results
The study group consisted of 50 patients with mean age
60.3 ± 10.3 years. There was no relevant difference in basic
clinical parameters at baseline between the patients that during the study appeared to be CPAP users or non-CPAP users
(Table 1). All patients had preserved left ventricular (LV)
systolic function.
There was no significant difference in the levels of biomarkers between the patients with or without cardiovascular risk factors except for the significant influence of body
weight on sICAM-1 and endothelin-1 (Table 2). D-dimers
were higher in women and patients over 65 years of age.
Furthermore, significant changes in RV structure and contractility were observed. The increase of RV size expressed
as RVD and the decrease of RV function calculated as TDIderived S′ were related to an increase of TAT and endothelin-1 levels, respectively (Table 3). The sleep study parameters (AHI, mean SpO2) were associated with sICAM-1 levels
(Table 4). In patients with AHI ≥ 30, significantly higher
sICAM-1 levels were found in males, females, patients
aged < 60 or ≥ 60, and those with BMI < 35 or ≥ 35 (Table 5).
The mean follow-up period was 38 ± 4.2 months. All
patients using CPAP achieved a significant reduction in AHI
as shown in Table 1. In our study, the mean duration of CPAP
use was 3 ± 2.3 h/night (all-day analysis), and CPAP usage
Sleep and Breathing
Table 1 Main clinical characteristics of OSAS patients
Parameter
Male sex, n (%)
Age (years)
BMI (kg/m2)
Sleep study results
AHI (h−1)
OA (h−1)
CA (h−1)
MIX (h−1)
H (h−1)
mean SpO2 (%)
ESS
Time to control (months)
Comorbidities
Arterial hypertension, n (%)
Diabetes mellitus 2, n (%)
Hypercholesterolemia, n (%)
LVEF (%)
Group 1 (CPAP users)
Group 2 (non-CPAP users)
Baseline (n = 16)
Follow-up (n = 16)
Baseline (n = 34)
Follow-up (n = 22)
12 (75)
57.3 ± 9.2
35 ± 4.4
12 (75)
60.1 ± 9
35 ± 5.1
20 (59)
61.8 ± 10.4
33.7 ± 6.5
12 (54)
63.4 ± 10.8
32.7 ± 5.1
46.3 ± 18.5
23.6 ± 22.2
1.8 ± 3.4
5.7 ± 6.7
15.2 ± 9.5
90.1 ± 4
10.5 ± 6
2.7 ± 2.6
0.5 ± 0.5
0.1 ± 0.2
33.3 ± 18.1
14.5 ± 14
1.2 ± 2.1
2.2 ± 5.8
15.6 ± 8.4
88.6 ± 13.7
8.9 ± 6
1.4 ± 1.8
38 ± 4.1
15 (94)
5 (31)
14 (88)
62.1 ± 5.4
15 (94)
5 (31)
14 (88)
38 ± 4.3
26 (76)
10 (29)
28 (82)
64.4 ± 2.3
16 (73)
6 (27)
20 (91)
Data expressed as mean ± SD or number (%) of patients; SD standard deviation, AHI apnea–hypopnea index, BMI body mass index, CA central apnea, CPAP continuous positive airway pressure, ESS Epworth Sleepiness Scale score, H hypopnea, LVEF left ventricular ejection fraction, Mean SpO2 mean blood oxygen saturation, MIX mixed apnea, OA obstructive apnea, ODI oxygen desaturation index
mean time during days with device usage was 4.7 ± 2.1 h/night,
according to CPAP machines’ readings. The analysis of studied biomarkers in CPAP users and non-CPAP users showed no
significant change during the observation (Table 6).
Discussion
The main finding of the study was that a high apnea–hypopnea index correlates significantly with higher sICAM-1
levels. Correspondingly, it was shown that higher sICAM-1
levels are present in patients with mean saturation < 90%.
