Cardiovascular regulation in different sleep stages in the obstructive sleep apnea syndrome.
ABSTRACT Heart rate and blood pressure variability analysis as well as baroreflex sensitivity have been proven to be powerful tools for the assessment of autonomic control in clinical practice. Their ability to detect systematic changes caused by different states, diseases and treatments shall be shown for sleep disorders. Therefore, we consider 18 normotensive and 10 hypertensive patients suffering from obstructive sleep apnea syndrome (OSAS) before and after a three-month continuous positive airway pressure (CPAP) therapy. Additionally, an age and sex matched control group of 10 healthy subjects is examined. Linear and nonlinear parameters of heart rate and blood pressure fluctuation as well as the baroreflex sensitivity are used to answer the question whether there are differences in cardiovascular regulation between the different sleep stages and groups. Moreover, the therapeutic effect of CPAP therapy in OSAS patients shall be investigated. Kruskal-Wallis tests between the sleep stages for each group show significant differences in the very low spectral component of heart rate (VLF/P: 0.0033-0.04 Hz, p<0.01) which indicates differences in metabolic activity during the night. Furthermore, the decrease of Shannon entropy of word distribution as a parameter of systolic blood pressure during non-REM sleep reflects the local dominance of the vagal system (p<0.05). The increased sympathetic activation of the patients leads to clear differences of cardiovascular regulation in different sleep stages between controls and patients. We found a significant reduction of baroreflex sensitivity in slow wave sleep in the OSAS patients (Mann-Whitney test, p<0.05) compared to controls, which disappeared after three months of CPAP therapy. Hence, our results demonstrate the ability of cardiovascular analyzes to separate between healthy and pathological regulation as well as between different severities of OSAS in this retrospective study.
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ABSTRACT: BACKGROUND: Obstructive sleep apnea (OSA) in adults has been associated with hypertension, low baroreflex sensitivity (BRS), a delayed heart rate response to changing blood pressure (heart period delay [HPD]), and increased blood pressure variability (BPV). Poor BRS may contribute to hypertension by impairing the control of blood pressure (BP), with increased BPV and HPD. Although children with OSA have elevated BP, there are scant data on BRS, BPV, or HPD in this group. METHODS: 105 children ages 7-12years referred for assessment of OSA and 36 nonsnoring controls were studied. Overnight polysomnography (PSG) was performed with continuous BP monitoring. Subjects were assigned to groups according to their obstructive apnea-hypopnea index (OAHI): primary snoring (PS) (OAHI ⩽1event/h), mild OSA (OAHI>1-⩽5events/h) and moderate/severe (MS) OSA (OAHI>5events/h). BRS and HPD were calculated using cross spectral analysis and BPV using power spectral analysis. RESULTS: Subjects with OSA had significantly lower BRS (p<.05 for both) and a longer HPD (PS and MS OSA, p<.01; mild OSA, p<.05) response to spontaneous BP changes compared with controls. In all frequencies of BPV, the MS group had higher power compared with the control and PS groups (low frequency [LF], p<.05; high frequency [HF], p<.001). CONCLUSIONS: Our study demonstrates reduced BRS, longer HPD, and increased BPV in subjects with OSA compared to controls. This finding suggests that children with OSA have altered baroreflex function. Longitudinal studies are required to ascertain if this dampening of the normal baroreflex response can be reversed with treatment.Sleep Medicine 06/2013; · 3.49 Impact Factor
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ABSTRACT: Sleep is involved in the regulation of major organ functions in the human body, and disruption of sleep potentially can elicit organ dysfunction. Obstructive sleep apnea (OSA) is the most prevalent sleep disorder of breathing in adults and children, and its manifestations reflect the interactions between intermittent hypoxia, intermittent hypercapnia, increased intra-thoracic pressure swings, and sleep fragmentation, as elicited by the episodic changes in upper airway resistance during sleep. The sympathetic nervous system is an important modulator of the cardiovascular, immune, endocrine and metabolic systems, and alterations in autonomic activity may lead to metabolic imbalance and organ dysfunction. Here we review how OSA and its constitutive components can lead to perturbation of the autonomic nervous system in general, and to altered regulation of catecholamines, both of which then playing an important role in some of the mechanisms underlying OSA-induced morbidities.Frontiers in Neurology 01/2012; 3:7.
