Content uploaded by Kurt Rasche
Author content
All content in this area was uploaded by Kurt Rasche on Jul 15, 2023
Content may be subject to copyright.
Sleep-Disordered Breathing and Cardio- and Cerebrovascular
Diseases: 2003 Update of Clinical Significance and Future
Perspectives
Schlafbezogene Atmungssto¨rungen und kardio- und zerebrovaskula¨re Erkrankungen:
Update 2003 der klinischen Bedeutung und zuku¨ nftiger Entwicklungen
Hans-Werner Duchna
1
, Ludger Grote
2
, Stefan Andreas
3
, Richard Schulz
4
, Thomas E.
Wessendorf
5,6
, Heinrich F. Becker
7
, Peter Clarenbach
8
, Ingo Fietze
9
, Holger Hein
10
, Ulrich
Koehler
7
, Andreas Nachtmann
6
, Winfried Randerath
11
, Kurt Rasche
12
, Karl-Heinz Ru¨ hle
11
,
Bernd Sanner
13
, Harald Scha¨ fer
14
, Richard Staats
15
, Volker To¨pfer
5
and the Working Group
‘Kreislauf und Schlaf’ of the Deutsche Gesellschaft fu¨ r Schlafforschung und Schlafmedizin
(German Sleep Society)
1
BG-Kliniken Bergmannsheil, Universita¨tsklinikum der Ruhr-Universita¨ t Bochum, Med. Klinik III, Bochum, Germany
2
Sleep Laboratory, Pulmonary Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
3
Abt. Kardiologie und Pneumologie, Georg-August-Universita¨t Go¨ttingen, Go¨ ttingen, Germany
4
Med. Klinik II, Universita¨t Giessen, Giessen, Germany
5
Ruhrlandklinik, Abt. Pneumologie, Schlaf- und Beatmungsmedizin, Essen, Germany
6
Fachklinik Rhein-Ruhr, Abt. Neurologie, Essen, Germany
7
Abt. fu¨r Pneumologie, Schlafmedizinisches Labor, Universita¨t Marburg, Marburg, Germany
8
Ev. Johannes Krankenhaus, Neurologische Klinik, Bielefeld, Germany
9
Med. Klinik, Kardiologie, Pneumologie, Angiologie, Schlafmedizinisches Zentrum, Charite´, Berlin, Germany
10
Zentrum fu¨r Pneumologie und Thoraxchirurgie, Großhansdorf, Germany
11
Klinik fu¨r Pneumologie, Klinik Ambrock, Universita¨t Witten/Herdecke, Hagen, Germany
12
Kliniken St. Antonius, Akad. Lehrkkh. Universita¨t Du¨sseldorf, Zentrum f. Innere Med., Schwerpunkt Pneumologie, Wuppertal, Germany
13
Bethesda Krankenhaus Wuppertal GmbH, Med. Klinik, Wuppertal, Germany
14
Klinikum Saarbru¨cken, Abt. fu¨r Pneumologie, Saarbru¨cken, Germany
15
Medizinische Fakulta¨t / Klinikum der Universita¨ t Rostock, Abt. Pneumologie, Rostock, Germany
Summary The purpose of this review is to summarize current knowledge about the link between sleep-
disordered breathing (SDB) and cardiovascular and cerebrovascular diseases. Obstructive
sleep apnoea (OSA) is a well-established risk factor for systemic arterial hypertension, and
its treatment with continuous positive airway pressure leads to a decrease in daytime and
night-time blood pressure profiles. Pulmonary arterial hypertension occurs in 20–30% of
OSA patients and is usually mild. It is not yet clear if OSA per se leads to pulmonary
hypertension or if the coexistence of chronic obstructive pulmonary disease with daytime
and/or sleep-related hypoxaemia is required to provoke a persistent rise in pulmonary artery
pressure. Furthermore, OSA is associated with nocturnal cardiac arrhythmias, especially
cyclical fluctuations of the heart rate in response to recurrent apnoeas. Atrioventricular
conduction blocks and ventricular premature beats are less often observed and seem to be
confined to patients with severe OSA and those with accompanying ischaemic heart disease.
The association between OSA and vaso-occlusive disease (i.e. atherosclerosis) is less clear.
However, accumulating experimental and epidemiological data support such a link. Thus,
OSA may lead to coronary artery disease (CAD) and stroke by promoting atherosclerosis.
Correspondingly, patients with CAD or acute stroke show a high prevalence of SDB.
Cheyne–Stokes respiration (CSR) is a specific pattern of central sleep apnoea occurring in
Correspondence: Priv.-Doz. Dr. med. Hans-Werner Duchna, Berufsgenossenschaftliche Kliniken Bergmannsheil, Universita¨tsklinik, Klinikum der Ruhr-Uni-
versita¨t Bochum, Medizinische Klinik III, Schwerpunkte: Pneumologie, Allergologie, Schlaf- und Beatmungsmedizin, Bu¨ rkle-de-la-Camp-Platz 1, D-44789
Bochum, Germany
E-mail: Hans-Werner.Duchna@ruhr-uni-bochum.de
Received 25.4.2003/Accepted 20.5.2003
2003 Blackwell Verlag, Berlin ÆWien www.blackwell.de/synergy
Somnologie 7: 101–121, 2003
patients with advanced congestive heart failure (CHF). If present, CSR clearly has a negative
impact on the clinical course of CHF. Although the optimal treatment strategy for CSR is
less well defined than that for OSA, the successful reversal of CSR might increase overall
survival in affected patients.
Keywords Sleep-disordered breathing – obstructive sleep apnoea – central sleep apnoea –
Cheyne – Stokes breathing – pulmonary disease – cardiovascular disease – hypertension –
stroke.
Zusammenfassung Ziel dieser U
¨bersichtsarbeit ist die Darstellung aktueller Zusammenha¨nge zwischen
schlafbezogenen Atmungssto¨ rungen und kardio- bzw. zerebrovaskula¨ren Erkrankungen:
Das obstruktive Schlafapnoe-Syndrom (OSAS) ist als unabha¨ ngiger Risikofaktor fu¨ r die
Entstehung einer arteriellen Hypertonie anzusehen. Die nasale U
¨berdruck-Therapie (CPAP)
fu¨ hrt zu einer Senkung des Tages- und Nachtblutdruckes. Ca. 20–30% der Patienten mit
OSAS weisen eine pulmonal-arterielle Hypertonie auf; unklar ist jedoch, ob eine zusa¨ tzliche
Lungenerkrankung mit Tages- und/oder Nachthypoxa¨mie eine notwendige Voraussetzung
zur Entstehung der pulmonal-arteriellen Hypertonie bei diesen Patienten ist. Herzrhythmus-
sto¨ rungen, insbesondere apnoebedingte Schwankungen der Herzfrequenz, treten bei OSAS
geha¨uft auf. Atrioventrikula¨ re Blockbilder oder ventrikula¨ re Extrasystolen sind seltener
anzutreffen und scheinen auf schwere Formen des OSAS und solche mit zusa¨ tzlicher
koronarer Herzkrankheit beschra¨nkt zu sein. Die Zusammenha¨nge zwischen OSAS und der
Entwicklung einer Arteriosklerose sind nicht vollsta¨ndig gekla¨rt, jedoch belegen experi-
mentelle und epidemiologische Studien diesbezu¨ glich eine enge Verbindung. Durch
Induktion einer Arteriosklerose kann das OSAS zur Entstehung einer koronaren Herzkrank-
heit oder eines beitragen. Patienten mit einer koronaren Herzkrankheit oder einem
apoplektischen Insult weisen dementsprechend eine hohe Pra¨valenz schlafbezogener
Atmungssto¨ rungen auf. Eine spezielle Form zentraler Apnoen stellt die Cheyne–Stokes
Atmung dar, die bei Patienten mit fortgeschrittener Herzinsuffizienz geha¨uft vorliegt.
Gesichert ist der negative Einfluß der Cheyne–Stokes Atmung auf den klinischen Verlauf der
Herzinsuffizienz. Obwohl die Behandlungsstrategie der Cheyne–Stokes Atmung weniger
etabliert ist als beim OSAS, fu¨ hrt deren erfolgreiche Behandlung zu einer Steigerung der
Lebenserwartung bei den Betroffenen.