Similarly, an increase in NT-proBNP as an indicator of
impaired RV contractile function measured by TDI-derived
S′ was demonstrated. The other interesting finding is a
decreased level of endothelin-1 in a subgroup of CPAP users
with a baseline BMI ≤ 35. However, the study did not reveal
any significant changes in the levels of observed biomarkers
as a result of CPAP treatment.
with impaired parameters of RV contractile function (statistically significant for RV S′ and the trend for TAPSE) and
structural function (the trend for right atrial area, RAA).
Moreover, we found that NT-proBNP tends to be higher in
patients with high AHI. This corresponds well with other
studies, which found no statistical difference in baseline values of NT-proBNP [21].
A further analysis of sleep study parameters in our
patients revealed a tendency to higher NT-proBNP values
in patients presenting more episodes of apnea, which was
confirmed also by Kohno et al. [22]. This finding extends
the recent data obtained by Kulkas et al. [23] who claimed
that since apneic episodes arise as a consequence of the
complete upper-airway collapse, they result in a more pronounced drop in blood saturation level. Consequently, they
may impose a more serious pathophysiologic impact than
hypopneas which results from the incomplete collapse of the
upper airway. Indeed, apneas may be regarded as more significant than hypopneas when assessing the related impact
on the long-term cardiac risk.
Biomarkers in OSAS
Endothelial dysfunction markers
NT‑proBNP
NT-proBNP analysis in our study provided the assumed conclusion that its values tend to be higher with age. The study
also demonstrated an increase in NT-proBNP in patients
In our study, sICAM-1 levels were significantly higher in
patients with BMI ≥ 40. Moreover, endothelin-1 levels were
higher in patients with decreased right ventricular function.
Overall, our data support the concept that the severity of
13
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Table 2 Clinical parameters and biomarkers levels at the beginning of the study in OSAS patients (n = 50)
Gender
Age
BMI
BMI
Normotensive patients
Arterial hypertension
Non-diabetic
Diabetes mellitus
Normal lipid profile
Hypercholesterolemia
Males
Females
< 65
≥ 65
< 30
≥ 30
< 40
≥ 40
NT-proBNP (pg/ml)
p
sICAM-1 (ng/ml)
p
Endothelin-1 (pg/ml)
p
vWF
(%)
p
D-dimers
(µg/L)
p
TAT
(ng/ml)
p
157.7 ± 569.8
170.3 ± 166.2
60.5 ± 76.3
302.7 ± 695.1
142.5 ± 199.6
168.5 ± 522.3
181.5 ± 504.2
61.2 ± 52.8
134.0 ± 229.9
168.4 ± 502.6
101.7 ± 137.8
303.5 ± 822.3
97.2 ± 119.1
174.6 ± 503.6
ns
11.9 ± 19.8
19.4 ± 44.0
13.3 ± 20.7
16.4 ± 40.9
6.8 ± 3.7
17.1 ± 17.4
10.5 ± 8.7
35.9 ± 32.2
10.7 ± 9.4
15.5 ± 33.4
17.3 ± 36.2
8.3 ± 5.0
8.2 ± 4.1
15.8 ± 33.2
ns
12.5 ± 16.6
18.1 ± 30.0
13.7 ± 18.6
15.7 ± 28.1
3.1 ± 3.3
18.2 ± 12.6
11.4 ± 7.9
30.9 ± 21.5
13.0 ± 21.8
14.9 ± 23.3