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ABSTRACT: Obstructive sleep apnea (OSA) may lead to the development of hypertension and therapy with continuous positive airway pressure (CPAP) can promote reduction in blood pressure.Journal of hypertension. 06/2014;
Cardiovascular Regulation in Different Sleep Stages in the Obstructive Sleep
Jan F Kraemer1, Andrej Gapelyuk1, Maik Riedl1, Alexander Suhrbier2,3, Georg Bretthauer2,
Hagen Malberg3, Thomas Penzel4, Jürgen Kurths1,5,6, Niels Wessel1
1Department of Physics, Humboldt-Universität zu Berlin, Berlin, Germany
2Institute for Applied Computer Science, Forschungszentrum Karlsruhe GmbH
(Karlsruhe Research Center), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
3Institute of Biomedical Engineering, Dresden, Germany
4Sleep Center, Charité University Hospital, Berlin, Germany
5Potsdam Institute for Climate Impact Research, Potsdam, Germany
6Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen,
In order to show the value of the analysis of heart
rate variability (HRV), blood pressure variability (BPV) and
baroreflex sensitivity (BRS) for the study of sleep disorders
we consider 38 subjects, 18 of which are normotensive
(NT) and 10 hypertensive (HT) patients suffering from ob-
structive sleep apnea syndrome (OSAS), the rest being
controls. To detect differences in cardiovascular regula-
tion between the different sleep stages and these age and
sex matched groups, linear and nonlinear parameters are
used. The therapeutic effect of continuous positive airway
pressure (CPAP) therapy is investigated by comparing an
initial diagnostic measurement with a follow-up after three
month of therapy.
Sleep is a complex phenomenon whose internal struc-
ture is currently described as a sequence of sleep stages.
While this description is predominantly based on features
of the electroencephalogram (EEG), other systems such as
the cardiovascular one are clearly also affected by this
Rapid eye movement sleep (REM) presents a level of
sympathetic activity that is very similar in the averages of
blood pressure (BP) and heart rate (HR) to the ones found
while awake (W). The non-REM sleep on the other hand is
a phase of relative autonomic stability, dominated by sym-
pathetic inhibition and an increase in vagal tone. Brady-
cardia, enhanced respiratory sinus arrhythmia (RSA) and
an increased baroreceptor gain are the usual results. The
average BP decreases from wakefulness to light sleep (LS)
and reaches its minimum in deep sleep (DS).
Epidemiological studies confirm a causal relation be-
tween sleep disorders and a number of cardiovascular dis-
eases . An important of such disorders is the OSAS,
which means a patient has more than 15 respiratory events
per hour, respectively an apnea hypopnea index (AHI) of
15. These closures of the upper airways lasting longer
than 10s can be either complete, a so called obstructive
apnea, or partial, meaning a reduction of airflow of more
than 50%, called hypopnea. The rising sympathetic ac-
tivity, assumed to be caused by the rising level of carbon
dioxide in the blood, is one of the main factors that leads
to a rise in BP of up to 250/110mmHg at the moment the
obstruction is cleared .
A powerful tool for the assessment of such changes in
autonomic control and cardiovascular state has been devel-
oped in the last 20 years with the analysis of HRV and BPV
[3,4]. In this article the diagnostic relevance in parameters
of HRV and BPV for detecting and evaluating pathological
changes in cardiovascular regulation should be exemplar-
ily demonstrated. Therefore differences in this regulation
between the sleep stages as well as those resulting from
OSAS shall be investigated. In addition to a comparison to
sleep healthy controls, the effects of CPAP are considered.
This study investigates cardiovascular regulation in dif-
ferent sleep stages on data obtained through polysomnog-
Computing in Cardiology 2011;38:349−352.
Table 1. Overview of the subjects in the control group (C) as well as normotensive (NT) and hypertensive (HT) obstructive
sleep apnea syndrome (OSAS) patients in regard to blood pressure (BP), age, body mass index (BMI) and apnea hypopnea
123 ± 11/84 ± 5
120 ± 19/81 ± 7
142 ± 4/93 ± 8
44.8 ± 6.7
44.6 ± 7.6
44.1 ± 8.1
25.3 ± 2.7
30.2 ± 2.9
34.1 ± 4.9
1.2 ± 1.6
42.5 ± 23.9
71.7 ± 32.7
raphy of 38 subjects, 28 of which suffered from OSAS.