Schlu¨ sselwo¨ rter Schlafbezogene Atmungssto¨ rungen – obstruktives Schlafapnoe-Syn-
drom – zentrale Schlafapnoe – Cheyne – Stokes Atmung – COPD – kardiovaskula¨re
Erkrankungen – Bluthochdruck – apoplektischer Insult.
Introduction
In 2000, the working group ‘Kreislauf und Schlaf’ of the
German Sleep Society (DGSM) was founded. In this group,
scientists combine their efforts to promote research in the field
of sleep medicine and cardio- and cerebrovascular disease
(CVD). CVDs are the most common life-threatening and
debilitating diseases in the industrialized world. Recent
studies have elucidated the importance of sleep-disordered
breathing (SDB) with new epidemiological data and modern
pathophysiological concepts supporting the hypothesis of a
complex association and pathophysiological interaction of
SDB and CVD. Thus, a better understanding of both disease
entities is gained, which may result in a reduction of morbidity
and mortality. The interaction of SDB and CVD can be
regarded from various points of view: for example, in
obstructive sleep apnoea (OSA), SDB plays an important role
as a risk factor leading to the development of CVD. On the
other hand, CVD (especially chronic heart failure) can cause
SDB (i.e. Cheyne–Stokes respiration). The first aim of the
working group was to summarize current knowledge about the
interaction between SDB and CVD. The results of this
collaborative work are reported in the present review paper. To
avoid being too theoretical, the authors focussed on the
interaction of SDB and relevant CVD, i.e. atherosclerosis,
cardiac arrhythmias, systemic and pulmonary hypertension,
coronary artery disease, heart failure, and cerebrovascular
disease. All of these different subjects are similarly subdivided
into introduction, epidemiology, physiology/pathophysiology,
impact on clinical practice, therapeutic intervention, diagnos-
tic and therapeutic recommendations, and conclusions
and future perspectives in order to make life easier for the
reader.
Atherosclerosis
H.-W. Duchna, R. Schulz
Introduction
Atherosclerosis forms the basis for many cardiovascular
disorders, and patients with OSA present with a high
comorbidity of CVD. However, it has been difficult to
establish a cause–effect relationship between OSA and CVD
because these patients typically present with traditional risk
102 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
factors for the development of CVD such as obesity and
metabolic disease, i.e. hyperlipidaemia and insulin resistance.
Keeping in mind these confounding factors, the interaction of
OSA, vascular risk factors, and CVD has been called
‘syndrome Z’ [251].
Epidemiology
There is a low grade of evidence of epidemiological data
dealing with systemic atherosclerosis in patients with OSA.
As atherosclerosis is a causal factor in most CVDs, its
prevalence in patients with OSA might be estimated from the
prevalence rates of coronary artery disease, myocardial
infarction, and stroke. Preliminary studies investigating the
prevalence of carotid atheromas and stenoses indicate a
significant correlation with the presence of OSA [1, 64], but
the number of patients investigated is low.
Physiology/pathophysiology
Atherosclerosis is the end point of a vascular disease, which
begins as a functional disorder of the complex interaction
between blood with its cellular components, vascular
endothelial cells, and vascular smooth muscle cells. The
vascular endothelial cells are in control of vascular tone,
immunomodulatory functions, growth, vascular permeability,
cell adhesion, and vascular architecture via a multitude of
enzymes and kinases [46, 131, 192]. Vascular endothelial
cells, however, are integrated in systemic vascular reflex
mechanisms, mainly influenced by sympathetic and para-
sympathetic tone, hormones such as catecholamines, atrial
natriuretic peptide, angiotensin II, vasopressin, and others
[85]. An endothelial dysfunction appears to play a key role in
the development of atherosclerosis [91, 192, 193].
An endothelial dysfunction has been demonstrated in
almost all known risk factors for CVD, as for example
diabetes mellitus, smoking, hypercholesterolaemia, and
arterial hypertension [27, 28, 35, 130, 180, 229]. Recent
studies support the hypothesis that OSA also leads to
vascular endothelial dysfunction. According to the results of
three different studies, endothelium-dependent vascular
relaxation is blunted in awake patients with OSA, in the
absence of any other disease state or potential cause of
endothelial dysfunction [26, 48, 107, 117]. These data from
in vivo studies in humans are supported by the results of an
investigation of vascular reactivity in rats, in which recurrent
episodic hypoxia served as a model for OSA [232].
Another current pathophysiological concept is that the
OSA-related stimuli of hypoxaemia and shear stress enhance
vasoconstrictive and prothrombotic forces within the vascular
milieu and thereby lead to accelerated atherosclerosis [39, 56,
67, 115, 121, 126, 138, 155, 191]. This is strongly suggested
by abnormalities of biochemical markers of CVD, which
have been described in patients with OSA. First of all, there
is increased sympathetic tone as evidenced by elevated
catecholamine levels in plasma and urine and by an increase
of muscle sympathetic nerve activity [25]. Furthermore,
endothelial nitric oxide (NO) generation is suppressed, thus
giving an explanation for the above-mentioned reduction of
endothelium-dependent vascular relaxation in OSA. In this
context, decreased serum levels of NO-derived nitrite and
nitrate have been found in OSA [100, 213]. In addition to its
decreased release, NO is probably scavenged by excessively
generated free oxygen radicals. This assumption is supported
by the finding of an enhanced superoxide release from
circulating neutrophils and monocytes in OSA patients [51,
211]. The role of the vasoconstrictor endothelin in the
development of OSA-associated CVD is less well estab-
lished. Some studies reported increased serum concentrations
of endothelin in OSA [176, 195], whereas other investiga-
tions could not reproduce these findings [73]. Apart from
these changes in vasoactive mediator systems, inflammatory
markers of vascular injury are also upregulated in OSA. This
concerns vascular adhesion molecules as evidenced by
measurements of soluble VCAM, ICAM, and E-selectin
[33, 166], levels of highly sensitive C-reactive protein [218]
and cytokines such as IL-6 and TNF-a[242]. Finally,
activation and aggregation of platelets and increased fibrin-
ogen levels have been reported in OSA and are presumed to
underlie the development of CVD in these patients [21, 34,
248]. The two major hypotheses regarding the development
of CVD and atherosclerosis in OSA are summarized in
figure 1.
The first direct evidence that OSA indeed leads to vascular
remodelling and atherosclerosis is provided by ultrasono-
graphic measurements of the intima media thickness of the
common carotid artery (IMT-CCA). This parameter reflects
the actual atherosclerotic burden of the organism and predicts
the risk of future cardiovascular and cerebrovascular events
in patients with or without pre-existing CVD. In this context,
two independent studies have found an increase in IMT-CCA
in untreated OSA patients as compared to matched control
groups [210, 219].
Impact on clinical practice
Experimental data strongly suggest a negative effect of OSA-
induced repetitive pressor surges and hypoxaemia on
vascular endothelial function, although the level of clinical
evidence is low. Endothelial dysfunction is a precursor of
atherosclerosis. Abnormalities of microvessel function,
structure and microvascular network are an important cause
of hypertension, also likely to be central to many forms of
atherosclerotic or hypertensive end-organ damage [125].
Therapeutic intervention
At present, there are no data available showing an improve-
ment in atherosclerotic lesions by treatment of OSA In vivo
OSA
Hypoxaemia / Shear Stress
Disturbance of Microvascular Milieu
Endothelial Dysfunction
Atherosclerosis
Cardio- and Cerebrovascular Diseases
Genetic factors
Traditional cardio-
vascular risk factors
•Nicotin
•Diabetes mellitus
•Arterial hypertension
•Hyperlipidaemia
Figure 1. Hypothesis for the development of atherosclerosis and
CVD in OSA.