15.3 ± 26.0
12.7 ± 12.0
12.6 ± 17.6
14.9 ± 23.8
ns
162.5 ± 58.1
166.6 ± 53.7
152.9 ± 59.8
179.3 ± 47.6
142.6 ± 44.6
170.7 ± 58.1
160.6 ± 57.3
181.7 ± 48.4
142.2 ± 40.4
168.7 ± 58.3
163.6 ± 62.2
164.8 ± 39.9
141.2 ± 36.3
168.3 ± 58.4
ns
435.7 ± 497.2
1058.2 ± 1468.6
383.4 ± 354.6
1038.1 ± 1410.3
307.1 ± 145.8
748.1 ± 1096.1
693.1 ± 1077.1
471.8 ± 293.7
304.3 ± 138.8
726.6 ± 1072.5
718.4 ± 1170.7
519.3 ± 369.7
351.2 ± 208.1
717.2 ± 1074.0
0.03
1.14 ± 1.82
0.94 ± 1.31
1.08 ± 1.83
1.05 ± 1.39
1.27 ± 2.20
1.01 ± 1.40
1.12 ± 1.66
0.82 ± 1.66
0.87 ± 1.05
1.11 ± 1.75
1.17 ± 1.80
0.83 ± 1.21
0.74 ± 1.43
1.13 ± 1.69
ns
ns
ns
ns
ns
ns
ns
ns
0.04
0.01
ns
ns
ns
ns
0.04
0.02
ns
ns
ns
ns
ns
ns
ns
ns
ns
0.02
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
BMI body mass index, NT-proBNP N-terminal part of the propeptide of BNP, sICAM-1 soluble form of intracellular adhesion molecule-1, TAT thrombin-antithrombin III complex, vWF von
Willebrand factor
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Sleep and Breathing
Table 3 Functional and structural changes in the right heart and biomarkers levels at the beginning of the study in OSAS patients (n = 50)
NT-proBNP (pg/ml)
RV structural changes
RVOT
≤ 30
99.2 ± 89.8
(mm)
> 30
182.5 ± 529.8
≤ 37
220.7 ± 592.4
RVD
(mm)
> 37
65.5 ± 74.6
≤ 20
110.2 ± 114.6
RAA
(cm2)
> 20
246.5 ± 655.0
RV functional changes
TAPSE
≥ 24
69.5 ± 52.2
(mm)
< 24
241.2 ± 623.6
RV S’
≥ 12
68.9 ± 61.2
(cm/s)
< 12
466.8 ± 559.1
≤ 25
87.4 ± 94.5
TRPG
(mmHg)
> 25
305.9 ± 634.8
p
sICAM-1 (ng/ml)
p
Endothelin-1 (pg/ml)
p
vWF
(%)
p
D-dimers (µg/L)
p
TAT
(ng/ml)
p
ns
7.5 ± 5.0
17.1 ± 34.7
15.5 ± 34.4
16.2 ± 24.4
16.7 ± 36.8
13.2 ± 22.3
ns
10.7 ± 13.2
15.9 ± 25.1
15.2 ± 26.4
13.4 ± 15.1
14.6 ± 27.3
14.6 ± 16.6
ns
137.4 ± 35.9
170.3 ± 59.0
164.6 ± 51.4
168.5 ± 63.8
158.3 ± 46.9
173.4 ± 65.0
ns
797.2 ± 1693.5
600.8 ± 639.5
836.7 ± 1244.1
460.5 ± 340.1
795.6 ± 1279.4
499.2 ± 574.8
ns
0.53 ± 0.93
1.14 ± 1.79
0.86 ± 0.70
1.96 ± 1.20
0.90 ± 1.66
1.25 ± 1.64
ns
12.4 ± 22.8
16.5 ± 36.1
14.1 ± 29.2
18.6 ± 37.6
21.0 ± 43.2
9.0 ± 5.8
ns
11.3 ± 16.3
17.3 ± 27.2
11.5 ± 10.9
26.0 ± 13.2
18.4 ± 30.8
10.8 ± 9.7
ns
164.5 ± 45.6
163.6 ± 64.6
159.3 ± 51.8
184.4 ± 69.7
153.8 ± 55.6
190.4 ± 56.0
ns
498.4 ± 578.9
789.8 ± 1235.0
676.3 ± 1023.4
656.8 ± 869.1
745.3 ± 1307.2
727.4 ± 585.7
ns
0.86 ± 1.41
1.25 ± 1.82
1.00 ± 1.63
1.47 ± 1.69
1.38 ± 2.01
0.84 ± 1.18
ns
ns
ns
ns
0.01
ns
ns
ns
ns
ns
ns
ns
0.04
ns
ns
ns
ns
ns
ns
ns
ns
ns
0.04
ns
ns
ns
NT-proBNP N-terminal part of the propeptide of BNP, RAA right atrial area, RVD mid-cavity right ventricular diamete, RVOT right ventricular outflow tract, sICAM-1 soluble form of intracellular adhesion molecule-1, S′ peak early systolic tricuspid annular velocity, TAPSE tricuspid annular plane systolic excursion, TAT thrombin-antithrombin III complex, TRPG tricuspid regurgitant