These subjects where measured thrice: One diagnostic
night (labeled DD) followed by a consecutive treatment
night using CPAP and a follow-up night (labeled CPAP) after
three month of treatment.
In order to assess the relationship to elevated BP, we
seperatly consider the 18 normotensive (NT) and 10 hy-
pertensive (HT) patients. Hypertension was defined by an
office systolic BP (SBP) higher than 140mmHg or diastolic
BP (DBP) higher than 90mmHg.
A group of 10 normotensive and sleep healthy persons
were examined in a polysomnographic diagnostic night as
controls (C). All groups were age and sex matched (all
subjects were male) and a comparison is provided in ta-
ble 1. Excluding criteria were comorbid illnesses such as
diabetes, renal failure or heart rhythm disturbances. This
study was approved by the local ethics committee and the
informed consent of all subjects was obtained.
Standard polysomnographs were recorded with the ad-
dition of continuous BP measured using a finger cuff
(Portapres device model 2, BMI-TNO, Amsterdam, The
Netherlands). The recordings were classified according to
Rechtschaffen and Kales  to derive the sleep stage for
each 30s epoch and the respiratory events, i.e. apneas and
hypopneas. In this study, sleep stages S1, S2 and S3, S4
were combined as LS and DS respectively.
To investigate the cardiovascular regulation non-
invasively we use statistical time-domain and frequency-
domain measures as proposed by the Task Force of the
European Society of Cardiology and the North American
Society of Pacing and Electrophysiology . To allow sta-
tistical measures of variability that require stationary con-
ditions in the underlying process, only the first 5 minutes
of the largest undisturbed period of each sleep stage is con-
sidered for each subject. In some cases disturbances, such
as repetitive episodes of apneas or hypopneas or artifacts
due to calibration or measurement error, are so frequent
that no 5 minute epoch is available for analysis. The re-
sulting variable number of epochs is presented in Table 2.
The time domain parameters of HRV, BPV as well as BRS
are used to characterize the autonomous regulation in dif-
ferent sleep stages and quantify the impacts of OSAS and
associated hypertension on the vegetative control. Param-
eters in the frequency domain of HRV can be used to dis-
tinguish sources of influence. While the power in the fre-
quency band between 0.15Hz and 0.4Hz (HF) is generally
accepted as a reflection of the vagally induced respiratory
oscillations in HR, there is controversial discussion about
the power in the range of 0.04Hz to 0.15Hz (LF) as a
marker of sympathetic activity. This is due to the rather
unknown vagal influence on this spectral band. Oscilla-
tions in the power in frequencies ≤ 0.04Hz (VLF) are con-
sidered to be the result of neuroendocrine regulation such
as the Renin-Angiotensin system . Applied to the BPV
of the SBP and DBP, HF is thought to be generated by the
mechanical influence of the respiratory movement on the
intra-thoracic pressure whereas LF quantifies the sympa-
thetic activity through the peripheral resistance of the ves-
The BRS, which has proven to be an important marker
for BP-HRV interaction, is defined as the reflectory change
of beat-to-beat intervals (BBIs) related to increasing or de-
creasing SBP. The sequence method provides a simple tool
for the estimation of this parameter. It works by scanning
the SBP time series, identifying sequences of monotonic
increases/decreases of length 3 with synchronous counter-
parts in BBI. The mean of the slopes of the regression line
of BBI against BP for the SBP sequences is taken as an esti-
mate of BRS .
(control (C), normotensive patients (NT) and hypertensive
patients (HT)) and sleep stages (nocturnal epochs of awake
stage (W), light sleep (LS), deep sleep (DS) and rapid eye
movement sleep (REM))
Number of selected data sets for all groups
Figure 1. Normalized power of the very low power spec-
tral band (0.0033–0.04Hz) for control subjects (C) as well
als normotensive (NT) and hypertensive (NT) patients in all
sleep stages during the diagnostic night. Kruskal-Wallis
test for differences between the sleep stages is significant
for each group (C and NT: p < 0.001, HT: p < 0.01).
to describe those properties of HRV and BPV that cannot be
captured using linear parameters [4, 9]. Non-linear fea-
tures based on symbolic dynamics, such as the word dis-
tribution Shanon entropy (FWSHANNON), have been proven
to be very sucessfull in describing complex behaviour and
are applied as described in .