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 103
Somnologie 7: 101–121, 2003
studies have shown that treatment of OSA with continuous
positive airway pressure (CPAP) improves endothelial
function [49, 99]. In a selected group of 11 patients with
OSA, in the absence of any other disease state or potential
cause for endothelial dysfunction, a 6-month therapeutic
CPAP trial led to complete normalization of endothelium-
dependent vascular relaxation, showing a restoration of
endothelial cell function [49]. These data were confirmed by
similar results in seven OSA patients treated with CPAP for
2 weeks, although a different technique investigating endot-
helial cell function had been used [99]. Furthermore, CPAP
therapy is able to reverse the majority of the described
biochemical alterations of the vascular system in OSA. Thus,
there is good reason to speculate that by restoring normal
vascular homeostasis, treatment of OSA may improve
vascular function and thereby reduce cardiovascular morbid-
ity and mortality in OSA.
Diagnostic recommendations
At present, a recommendation for screening patients with
OSA for atherosclerotic lesions cannot be made. However, it
is prudent to check for traditional risk factors (i.e. arterial
hypertension, smoking, hyperlipidaemia, and diabetes).
Investigation of endothelial function in order to estimate
the ‘atherosclerotic load’ of a patient [57] would be of great
value but is not practicable today.
Therapeutic recommendations
The above-mentioned studies suggest an improvement in
important vascular functions in OSA patients treated with
CPAP therapy. This led to the discussion of whether even
non-sleepy patients with OSA should be treated with CPAP
[88, 222]. Thus, future studies will have to prove the
beneficial effects of CPAP therapy on cardiovascular out-
come parameters in OSA.
Conclusions and future perspectives
OSA patients without overt CVD present with subtle vascular
abnormalities such as impaired endothelial function and
alterations of biochemical vascular markers, which can be
reversed by CPAP treatment. There is now ample evidence
that these subtle disturbances are the beginning of a cascade
that may lead to the development of atherosclerosis and end
in overt CVD (figure 1). Among other aspects, future studies
should investigate the time course of the emergence of CVD
in OSA, the possible role of vasoprotective mechanisms, and
the impact of effective therapy on cardiovascular morbidity
and mortality in OSA.
Cardiac Arrhythmias and Sleep Disordered
Breathing
H.F. Becker, H. Hein, U. Koehler
Introduction
Research in SDB began in patients suffering from the
pickwickian syndrome. As these patients have a high
mortality – hospital mortality was 70% in pickwickian
syndrome patients admitted to hospital due to decompensated
ventilatory failure – and often die from sudden cardiac death
[141, 142], broad interest in the occurrence and significance
of cardiac arrhythmias as a possible clue to the increased
mortality in these patients has evolved. It has become clear
that not only pickwickian patients but also most patients with
OSA exhibit characteristic arrhythmias. The current infor-
mation concerning epidemiology, pathophysiology and clin-
ical significance of cardiac arrhythmias in patients with OSA
will be reviewed here.
Epidemiology
Concerning the epidemiology of cardiac arrhythmias, four
different heart-rhythm disorders with different prevalence
rates should be distinguished: (i) sinus arrhythmia/cyclical
variation of heart rate, (ii) heart block (AV conduction block,
sinuatrial block or sinus arrest), (iii) ventricular premature
beats (VPBs) and (iv) atrial fibrillation.
Sinus arrhythmia/cyclical variation of heart
rate (CVHR)
Sinus arrhythmia/CVHR is a typical finding in all patients
with OSA except in cases with reduced heart rate variability
due to diabetes or severe heart failure. CVHR is charac-
terized by an abrupt increase in heart rate (HR) due to an
arousal that terminates apnoeas, hypopnoeas, or obstructive
snoring, followed by an HR decrease during respiratory
events as a consequence of hypoxia and lack of thoracic
expansion. This heart rate pattern is so typical that it may
even be of diagnostic value: by the use of computerized
analysis of Holter ECG alone, four algorithms of analysis
correctly classified all patients with OSA out of a total of
35 patients. The best algorithm was able to detect 92% of
1-min epochs with or without breathing disorders correctly
[173].
Heart block
In the early days of sleep research, heart block (second
and third degree atrioventricular block [IIand IIIAV
block]), sinus arrest or sinuatrial block were thought to be
highly prevalent in patients with OSA, and the reported
incidence ranged between 18% and 50% [167, 235]. More
recent data of unselected patients treated in a sleep
laboratory revealed prevalence rates between 7% and
13% [15, 22, 142]. One publication has challenged
previous results stating that the prevalence of bradyar-
rhythmias was not increased in patients with OSA
compared to those without OSA [59].
Ventricular premature beats
Systematic evaluation of the incidence and severity of
ventricular premature contractions (VPCs) in patients with
OSA is still missing Flemons et al. [59] compared the
incidence of frequent or complex VPCs in 173 patients
studied because of suspected OSA, 76 of whom were
diagnosed with OSA defined by more than 10 apnoeas and
hypopnoeas per hour of sleep. The prevalence of VPCs was
higher in patients without OSA, but the differences were not
statistically significant.
In 29 heart failure patients with more than 15 apnoeas per
hour of sleep – predominantly central apnoeas in 21 and
obstructive apnoeas in eight patients – the effect of CPAP on
VPCs was studied prospectively [102]. SDB was almost
completely prevented by CPAP in 16 patients. In these
patients, the number of hourly episodes of nocturnal VPCs
was significantly reduced from 66 ± 117 to 18 ± 20 and the
104 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
number of couplets decreased from 3.2 ± 6 to 0.2 ± 0.21. In
those 13 patients who did not respond to CPAP, VPCs
remained unchanged. Based on the very limited data
available, the influence of OSA on VPCs in patients without
overt heart disease remains unclear, whereas SDB might
worsen the occurrence of VPCs in heart failure patients.
Atrial fibrillation
Systematic evaluations of the incidence of atrial fibrillation in
patients with OSA are missing. There is one report
demonstrating that OSA is an independent risk factor for
the development of atrial fibrillation following coronary
bypass surgery [147]. The odds ratio for postoperative atrial
fibrillation was 2.8 in patients with an oxygen desaturation
index of ‡5/h compared to patients without SDB. Atrial
fibrillation has been identified as an important risk factor for
Cheyne–Stokes respiration [221].
Physiology/pathophysiology
CVHR is caused by an alternation between increased
sympathetic and parasympathetic tone. Hypoxaemia-induced
peripheral chemoreceptor stimulation leads to an activation of
the sympathetic nervous system. As a consequence, ventila-
tion increases and the resulting lung inflation has a vagolytic
influence via the Hering–Breuer reflex. Therefore, hypoxae-
mia causes tachycardia in the presence of lung inflation;
however, in the absence of lung inflation it causes bradycar-
dia. Arousal at the termination of breathing disorders causes
sympathetic activation and thus tachycardia. The repetitive
occurrence of both mechanisms leads to CVHR, which is
markedly attenuated by oxygen. The physiological meaning
of bradycardia during apnoea-induced hypoxia might be a
reduction in oxygen consumption by the heart, as this can be
regularly demonstrated in humans before or during birth if the
foetus is hypoxic, and also in diving mammals.
Heart block mainly occurs during REM sleep, most likely
because parasympathetic activation and hypoxaemia are most
pronounced in this sleep stage [17, 93, 111]. Hypoxia,
tachycardia, sympathetic activation and increased blood
pressure are possible mechanisms that might lead to
ventricular premature beats in patients with SDB; however,
the importance of these mechanisms remains uncertain.
Impact on clinical practice
CVHR seems to be a symptom that does not cause
cardiovascular sequelae per se. It has been suggested that
VPBs might play a role in the increased mortality rate of
patients with OSA. However, there is no proof for this
hypothesis. Heart block may lead to asystole of up to 15 s or
longer. If this occurs exclusively during sleep, patients are
often asymptomatic. In fact, OSA is the main cause of
asymptomatic heart block occurring mainly during the night
[151]. In 29 OSA patients with heart block, bradyarrhythmias
could be completely prevented with CPAP treatment.
Furthermore, none of these patients experienced syncope or
died after an average of 54 months of CPAP treatment
without implantation of a cardiac pacemaker [72].
Diagnostic recommendations
All patients with predominant nocturnal arrhythmias should
be investigated with polysomnography in order to identify or
rule out SDB.