peak gradient, vWF von Willebrand factor
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13
ns
ns
ns
0.04
ns
(%)
mean SpO2
AHI apnea–hypopnea index, mean SpO2 mean blood oxygen saturation, NT-proBNP N-terminal part of the propeptide of BNP, sICAM-1 soluble form of intracellular adhesion molecule-1, TAT thrombin-antithrombin III complex, vWF von Willebrand factor
ns
ns
1.13 ± 1.22
1.13 ± 1.89
1.27 ± 1.79
0.52 ± 0.98
ns
722.9 ± 1309.4
605.5 ± 705.8
653.3 ± 1084.4
657.9 ± 718.7
ns
159.4 ± 62.2
167.1 ± 52.2
162.9 ± 61.5
168.9 ± 38.4
ns
8.9 ± 11.7
18.3 ± 27.5
14.5 ± 18.8
14.9 ± 32.5
0.04
7.3 ± 4.7
19.5 ± 19.4
11.9 ± 9.3
23.6 ± 25.8
ns
106.8 ± 84.8
199.2 ± 595.9
196.2 ± 536.0
65.2 ± 51.7
< 30
≥ 30
≥ 90
< 90
(h−1)
AHI
Endothelin-1 (pg/ml)
p
sICAM-1 (ng/ml)
p
NT-proBNP (pg/ml)
Table 4 Sleep study parameters and biomarkers levels at the beginning of the study in OSAS patients (n = 50)
p
vWF
(%)
p
D-dimers (µg/L)
p
TAT
(ng/ml)
p
Sleep and Breathing
OSAS might be related to endothelial dysfunction. Cyclic
changes in the breathing pattern causing episodes of apnea
and hypopnea result in hypoxemia and hypercapnia. Hypoxia
increases endothelin-1, a potent vasoconstrictor with proinflammatory properties. Hypoxia also enhances the expression of adhesion and is involved in the induction of endothelial and myocyte apoptosis. Since endothelial dysfunction
has been demonstrated in several cardiovascular disorders,
potential common pathophysiological pathways appear to
influence the morbidity of OSAS patients [24].
As presented in this study, a high level of AHI, corresponding to the effect of sleep apnea on the body, correlates significantly with the levels of sICAM-1. Similarly, a
higher sICAM-1 levels were confirmed in our patients for
mean saturation < 90%. This finding supports the thesis that
endothelial damage is manifested by an increase in the levels of pro-inflammatory molecules as a result of repeated
desaturation during sleep [25].
Our data confirm the results of the previously published
study by Carratu et al. [26] who claimed that endothelin-1
levels were significantly higher in obese patients. Similarly,
it was determined that the difference was more strongly associated with weight than the severity of sleep apnea.
Consistent with such a conclusion is the significant relationship between the degree of obesity and the levels of
sICAM-1 found in our and other studies [27]. Several studies demonstrated that plasma levels of adhesion molecules
are increased among obese individuals, whereas weight
reduction was associated with a decrease in ICAM levels
[28]. ICAM levels are elevated in obese individuals, even
in potentially healthy individuals, but this also applies to
patients diagnosed with OSAS [29]. In our study, there is a
clear tendency towards an increase of sICAM-1 with increasing body mass index (BMI) in patients with BMI ≥ 40.