Each parameter is seperately compared using a Kruskal-
Wallis test for each group and sleep stage to detect sleep-
stage-dependent changes in cardiovascular short term reg-
ulation. A Mann-Whitney test is applied to significant pa-
rameters to reveal the amount of contribution of the dif-
ferent sleep-stages. The influence of CPAP on parameters
of HRV and BPV is evaluated by means of a Mann-Whitney
test. The parameters are compared between the DD and
CPAP nights for each sleep stage in groups NT and HT. All
statistical data processing is performed using SPSS version
Our study shows that several HRV and BPV parameters
adequatly reflect complex sleep dynamics, demonstrating
appreciable differences between sleep stages. Due to lim-
its on available space and for reasons of comprehensibility
only a limited set of the most significant parameters are
presented here. Further results are available in .
sleep (DS) for control subjects (C) as well as obstructive
sleep apnea syndrome (OSAS) patients furing the diagnos-
tiv night and after three month of continuous positive air-
way pressure (CPAP) for normotensive (NT) and hyperten-
sive (HT) OSAS patients. Mann-Whitney tests show a sig-
nificant improvement in BRS (NT: 7.67 ± 32 vs. 11.4 ±
3.8ms/mmHg, p = 0.007; HT: 6.87 ± 1.7 vs. 10.7 ±
3.8ms/mmHg, p = 0.02)
Baroreceptor sensitivity (BRS) during deep
Significant differences between the sleep stanges in all
three goups are identifiable in the HRV parameter of VLF
normalized to the full spectral power (VLF/P) in BBI (C and
NT: p < 0.001, HT p < 0.01, cf. Figure 1). Mann-Whitney
tests allow a more detailed comparison and reveal signifi-
cantly changed values between: W and LS (C: p < 0.001),
W and DS (C: p < 0.01, NT: p < 0.01, HT: p < 0.05),
LS and DS (NT: p < 0.01, HT: p < 0.05), LS and REM
(C: p < 0.01, NT: p < 0.01) as well as DS and REM (C:
p < 0.05, NT: p < 0.01), HT: p < 0.01).
For BPV data, FWSHANNON of the SBP beat-to-beat time
series successfully demonstrates regulatory changes be-
tween the sleep stages. The Kruskal-Wallis test shows sig-
nificant differences for all groups (C and HT: p < 0.05,
NT: p < 0.01). The detailed analysis using Mann-Whitney
tests produces significant differences between: W and LS
(C and HT: p < 0.05, NT: p < 0.01), W and DS (C, NT and
HT: p < 0.01), W and REM (NT and HT: p < 0.05), LS and
REM (NT: p < 0.05), and DS and REM (NT: p < 0.0001).
Evaluating the effects of CPAP on OSAS patients, BRS
shows significant increases during non-REM sleep stages.
Mann-Whitney tests reveal this improvement in LS (NT:
9.26 ± 2.6 vs. 12.6 ± 3.9ms/mmHg, p = 0.007) and DS
(NT: 7.67 ± 3.2 vs. 11.4 ± 3.8ms/mmHg, p = 0.007; HT:
6.87 ± 1.7 vs. 10.7 ± 3.8ms/mmHg, p = 0.02; cf. Figure
4.Discussion and conclusions
The presented results demonstrate the importance of
HRV and BPV analysis in the investigation of the au-
tonomous nervous system. The difference in regulation in
the different sleep stages are clearly shown. Additionally
a positive effect of the three month CPAP therapy can be
quantified using BRS.
The most pronounced changes in regulation during dif-
ferent sleep stages can be identified between DS and REM
(cf. Figure 1). The substantial decrease in VLF/P of HRV
apparent during non-REM sleep, particularly DS, may be
presumed to arise through the depressed metabolic activity
[6,12]. This agrees with results of a study by Schumann
et al. , which showed similar effects by means of de-
trended fluctuation analysis in that the long term correla-
tions decrease in non-REM sleep in healthy subjects.