Therapeutic intervention – therapeutic
recommendations
CVHR is prevented with effective treatment for OSA. In
most patients, effective treatment for OSA using CPAP or
tracheotomy prevents patients from getting heart block [15,
108, 112, 235]. In only two out of 45 OSA patients, relevant
VPCs occurred, and in one of these patients VPCs were no
longer present with CPAP therapy [84]. There are no data
available concerning the effect of CPAP treatment on atrial
fibrillation in patients with OSA. It has recently been shown
that SDB can be improved by atrial overpacing at a heart rate
of approximately 15 beats per minute above the patient’s
spontaneous heart rate [68], but further research is necessary
to support the clinical value of these findings.
Conclusions and future perspectives
In patients presenting with asymptomatic intermittent brad-
yarrhythmias, OSA should be considered as a possible cause.
Episodes of heart block can be expected in approximately
20% of patients with severe OSA (apnoea–hypopnoea index
[AHI] >60/h) and in approximately 7.5% of an unselected
group of OSA patients. There is no threshold of SDB degree
above which bradyarrhythmia exclusively occurs, although
the risk increases with the amount of oxygen desaturation.
REM sleep is an independent factor leading to heart block,
irrespective of apnoea duration and oxygen desaturation.
Effective treatment with CPAP leads to complete prevention
of heart block in 80–90% of OSA patients. Sinus arrhythmia/
CVHR is a typical finding in most patients with OSA and is
also removed with effective CPAP treatment. Data concern-
ing VPCs are scarce. There does not seem to be a clear link
between OSA and VPCs in patients without overt heart
disease, but SDB may be a factor that worsens VPCs in heart
failure patients.
Sleep Disordered Breathing and Systemic
Hypertension
B. Sanner, L. Grote
Introduction
The link between systemic hypertension and cardiovascular
disease is well documented in the medical literature. It has
been hypothesized that systemic hypertension is a short-term
complication of OSA that mediates the association between
OSA and CVD and increases cardiovascular morbidity in the
long term. In fact, there is increasing evidence that OSA may
cause systemic hypertension and that effective treatment of
sleep-disordered breathing lowers high blood pressure [75].
Epidemiology
Epidemiological studies in the general population and in
large clinical cohorts have demonstrated an independent
association between OSA and systemic hypertension after
controlling for confounders such as age and body weight
[76, 122, 257]. A recent prospective study showed that
patients with SDB have an increased incidence of systemic
hypertension as compared with a non-SDB control group
[174]. In summary, there is strong evidence based on high-
quality epidemiological data that even a small degree of
SDB causes elevation of blood pressure and systemic
hypertension.
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 105
Somnologie 7: 101–121, 2003
Physiology/pathophysiology
A number of pathophysiological mechanisms have been
identified by case-control studies. They all suggest that SDB
may cause sustained elevation of blood pressure [87]. Briefly,
hypoxia and repetitive arousal from sleep are well-documen-
ted factors that cause an overall increase of sympathetic
activity in patients with SDB [60]. Furthermore, changes in
the renin–angiotensin system as well as in blood volume
regulation are shown in OSA patients. Recent work has
pointed out that vascular function is altered in OSA. It has
been shown that the pressor response to hypoxia and to a
given amount of angiotensin II is increased in OSA patients
as compared with controls. In contrast, dilatory vascular
response to the application of nitric oxide or to intra-arterial
vascular b-2 receptor stimulation is attenuated in patients
with SDB. However, it remains unclear whether altered
vascular function is a cause or consequence of elevated blood
pressure in SDB patients. In summary, there is pathophys-
iological plausibility and strong experimental evidence that
SDB may cause systemic hypertension.
Impact on clinical practice
SDB is common in hypertensive patients (30–80%). In
particular, OSA has been observed in up to 80% of patients
with therapy-resistant hypertension [38, 124].
Therapeutic intervention
Treatment of SDB with CPAP results in a significant decrease
in daytime and night-time blood pressure values in hyperten-
sive patients [16, 43, 86, 137, 143, 146, 162, 175, 189, 230],
indicating a causal relationship between the two conditions.
High blood pressures or elevated heart rates at baseline –
indicators of an increased sympathetic activity – may be
predictors of a beneficial effect of CPAP therapy on blood
pressure [204, 258]. Under CPAP therapy, also normotensive
patients experience a decrease in blood pressure. On the other
hand, not all hypertensive SDB patients show a blood
pressure reduction in response to CPAP.
Diagnostic recommendations
Acute rises in blood pressure caused by SDB can be
documented during sleep by invasive or noninvasive tech-
niques. When daytime hypertension is suspected, blood
pressure should be measured at least three times during two
separate examinations. Blood pressure values above or equal
to 140/90 mm Hg are considered hypertensive. Ideally, the
diagnosis of hypertension should be verified by noninvasive
ambulatory 24-h blood pressure monitoring or self-measure-
ment. Given the epidemiological data, SDB proved to be the
most common secondary cause of hypertension. Thus
polysomnography should be performed in all patients with
hypertension of unknown origin (so-called ‘idiopathic hyper-
tension’), especially in the absence of a nocturnal blood
pressure dip [54].
Therapeutic recommendations
Usually, there is no association between the degree of blood
pressure decrease with CPAP and polysomnographic param-
eters indicative of the degree of SDB improvement. This
could be explained by the fact that hypertension – even if
induced by SDB – might subsequently be perpetuated by
vascular remodelling or some secondary renal response to
chronic preglomerular vasoconstriction and altered perfusion.
Furthermore, SDB is probably not the only cause of
hypertension in these patients. For that reason, CPAP
treatment can rarely replace medical treatment of systemic
hypertension completely [118].
Conclusions and future perspectives
Hypertension and SDB are frequently associated: Approxi-
mately one-third of hypertensive patients have OSA, whereas
about 50% of OSA patients are hypertensive. Epidemiolog-
ical studies of the last years have documented that there is a
causal relationship between these two conditions – inde-
pendent of other known risk factors. Consequently, CPAP
therapy has a significant blood pressure-lowering effect in a
subgroup of hypertensive patients with OSA.
These data emphasize the need to consider OSA as a
potential cause or aggravating factor in hypertensive patients,
especially if hypertension is difficult to control. Furthermore,
blood pressure monitoring should be performed in patients
suspicious of OSA, and patients with ‘idiopathic’ arterial
hypertension should be evaluated by full polysomnography,
especially in the absence of a nocturnal blood pressure dip.
Coronary Artery Disease – Acute Myocardial
Infarction
S. Andreas, U. Koehler, R. Staats
Introduction
Coronary artery disease (CAD), also named ischaemic heart
disease, is defined as the manifestation of atherosclerosis in
the coronary arteries. CAD may lead to coronary stenosis
with flow limitation and consequently to an imbalance of
myocardial oxygen supply and demand. Severity and
duration of ischaemia determine the clinical manifestation
as asymptomatic, stable or instable angina pectoris, myocar-
dial infarction, arrhythmias, and sudden cardiac death.
Epidemiology
Today, CAD is the most common, chronic, life-threatening
disease. According to data from the MONICA study,
cardiovascular mortality in Germany affects 428 men and
272 women per 100 000 persons per year, with a slight
decrease from 1993 to 1996 [252]. More than 60% of the
overall cardiovascular mortality is attributed to CAD and
>30% to cerebrovascular disease. There were 380 acute
myocardial infarctions per 100 000 persons in the age group
of 35–64 years. Similarly, the Physicians’ Health Study
revealed 440 cases of acute myocardial infarction (AMI) per
100 000 physicians per year [227]. Risk factors, life style,
and socioeconomic circumstances are probably the most
important explanations for a large regional variation [252].