As presented in our study, high BMI is a strong factor
increasing the levels of endothelin-1. Therefore in obese
patients, the levels of endothelin-1 did not decrease, because
BMI did not change during the observation period in our
study. However, in a subgroup of CPAP users with a baseline
BMI ≤ 35, endothelin-1 decreased significantly.
The results of our study indicate that patients with
AHI > 30 (OSAS grade 3) tend to have higher endothelin-1
levels. This value does not reach statistical significance,
which is most likely due to the size of the study group. By
contrast, Ursavaş et al. [30] found that OSAS can increase
the circulating levels of adhesion molecules independently
of BMI, smoking status, or cardiovascular disease, although
the analysis also included patients with mild OSAS.
Our findings suggest that RV systolic dysfunction is
associated with higher levels of endothelin-1. Our study
shows significantly lower RV TDI-derived S′ values, but a
trend was also observed for TAPSE values. The increase in
endothelin-1 levels may be the result of persistent nocturnal
Sleep and Breathing
Table 5 sICAM-1 levels
in subgroups of patients
differentiated according to
gender, age or BMI
−1
AHI (h )
< 30
≥ 30
p
Males
Females
< 60 years
≥ 60 years
BMI < 35
BMI ≥ 35
6.9 ± 4.5
14.6 ± 11.9
0.04
7.8 ± 5.3
30.8 ± 30.5
0.03
6.2 ± 2.0
19.8 ± 14.4
0.03
7.9 ± 5.7
19.2 ± 23.3
0.04
7.0 ± 4.9
14.9 ± 13.5
0.04
8.5 ± 4.5
24.6 ± 24.5
0.03
AHI apnea–hypopnea index, BMI body mass index, sICAM-1 soluble form of intracellular adhesion molecule-1
hypoxia, thereby leading to an increase in the vascular
resistance in pulmonary vessels. This may be followed
by pulmonary arteriolar vasoconstriction, which could
adversely affect RV function. It is to note that RV function
is substantially influenced by RV afterload, which is mainly
determined by pulmonary vascular resistance and slightly
influenced by preload. As a result, we observed RV damage
expressed as a decrease in RV contractility parameters. Consistently one could expect an increase of RVSP; however, it
is not confirmed by this study. The explanation might be the
fact that the sensitivity of RVSP estimation by echocardiography is suboptimal. Consequently, imprecise results might
follow, particularly in situations when significant tricuspid
jet cannot be visualized or there is a suboptimal Doppler
Wave angle, or poor acoustic window, which is frequent in
OSAS patients [31].
Coagulation biomarkers
Our study shows that plasma levels of TAT were significantly correlated with the increased right ventricular size.
Furthermore, significantly higher levels of D-dimer in
women and patients ≥ 65 years were observed. Nonetheless,
there was no significant difference in coagulation biomarkers
between OSAS and patients with AHI 15–30 or ≥ 30, and
those levels remained unchanged after CPAP treatment. This
conclusion is in line with the available data from Zamaron
et al. [32] and von Känel et al. [33]. It should be emphasized
that single studies have shown that an increased level of
pro-thrombotic factors in OSAS patients is related to other
comorbidities (e.g., hypertension) [34].
Biomarkers in CPAP
Our study had a long follow-up period, and there was a significant reduction in AHI in all CPAP patients which applied
to each category of sleep events. Nevertheless, no significant changes in the levels of observed biomarkers (NTproBNP, sICAM-1, endothelin-1, vWF, D-dimers, TAT)
were revealed as a result of CPAP treatment.