Both groups of OSAS patients (NT and HT) show a clear
reduction of this effect where no differences between W
and LS are visible. These changes are attributed to effects
due to OSAS as they disappear in the follow-up measure-
ment after CPAP treatment. A previous study by Hedner et
al. using biomarkers  found reduced sympathetic ac-
tivity after long-term CPAP treatment, which the results of
our study confirm.
pathicus, from W and REM to LS and finally DS, is accom-
panied by a lower FWSHANNON. This indication of more
deterministic BP fluctuations is caused by an increase of
compliance in the whole arterial system . An over-
activation of the sympathetic drive in OSAS patients leads
to decreased FWSHANNON values for all sleep stages.
The increase of BRS, as a measure of the coupling be-
tween HR and BP, in all patients after three month of CPAP
treatment towards those values found in controls, indicates
a regression of a previous regulatory dysfunction (cf. Fig-
ure 2). This finding confirms previous findings of CPAP-
based improvement of BRS .
The small number of OSAS patients and controls as well
as the non-ubiquity of undisturbed epochs for each sleep
phase are a limitation of this study. No repeated measure
tests could be applied as a result. To confirm our findings,
prospective studies with larger patient and control groups
This paper is based on work previously published in
Caples SM, Garcia-Touchard A, Sommers VK.
disordered breathing and cardiovascular risk. Sleep 2007;
Butt M, Dwivedi G, Khair O, Lip GYH. Obstructive sleep
apnea and cardiovascular disease.
Malik M, Bigger T, Camm AJ, et al. Heart rate variabil-
ity: Standards of measurement, physiological interpreta-
tion, and clinical use. Eur Heart J 1996;17(3):354–381.
Wessel N, Malberg H, Bauernschmitt R, Kurths J. Non-
linear methods of cardiovascular physics and their clinical
applicability. Int J Bifurcat Chaos 2007;17:3325–3371.
Rechtschaffen A, Kales A. A manual of standardized ter-
minology, techniques and scoring system for sleep stages of
human subjects. National Institute of Health, 1968.
Akselrod S, Gordon D, Madwed JB, et al. Hemodynamic
regulation: investigation by spectral analysis. Am J Physiol
Heart Circ Physiol 1985;249(4):867–875.
Parati G, Saul JP, Di Rienzuo M, Mancia G. Spectral analy-
sis of blood pressure and heart rate variability in evaluating
cardiovascularregulation: acriticalappraisal. Hypertension
Malberg H, Wessel N, Hasart A, et al. Advanced analy-
sis of spontaneous baroreflex sensitivity, blood pressure and
heart rate variability in patients with dilated cardiomyopa-
thy. Clin Sci 2002;102(4):465–473.
Porta A, Di Rienzo M, Wessel N, Kurths J. Addressing the
complexity of cardiovascular regulation. Philos Transact A
Math Phys Eng Sci 2009;367:1215–1218.
 Voss A, Kurths J, Kleiner HJ, et al. The application of meth-
ods of non-linear dynamics for the improved and predictive
recognition of patients threatened by sudden cardiac death.
Cardiovasc Res 1996;31(3):419–433.
 Gapelyuk A, Riedl M, Suhrbier A, Kraemer JF, et al. Car-
diovascular regulation in different sleep stages in the ob-
structive sleep apnea syndrome. Biomed Tech (Berl) 2011;
 Busek P, Vankova J, Opavsky J, et al. Spectral analysis of
heart rate variability in sleep. Physiol Res 2005;54(4):369–
 Schumann AY, Bartsch RP, Penzel T, et al. Aging effects on
cardiac and respiratory dynamics in healthy subjects across
sleep stages. Sleep 2010;33(7):943–955.
 Hedner J, Darpo B, Ejnell H, et al. Reduction in sympa-
thetic activity after long-term cpap treatment in sleep-apnea
- cardiovascular implications. Eur Respir J 1995;8(2):222–
 Westerhof N, Lankhaar JW, Westerhof BE. The arterial
windkessel. Med Biol Eng Comput 2009;47(2):131–141.
 Kohler M, Pepperell JCT, Casadei B, et al. Cpap and mea-
sures of cardiovascular risk in males with osas. Eur Respir
Int J Cardiol 2010;
Address for correspondence:
Dr. Niels Wessel (email@example.com)
Humboldt-Universität zu Berlin,
AG NLD / Cardiovascular Physics
Robert-Koch-Platz 4, 10115 Berlin, Germany