Obstructive sleep apnoea and coronary
artery disease
In a large study on the prevalence of OSA in CAD [149], 142
men with CAD verified by angiography were investigated by
polysomnography using a pressure-sensitive bed. Thirty-
seven per cent of patients had an AHI of 10 or more, which
was significantly higher than that of age-matched controls
[149]. A number of studies on patients with CAD who where
106 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
slightly overweight with a mean body mass index of 27 kg/
m
2
yielded similar results, with an incidence of OSA between
35% and 50% [6, 41, 113, 148, 171, 214]. In one study, 101
unselected males aged less than 66 years were investigated
by polysomnography 24 days (mean value) after they
survived an acute myocardial infarction (AMI) [97]. About
30% of these patients had an apnoea index (AI) >5/h. Mean
AHI in the patients was 12.7/h, while 53 male subjects of
similar age but without evidence of ischaemic heart disease
had an AHI of 3.7/h [97]. In an Italian study, the prevalence
of apnoeas, chiefly of the central type, soon after clinical
stabilization of unstable angina and following AMI, was
similar and higher than that in stable CAD [152]. In 440
patients with OSA proven by polysomnography, CAD was
demonstrated by angiography in 24.6% [203]. This high
prevalence might be explained by a referral bias because the
institution has a local reputation for CAD. The key question
of public health importance is: Is OSA a risk factor for CAD?
Although most studies found an association of OSA with
CAD, they were of limited value because they were either
hospital based with a selection bias, small in number, or
lacked a control group. Cross-sectional associations from the
baseline examination of the Sleep Heart Health Study [217]
in 6424 individuals are compatible with modest to moderate
effects of OSA on various manifestations of CVD within a
range of AHI values that is considered normal or only mildly
elevated. SDB was associated more strongly with self-
reported heart failure and stroke than with CAD: The relative
odds ratio for CAD was 1.27 (0.99–1.62 upper vs. lower AHI
quartile) [217].
Physiology/pathophysiology – impact on clinical
practice
In order to analyse the association of SDB, especially OSA,
and ischaemic heart disease with its different manifestations
such as chronic stable CAD and acute coronary syndrome
(e.g. unstable angina and myocardial infarction), it is
noteworthy to differentiate between acute effects and long-
term effects of SDB with possible causal relationships. In
general, myocardial ischaemia occurs as a result of
diminished oxygen supply or increased oxygen demand in
the case of inappropriate coronary reserve. Heart rate is an
important determinant of myocardial oxygen consumption,
especially during sleep without physical activity Quyyumi et
al. [181] found episodes of ST-segment depressions in
Holter ECG recordings preceded by an increase in heart
rate as a result of arousal, lightening of sleep, body
movements, and REM sleep in patients with CAD and
nocturnal angina without evidence of OSA. Experimental
data from animal studies exhibited an increase in coronary
blood flow in REM sleep due to an increased sympathetic
drive to the heart [42]. In the case of experimental coronary
artery stenosis, the coronary blood flow was diminished in
phasic REM sleep as a result of a mismatch between the
increase in heart rate and diastolic perfusion [42]. In these
circumstances, myocardial ischaemia is promoted by REM
sleep, which was described first by Nowlin and coworkers
in 1965 [165]. In OSA, myocardial oxygen supply is
diminished by apnoea-associated hypoxaemia. Besides the
effects of oxygen desaturation on myocardial ischaemia,
OSA may reduce myocardial blood flow supply and/or
increase oxygen demand by acute changes in heart rate and
elevations of blood pressure-induced left ventricular after-
load at the resumption of breathing at each apnoea
termination. In addition, interventricular septum shift leads
to an impediment of the diastolic function of the left
ventricle. The frequency and clinical impact of nocturnal
myocardial ischaemia in patients with OSA is unclear
because of a lack of systematic studies. Asymptomatic
ST-segment depressions during sleep were observed in
seven of 23 patients with OSA without evidence of CAD
by Holter ECG [79] Franklin et al. [63] found OSA in nine
of 10 patients with nocturnal angina pectoris. During
treatment of OSA with CPAP, nocturnal angina diminished
and the number of nocturnal myocardial ischaemic events
was reduced. In a study of 21 patients with OSA, Scha¨fer
et al. [209] found asymptomatic nocturnal ST-segment
depressions reflecting myocardial ischaemia only in those
patients with angiographically proven CAD and in one
patient with diffuse coronary vessel defects. The vast
majority of these episodes was associated with apnoea-
related oxygen desaturations and occurred predominantly in
REM sleep. Microstructure of sleep was disturbed to a
greater extent in ischaemic episodes than in control
episodes. Ischaemic episodes led to more and severer
arousals than control episodes, correlating with the extent of
oxygen desaturation. In a more recent study, Peled et al.
[172] investigated 51 patients with OSA and CAD and a
control group of 17 patients with OSA without CAD (only
15 of the total had coronary angiography). Nocturnal ST-
segment depression occurred in 10 patients with CAD, and
no events were seen in the control group. The exacerbation
of ischaemic events during sleep in OSA and CAD may be
explained by the combination of increased myocardial
oxygen consumption and decreased oxygen supply due to
oxygen desaturation, with peak haemodynamic changes
during the rebreathing phase of obstructive apnoea. Treat-
ment with CPAP significantly ameliorated nocturnal isch-
aemia [172]. With regard to the different manifestations of
ischaemic heart disease in selected subjects without risk
factors for OSA, the frequency and extent of sleep apnoea
was higher after an AMI or unstable angina than in stable
CAD [152]. Moreover, in stable CAD, apnoeas were of
obstructive type, whereas in unstable CAD the central type
of apnoea was predominant without any correlation to left
ventricular function. The increased sympathetic drive in
unstable CAD [132] may have an inhibitory effect on
respiratory drive as a possible cause of apnoea in these
patients [152]. The sympathetic activation and coagulation
disorders associated with OSA make it reasonable to
believe that acute coronary syndromes with or without
ST-segment elevation can be triggered by OSA. Treatment
of AMI is focussed on the rapid reopening of the infarct-
related artery, as detailed in national and international
guidelines. To reduce angina, anxiety and oxygen con-
sumption, morphine is used in the acute setting. This may
lead to sleep and apnoeas when angina ceases. One study
reports a high incidence of SDB in patients recovering from
AMI [97]. In another study of AMI, patients’ OSA was
related to premature ventricular contraction but not to major
complications of AMI [133]. Despite the greater incidence
of cardiac arrhythmias during AMI in OSA patients, these
patients have the same clinical course in hospital and
mortality rate as non-OSA patients [133]. Whether patients
with OSA and CAD are at increased risk of ‘dying in their
sleep’ is not clear, although in general the frequency of
AMI is highest in the early morning [153] due to increased
sympathetic drive and changes in rheological factors. In
patients with AMI occurring at night, the respiratory
disturbance index (RDI) was significantly higher than in
patients with AMI during wakefulness [114]. Besides the
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 107
Somnologie 7: 101–121, 2003
acute effects of OSA on myocardial and cardiovascular
physiology, a number of mechanisms link OSA and
vasculopathy, leading to atherosclerosis and CAD in the
long-term (see chapter on atherosclerosis).
Therapeutic intervention
Shahar et al. revealed that even an RDI considered normal or
mildly elevated might enhance the risk of developing CVD
including CAD, thus commencing the discussion of when to
start OSA treatment [88, 217]. Though it is appealing that
screening for OSA with the intention to treat patients with
known CAD will reduce cardiovascular mortality, no study
has specifically addressed this question. Some problems
should therefore be mentioned: Since patients with CAD do
not present to the medical system with complaints directly
related to OSA, compliance with CPAP treatment is likely to
be lower than that in a typical population of OSA patients
[147, 170]. This might improve when OSA is considered to be
a modifiable risk factor for CVD by all physicians involved in
the treatment of patients with CAD. Related to this question is
the problem of whether the treatment effect on blood pressure,
sympathetic activity, endothelial function, etc., of OSA
patients with an AHI >10/h and without significant daytime
sleepiness will be as good as that in the published studies on
‘classic’ OSA patients with daytime sleepiness [49, 175].
However, since the underlying pathophysiology of the OSA-
related cardiovascular complications and positive CPAP
effects are clearly related to nocturnal apnoeas and oxygen
desaturation [48, 175], the positive effects of CPAP on the
cardiovascular system are unlikely to be influenced by
daytime symptoms. There are several studies investigating
the effects of CPAP therapy on CAD symptoms and risk
factors of CVD in OSA patients. In OSA patients who also
suffered from CAD, ECG recordings revealed ST-segment
depression and therefore significant ischaemic events, often
accompanied by nocturnal angina. CPAP therapy ameliorated
the nocturnal ST-segment depression time and nocturnal
angina [63, 79]. Venous vascular reactivity to bradykinin was
found to be blunted in OSA patients as compared to controls.