CPAP therapy remains the gold standard of OSAS treatment, although the effects of long-term treatment on clinical parameters are not fully convincing [35]. The available
data confirm the effect of CPAP on the reduction of daytime sleepiness, decreased number of road accidents, and
the improvement of blood pressure control. On the other
hand, the impact of CPAP on cardiovascular events such as
heart attacks or heart failures remains controversial [36].
Similarly, the recent analysis of randomized clinical trials
shows no difference in all-cause mortality, major adverse
cardiovascular events, or cardiovascular death [37]. Some
argue that poor protection against cardiovascular outcomes
is a result of the low level of use, which may not be sufficient to achieve the therapeutic effect of CPAP. However,
the sensitivity analyses and the subgroup analyses in this
meta-analysis did not reveal consistent results concerning
the impact of longer CPAP use (≥ 4 h per night) on cardiovascular outcomes in OSAS patients [37].
In our observation, the level of CPAP use met the criteria of the recommended minimum of 4 h per night, but the
total number of days when the device was applied was not
satisfactory. Therefore, low adherence of patients as a probable cause of the lack of significant differences in biomarker
Table 6 The levels of biomarkers in CPAP users and non-users at baseline and at follow-up
CPAP users
NT-proBNP
sICAM-1
Endothelin-1
D-dimers
vWF
TAT
pg/ml
ng/ml
pg/ml
µg/L
%
ng/ml
Baseline (n = 16)
257.5 ± 806.9
8.31 ± 5.6
11.3 ± 12.7
659.1 ± 870.9
172.6 ± 72.8
0.87 ± 2.05
Follow-up (n = 16)
122.0 ± 93.5
8.1 ± 5.2
6.8 ± 6.8
635.8 ± 940.5
191.5 ± 117.5
0.53 ± 1.40
non-CPAP users
p
ns
ns
ns
ns
ns
ns
Baseline (n = 34)
103.2 ± 82.9
14.3 ± 23.6
16.9 ± 21.7
730.3 ± 1319.7
149.4 ± 43.1
1.45 ± 1.55
Follow-up (n = 22)
115.8 ± 170.7
13.0 ± 16.3
18.0 ± 30.0
480.6 ± 296.8
156.8 ± 43.9
0.99 ± 0.99
p
ns
ns
ns
ns
ns
ns
CPAP continuous positive airway pressure, NT-proBNP N-terminal part of the propeptide of BN, sICAM-1 soluble form of intracellular adhesion
molecule-1, TAT thrombin-antithrombin complex, vWF von Willebrand factor
13
Sleep and Breathing
levels is considered. The short time of follow-up duration,
proposed as another factor affecting the vascular outcome,
seems not to be the case in our study as the average time
from the inclusion to follow-up visit was 1138.8 ± 125 days
(38 ± 4.2 months).
In accordance with the results, Svatikova et al. [21] and
Çifçi et al. [38] demonstrated that CPAP therapy does not
affect NT-proBNP. On the contrary, Tasci et al. [39] showed
a reduction in NT-proBNP after CPAP treatment, but this
study differed in the time at which NT-proBNP was measured (first day after CPAP treatment initiation). The presented data do not conclude on the role of CPAP and its
impact on the potential reduction of NT-proBNP, which in a
situation of preexisting comorbidities such as heart failures,
is well established [40].
The expected reduction of endothelial dysfunction markers was not observed in our study; however, according to
some researchers, numerous pathophysiological pathways
can be reversed using effective CPAP therapy, and many
studies report a beneficial effect of CPAP on endothelial dysfunction markers. The Ohga study [41] showed a reduction
in sICAM-1 levels in patients using nasal continuous positive airway pressure (nCPAP) after 8–18 months of therapy.
Another study showed sICAM-1 reduction, which was most
pronounced in patients with severe obesity [29].