This effect was reversed with CPAP therapy [48]. In a recent
study, Imadojemu and coworkers analysed the reactive
hyperaemic blood flow and described an impaired arterial
vasodilator response in OSA patients. CPAP therapy
improved vascular function and decreased muscle sympa-
thetic nerve activity [99]. Two studies detected decreased
circulating NO levels in patients suffering from OSA. Serum
level of NO increased significantly after overnight CPAP
therapy [100, 213]. The relationship between OSA and
hypertension is discussed in another part of this paper.
CPAP therapy positively influenced platelet aggregabil-
ity, fibrinogen level, superoxide release, and cell adhesion
molecule expression [21, 24, 33, 34, 206, 211]. Hence,
future studies will disclose whether public awareness of a
possible association between OSA and CAD will improve
therapy compliance in non-sleepy patients with OSA. In
patients unable to tolerate CPAP, however, alternative
therapy strategies are required. Although less effective than
conventional CPAP therapy, oral appliance (OA) devices
proved to be beneficial with rare serious side effects in
patients unable to maintain CPAP therapy and, when
correctly indicated, as first choice therapy in selected OSA
patients with low RDI [20, 71, 89, 183, 190]. Patients with
AMI are usually monitored on an intensive care unit
(ICU). If OSA in this setting leads to severe surges in
blood pressure and/or myocardial ischaemia, treatment of
OSA should be initiated even on the ICU, but there are no
studies available supporting this hypothesis.
Diagnostic recommendations
Clinical examination in patients with CAD is directed by the
underlying heart disease itself as well as cardiovascular risk
factors and significant comorbidity. As detailed above, OSA
is common in patients with CAD and is a significant and
modifiable risk factor for CVD [129, 147, 217]. Therefore,
OSA should be included in the diagnostic work-up of
patients with CAD. If the CAD patient’s medical history is
positive regarding excessive daytime sleepiness, nocturnal
angina pectoris, witnessed snoring, or apnoeas, polysomnog-
raphy is recommended.
Therapeutic recommendations
A consensus statement published in 1999 recommended
CPAP therapy in any OSA patients with an RDI exceeding
30/h or at a minimal threshold of 5/h if the patient is
suffering from either excessive daytime somnolence,
impaired cognition, mood disorders, insomnia, or docu-
mented cardiovascular disease [129]. The recommendation
to treat non-sleepy patients with low RDI and CAD is
further supported by cross-sectional results of the Sleep
Heart Health Study [217]. In patients with AMI, CPAP
treatment should be initiated on the ICU if OSA in this
setting leads to severe surges in blood pressure or
myocardial ischaemia, but there are no data supporting
this hypothesis.
Conclusions and future perspectives
There is growing evidence suggesting that OSA is an
independent risk factor for CAD. While studies with
randomized therapeutic intervention are unlikely to be
performed in the near future, it seems prudent to advocate
CPAP therapy in patients with CAD and moderate to severe
OSA even if they do not suffer from excessive daytime
sleepiness.
Heart Failure
S. Andreas, I. Fietze, V. To¨ pfer
Introduction
Heart failure is defined by symptoms and objective evidence
of cardiac dysfunction [186]. Symptoms may be breathless-
ness, ankle swelling, signs of venous distension, and fatigue.
The severity of heart failure is classified by the New York
Heart Association (NYHA), but there is a poor relationship
between symptoms and cardiac dysfunction as well as
prognosis. The underlying causes of heart failure are CAD
and arterial hypertension, valvular disease, and idiopathic
dilated cardiomyopathy. Clearly evidenced guidelines for the
treatment of heart failure exist [186]. The prevalence of
symptomatic heart failure in the general European population
is 0.4–2% and increases rapidly with age [186]. The prognosis
of heart failure is poor, albeit significant improvements in
treatment have been gained. Still, about half of the patients
diagnosed with chronic heart failure (CHF) will die within
4 years [186]. Recently, diastolic heart failure has been
noticed to be common especially in the elderly population and
108 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
carries a prognosis nearly as grim as heart failure with systolic
dysfunction [55].
Epidemiology
Javaheri et al. reported on 81 ambulatory male CHF patients
with an left ventricular ejection fraction (LVEF) <45% [105].
The authors noted that 51% of their patients had an AHI
>15/h. Most of the patients had Cheyne–Stokes respiration
(CSR), but some more obese patients had obstructive
apnoeas. Similar findings were made in a comparable CHF
group [225] and in patients on a waiting list for heart
transplantation [127]. In patients with an LVEF <45%
investigated 1 month after an episode of pulmonary oedema,
an AHI >15/h was reported in about 80% of 34 consecutive
patients. Again, OSA was less common (25%) than CSR
(75%) and was chiefly observed in the more overweight
patients [239]. CSR seems to be more common in men [220],
which might be explained by the higher ventilatory drive in
men. It is our impression that presently the prevalence of
SDB in appropriately treated CHF patients is less than 30%.
This is likely the result of the increased prescription of ß-
blockers and probably their direct influence on central
controller gain (see Pathophysiology). There is insufficient
knowledge about SDB in patients with diastolic heart failure.
In one study, 11 out of 20 patients with diastolic heart failure
had an AHI >10/h with mainly obstructive apnoeas [29].
Furthermore, there was an independent association between
abnormal diastolic ventricular relaxation pattern and noctur-
nal oxygen desaturations in 68 patients with OSA [66].
Physiology/pathophysiology
In patients with impaired LVEF, a fundamental characteristic
of SDB is the central origin of the disorder. Periodic
breathing (CSR) with or without apnoea, central sleep
apnoea, as well as other respiratory disorders such as
hypopnoea and hypoventilation, all characterize the syn-
drome of SDB in CHF patients. The main factor leading to
SDB in CHF patients, especially during sleep onset, is a fall
in carbon dioxide (PaCO
2
) tension below the apnoea
threshold, with a consecutive decrease of central nervous
outflow to respiratory muscles [104]. Engaged in this
phenomenon are: carbon dioxide receptors in the medulla,
the carotid body and the aortic arc; oxygen receptors located
in the medulla and carotid body; ergoreceptors of the
respiratory muscles; and central mechanisms regulating the
sleep–wake rhythm. In CHF patients with CSR, hypocapnia
is more pronounced than in CHF patients without CSR [223].
PaCO
2
levels are consequently only 1–3 mm Hg above the
apnoea threshold during sleep in CSR patients, in comparison
with healthy subjects, among whom this difference is
3–5 mm Hg. An increase of CO
2
in inhaled air to the level
of 4% during sleep increases PaCO
2
and prevents occurrence
of apnoea in CHF patients [128].
PaCO
2
in CHF patients with CSR is inversely correlated
with pulmonary capillary wedge pressure (PCWP). An
increase in PCWP leads to activation of pulmonary vagal
afferent pathways, followed by hyperventilation and a fall in
PaCO
2
[223]. Another mechanism possibly involved in
generation of apnoea is enhanced peripheral and central
chemoreceptor sensitivity. This corresponds to enhanced
respiratory response, which is in turn correlated with the
amount of CSR [7] and daytime hyperventilation [159].
Although the role of hypoxaemia in the genesis of CSR is not
well known, it is possible that hypoxaemia elicits arousals
that provoke hyperventilation.
During sleep, the extent of CSR is also evidently a
function of sleep stage. Sleep-stage differences are based on
the degree of impaired arousability in REM sleep, during
which CSR is less common than in NREM sleep. One effect
of an arousal-related stage shift is that the sleeper suddenly
detects PaCO
2
as excessively high, which can in turn lead to
hyperventilation. Further mechanisms responsible for CSR in
CHF patients are increased blood circulatory time, enhanced
sympathetic nerve activity, decreased body oxygen and CO
2
stores, upper airway instability, impaired LVEF, and respir-
ation pattern preceding CSR [4, 77, 90, 109, 116, 124, 128,
156]. A correlation has been established, for example,
between the cyclic length of periodic breathing and the
degree of LVEF [77]. Changes in blood gas tension may
provoke instability (underdamping) of the respiratory system,
accompanied by exaggerated gas changes during CSR [116].
CSR is accordingly an expression of oscillations in feedback
regulation of respiration by the above-stated disturbance
variables, which prevent damping or physiological counter-
regulation.
The question arises: Is there a relationship between central
and obstructive apnoeas in CHF patients? Obstructive apnoea
may provoke acute nocturnal decompensation with interstitial
lung oedema, which in turn decreases functional residual
capacity (FRC) [161] and leads to the above-stated changes
in blood gas stores Tkacova et al. described a possible shift
from OSA to CSR under conditions of progressively rapidly
falling PaCO
2
and rising blood circulatory time, owing to
deterioration in cardiac function [237]. Conversely, it is
feasible that periodic breathing leads to instability in the
upper airway due to pharyngeal oedema. It is also possible
that obstructive breathing is followed by reduced respiratory
drive during the waning phase of periodic breathing, with
greater reduction of drive to the pharyngeal dilatator muscle
than to the diaphragm. CSR has also been described for CHF
patients during the day, as a symptom of disturbed autonomic
regulation and poor survival outcome. Augmented chemore-
ceptor sensitivity [178], impaired autonomic control, and
baroreflex inhibition [179] are possible mechanisms involved
in the genesis of daytime CSR.
Impact on clinical practice
Clinical markers that indicate CSR among CHF patients are
as follows: episodic hypoxaemia, numerous arousals during
sleep, sleep fragmentation, daytime sleepiness [80], and heart
rhythm disorders correlating with falls in PaCO
2
[98]. Other
phenomena include nocturnal heart rate and blood pressure
changes due to arousals, changes in sympathetic nerve
activity [90, 160, 241], increased chemoreceptor sensitivity,
and altered heart rate variability [164, 256].
Therapeutic intervention
Treatment options can be broadly divided into four groups:
intensive heart failure treatment, pharmacological therapy,
oxygen, and various forms of positive airway pressure such
as CPAP, bilevel pressure ventilation, and adaptive pressure
support servo-ventilation.
Intensive heart failure treatment
The first consideration is to optimize the heart failure therapy.
Cardiovascular drugs improve left ventricular function,
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 109
Somnologie 7: 101–121, 2003
decrease PCWP and favourably influence neuroendocrine
activation. Recent studies have reported a decrease in central
sleep apnoea (i.e. CSR) caused by heart failure treatment [37,
243]. Thus, before any specific therapy for CSR is
undertaken, appropriate utilization (including dose adjust-
ments) of cardiovascular drugs to optimize cardiovascular
function should be undertaken [103].
Pharmacological therapy
Theoretically, respiratory-drive stimulants such as theophyl-
line and acetazolamide can alleviate CSR beyond optimizing
CHF by cardiovascular drugs [40, 53, 106]. In a study by
Javaheri et al. [106], use of theophylline was associated with
a significant reduction in AHI, but a reduction in the
frequency of arousals or improvements in sleep structure
were not documented. Theophylline did not lead to any
improvement of cardiac function. Theophylline is problematic
because it could increase minute ventilation in CHF patients
with CSR whose minute ventilation is already elevated, and
because of its potentially dangerous effects on cardiac output
by causing cardiac arrhythmias. The effect of acetazolamide
[18, 238, 250] on CSR has not been systematically evaluated
in patients with CHF Sakamoto et al. [200] found that
acetazolamide did not consistently reduce the frequency of
respiratory events in patients with central sleep apnoea. In
summary, theophylline or acetazolamide are not recommen-
ded for treatment of CSR in patients with CHF.
Oxygen
The rationale for using oxygen is that it increases oxygen and
carbon dioxide stores and suppresses peripheral chemorecep-
tor drive, thereby dampening the respiratory control system
and making it more stable Hanly et al. [78] investigated the
effect of oxygen administration and demonstrated a sig-
nificant decrease in AHI, arousal index, and degree of
oxyhaemoglobin desaturation. In a subsequent randomized
placebo-controlled study of intranasal oxygen given for
1 week, Andreas et al. [5] also documented a modest decrease
of central apnoeas and hypopnoeas in patients with CSR. In
addition, these patients experienced a significant increase in
peak oxygen consumption during exercise without a change
in the duration of exercise, peak heart rate, or quality of life.
Furthermore, the hypercapnic ventilatory response (HCVR)
was reduced by nocturnal oxygen [8]. More recently,
Staniforth et al. [226] documented significant reductions in
AHI and in overnight urinary norepinephrine excretion in
patients with stable CHF and CSR while they were treated
with nocturnal oxygen over a 4-week period. Similar acute
effects were noticed in patients with chronic hypoxaemia due
to chronic obstructive pulmonary disease [90]. More effective
suppression of CSR may be achieved by adding carbon
dioxide to oxygen therapy. Therefore, Andreas et al. [9]
performed a study that evaluated the effects of nocturnal
oxygen plus carbon dioxide on CSR, sleep, and sympathetic
activation. Nocturnal combination of oxygen plus carbon
dioxide reduced the duration of CSR and increased arterial
oxygen saturation as well as mean transcutaneous carbon
dioxide tension but markedly increased sympathetic activa-
tion.
Forms of positive airway pressure
Continuous positive airway pressure
CPAP is the most extensively studied therapy for CSR in
patients with CHF and has been shown to alleviate this
breathing disorder in association with substantial beneficial
effects on cardiovascular function [253] Takasaki et al. [233]
were the first to study the effects of CPAP in patients with CHF
and CSR in a controlled trial in 1989. Application of CPAP
was associated with a highly significant reduction in AHI, an
increase in nocturnal SaO
2
and improvements in sleep
structure [158]. These initial observations of beneficial effects
of CPAP on CSR were confirmed by Naughton et al. [160] in a
controlled trial of CPAP in patients with stable CHF and CSR.
The group treated with CPAP experienced a decrease in the
frequency of central events, associated with a reduction in
minute ventilation and an increase in transcutaneous PCO
2
.
A randomized trial of CPAP was undertaken by Naughton et al.
[160], with LVEF as the primary outcome measure. There was
a greater improvement of LVEF in the CPAP group than in the
control group. In another study, Naughton et al. [157]
demonstrated that CHF patients with CSR had higher
overnight urinary and daytime plasma norepinephrine con-
centrations than CHF patients without CSR. By using CPAP,
there was a 40% reduction in overnight urinary norepinephrine
and a 24% reduction in daytime plasma with a significant
decrease in heart rate. The largest and longest randomized
clinical trial of CPAP therapy for CHF involved 29 patients
with and 37 without CSR [221]. Over a follow-up period of up
to 5 years, patients in the CSR group who complied with
CPAP therapy experienced a reduction in the combined rate of
mortality and cardiac transplantation rate. In contrast, CHF
patients without CSR but randomized to CPAP therapy did not
experience any significant decrease in the mortality or cardiac
transplantation rate.
Bilevel pressure ventilation
Willson et al. [254] recently reported preliminary data
showing that CSR was abolished and sleep improved with
noninvasive nasal ventilation using a time-cycled volume
preset ventilator. In these studies, the prolonged use of
noninvasive ventilation was also associated with a reduction
in the AHI, a decrease in arousal index, and an improvement
in cardiac function.
Adaptive pressure support servo-ventilation
Adaptive pressure support servo-ventilation (ASV) is a new
approach to the treatment of CSR, in which a small but
varying amount of ventilatory support is provided. The
intention is to provide the hydrostatic benefits of low levels
of CPAP while directly suppressing CSR and attendant sleep
disturbance without causing overventilation. In a recent study
by Teschler et al. [234], the acute effect of ASV on quality of
sleep and breathing was compared with nasal oxygen, nasal
CPAP, and bilevel spontaneous/time (ST) mode nasal
ventilation. The authors described a better improvement in
sleep and breathing with ASV than either nasal CPAP/bilevel
ventilation or 2 L/min nasal oxygen. The authors concluded
that sleep and breathing were better during 1 night of ASV
therapy than during 1 night of oxygen or CPAP/bilevel
pressure ventilation. Long-term studies of the effect of ASV
on quality of life and cardiovascular function are presently
under way.