We have shown that among non-CPAP users, endothelin-1 levels do not change significantly. However, patients
treated with CPAP tended to have lower endothelin-1 levels than non-CPAP users. We speculate that the differences
may become more apparent with a higher number of studied
patients. These results are in line with Zamarrón et al. study
[32], in which after 1 year of CPAP treatment, a significant decrease in circulating levels of sICAM-1 was found,
but none in vWF or endothelin-1 levels. Moreover, our data
are consistent with those reported by Grimpen et al. [42],
who found significant changes of endothelin-1 neither during sleep nor in the first night on CPAP therapy, nor under
14 months CPAP treatment, and with Diefenbach et al.
[43] who stated that endothelin-1 levels of untreated OSAS
patients and patients under effective long-term (> 6 months)
treatment with nCPAP were within the normal range and
were not elevated when compared with healthy subjects.
Furthermore, Turnbull et al. [44] found that the levels of
endothelin-1 also have not changed in patients treated with
CPAP for a year after temporary discontinuation of treatment. These results contradict the conclusions of recent
meta-analysis [45], although the authors admit that the studies included in the analysis were highly heterogeneous.
Among procoagulant molecules vWF, D-dimer, and TAT
were selected, due to their role in the coagulation system,
as well as the contradictory findings from previous studies
assessing their impact on OSAS. In previous studies, the
short-term evaluation did not reveal any significant impact of
13
CPAP on vWF and D-dimer levels [33], similar conclusions
can be drawn from the randomized study with sham-CPAP
[8]. Another short observation revealed changes in nocturnal
and early morning levels of vWF, whereas D-dimer levels
remained unchanged [46]. Some researchers have reported
hypercoagulability in patients with OSAS as manifested by
elevated TAT levels, but similarly, no change in this parameter was observed after 1 month of CPAP therapy [34].
Limitations
Non-CPAP users were a mixed group of patients, 5 of whom
were referred at the outset for conservative treatment and
17 who did not start or discontinued CPAP for different reasons, even though they met the treatment criteria. Therefore,
comparisons with the non-CPAP user group are limited by
their heterogeneity. The determination of the structure and
function of the right ventricle by echocardiography might
be somehow limited. Moreover, no other measurement of
right heart structures was attempted. Cardiac magnetic resonance (CMR) remains the gold standard of RV assessment,
although the advantages of echocardiography, such as low
costs of examination, possibility to perform the examination
in patients regardless of implanted pacemakers, or claustrophobia, play a significant role in everyday clinical practice. As portable devices remain useful in the diagnosis of
OSAS in patients with a high pretest likelihood of having
moderate-to-severe OSAS, full polysomnography was not
performed [47]. Finally, our study population was relatively
small but proportional to comparable studies performed in
OSAS patients.
Conclusions
Severe OSAS influences endothelial damage as manifested by
an increase in sICAM-1 levels. Changes in the right ventricular structure and function, observed mainly in patients with
higher TAT and endothelin-1 levels, are also manifested by
an increase in NT-proBNP levels. Long-term CPAP treatment
does not seem to influence biomarker levels in patients with
moderate-to-severe OSAS, which may help to explain the
lack of influence of CPAP on cardiovascular risk reduction.
Author contribution All authors contributed to the study conception
and design. Material preparation and data collection were performed by
Michał Harańczyk, and analysis was performed by Michał Harańczyk
and Wojciech Płazak. The first draft of the manuscript was written by
Michał Harańczyk, and all authors commented on previous versions
of the manuscript. All authors read and approved the final manuscript.
Funding This study was supported by grant no. N41/DBS/000521 from
the Jagiellonian University Medical College, Kraków, Poland.
Sleep and Breathing
Declarations
Ethics approval All procedures performed in this study were in accordance with the ethical standards of the institutional and national research
committee and with the 1964 Helsinki Declaration and its later amendments. All subjects gave their written informed consent to participate in
the study (Jagiellonian University Ethics Committee approval number
112.6120.2.2016).
Consent to participate All subjects gave their written informed consent
to participate in the study.
Consent for publication All subjects gave their written informed consent for publication.
Competing interests The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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