Diagnostic recommendations
As detailed above, CSR, and to a lesser degree OSA, is
common in CHF and is independently related to impaired left
ventricular performance and increased mortality [81, 120,
217, 221]. Therefore, CSR and OSA have to be included in
the diagnostic work-up of patients with CHF. Although OSA
110 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
often has a characteristic history, this seems to be much less
the case for CSR in the setting of CHF [3, 225]. Full
polysomnography is recommended in patients with CHF in
order to analyse breathing patterns, arousals, and sleep
structure, especially if nocturnal angina, excessive daytime
sleepiness, witnessed snoring, or apnoeas are present.
Therapeutic recommendations
Of paramount importance is maximal conservative CHF
treatment. It seems necessary to find the right method of
treatment of CSR on an individual basis. However, we
recommend trying oxygen therapy initially because it is
effective and simple to use. In case of an insufficient
therapeutic effect of oxygen, the next option is to use CPAP.
CPAP is the most extensively studied therapy for CSR and is
shown to alleviate this breathing disorder in association with
substantial beneficial effects on cardiovascular function. The
most effective suppression of CSR in patients with CHF is
achievable with ASV. In severe cases of CSR with a high
AHI or in cases where other options were ineffective,
treatment with ASV is recommended. Using ASV, however,
is not as simple as CPAP or oxygen, because special
equipment and software is needed.
Conclusions and future perspectives
In conclusion, there is good evidence suggesting that CSR is
common in CHF and is the cause of impaired sleep and
sympathetic activation with concomitant unfavourable effects
on left ventricular function and survival. However, large
controlled studies are needed to test the hypothesis that
successful treatment of CSR will reduce the high mortality of
CHF.
Pulmonary Hypertension in Obstructive Sleep
Apnoea Syndrome
W. Randerath, K.-H. Ru¨hle, B. Sanner, H. Scha¨ fer
Introduction
Pulmonary hypertension (PH) can be defined by a sustained
elevation of the mean pulmonary artery pressure (PAP) to
‡20 mm Hg or of the systolic pressure to ‡30 mm Hg [74].
PH results from increases in resistance of blood flow in
pulmonary venous drainage (e.g. elevated left ventricular
diastolic pressure), in the pulmonary vascular bed (e.g.
obstructive or restrictive pulmonary diseases) or from
resistance of flow itself (e.g. thromboembolism). Syndromes
associated with hypoventilation, namely the obesity–hypo-
ventilation syndromes, OSA or neuromuscular disorders, are
thought to lead to pulmonary hypertension. However, PH
might be secondary due to hypoxic pulmonary vasoconstric-
tion [74]. Other potential mechanisms are hypoxia-induced
vascular endothelial dysfunction [56], pulmonary vascular
remodelling [199], intrathoracic pressure changes, and
autonomic reflexes.
Epidemiology
The prevalence of PH in OSA without underlying pulmonary
disease is still controversial. Early studies reported preval-
ence rates between 20% and 80%. However, these investi-
gations included patients with lung disorders, especially
chronic obstructive pulmonary disease. According to these
studies, impairment of lung function and hypoxaemia seemed
to correlate best with PH. However, recent studies in patients
without pulmonary disease also showed prevalence rates of
about 30% of PH in OSA [11]. Studies in which pulmonary
pressure was measured invasively found a prevalence of
about 20%, whereas studies based on the noninvasive
Doppler technique showed figures of 40% [119, 197]. One
may conclude that PH can be found in OSA patients without
pulmonary disease, which however can aggravate PH.
Physiology/pathophysiology
Increases in PAP have been described both acutely during a
single apnoeic event and chronically in the course of the
OSA. In NREM sleep, PAP reaches its maximum during the
postapnoeic hyperventilation period, whereas in REM sleep,
even long apnoeas are not necessarily associated with
pressure increases [177].
While intravascular PAP decreases during apnoea and
increases at the resumption of breathing, transmural pulmon-
ary artery pressure (PAPtm, i.e. the correction for intratho-
racic pressure swings) tends to increase progressively
throughout an apnoea, with a maximum during the final
occluded efforts and sustained during the early phase of
hyperventilation [134]. Analysis of apnoea episodes in
NREM sleep revealed a progressive increase in systolic
mean PAPtm of 10 mm Hg towards the end of apnoea [208].
Among the underlying mechanisms of the acute changes,
alveolar hypoxia was suggested to play an important role
[134]. However, oxygen administration affected neither mean
PAPtm nor the amplitude of pressure swings in most patients
[135]. Other factors contributing to PAPtm changes are
mechanical events caused by intrathoracic pressure swings
with increased right ventricular preload and output or due to
increased left ventricular afterload.
Beat-by-beat analysis of the underlying factors showed
that hypoxia was a major determinant of the slow changes of
PAPtm over the whole course of an apnoea and rapid changes
in PAPtm were synchronous with intrathoracic pressure
changes [136]. Analysing the contributing factors, Scha¨fer
et al. [208] found hypoxaemia and intrathoracic pressure
swings both independently associated with an increase of
PAPtm. The authors did not find any association of arterial
blood pressure as a rough estimate of left ventricular
afterload with the changes in PAPtm in this study. According
to the time course of pulmonary haemodynamics during the
night, Scha¨fer et al. [208] did not find a progressive increase
in PAP, in contrast to another study, which showed a trend
towards a small progressive increase in PAP throughout the
night [216]. The authors concluded that this increase reflects
the cumulative effects of repetitive apnoeas and hypoxaemia.
However, apnoea duration increased throughout the night in
this study.
In 40% of OSA patients without overt CVD, Sajkov et al.
described a slightly elevated PAP at rest, which rose
significantly when pulmonary blood flow was increased
[199]. Patients with or without sustained PH did not show
any differences in the severity of SDB, lung function or body
mass index. However, in patients with PH, the authors found
more pronounced ventilation–perfusion mismatch and resting
hypoxia. PH in these patients was thought to be the result of
structural narrowing of the pulmonary vessels. The authors
speculated that this remodelling may be caused by an
increased pulmonary vascular pressure response to hypoxia
or an increased small airways closure with regional lung
hypoxaemia. In a more recent study, the same authors found
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 111
Somnologie 7: 101–121, 2003
a decreased hypoxic pulmonary constrictor response, which
was measured as the difference in PAP under hypoxic and
hyperoxic conditions [198]. This might result from an
impaired pulmonary vascular endothelial function, which is
responsible for the vascular tone [10, 19, 56]. Moreover,
Sajkov et al. described a reduction in the hypoxic pulmonary
vascular reactivity under treatment with CPAP. They conclu-
ded that intermittent nocturnal hypoxia might cause pulmon-
ary vascular endothelial dysfunction [198]. Recent studies
suggest that genetic factors determine the link between
hypoxia and manifestation of PH [47, 52].
Impact on clinical practice
In general, PH can lead to dyspnoea and right heart failure. It
is often difficult or impossible to differentiate whether OSA
or other pulmonary diseases are responsible for these
symptoms. If present, the degree of daytime PH is mild in
most patients with OSA alone. Hence, specific clinical
symptoms of PH are rarely described in these patients.
Although an association of OSA with PH has been shown
conclusively, there is no correlation between the severity of
OSA as measured by AHI and the severity of PH. Right
ventricular failure and PH define, in part, one subtype of
SDB, the pickwickian syndrome.
Diagnostic recommendations
The sensitivity of ECG or radiographic findings in the
diagnosis of PH is unsatisfactory Sanner et al. demonstrated
pulmonary wedge pressure and time spent below 90% SaO
2
during the night as independent predictors for PH when
coexisting pulmonary disease was excluded. Other parame-
ters of lung function or PaO
2
were not predictive for PH
[205]. There are controversial results concerning the predic-
tive value of resting PaO
2
, AHI, or lung function. PAP can be
evaluated invasively using right heart catheterization and
noninvasively by using Doppler echocardiography [150,
196]. Invasive pressure measurement is the diagnostic gold
standard, although Sajkov et al. described a good correlation
(P¼0.96) between catheter and Doppler techniques in the
investigation of PAP [196].
Therapeutic intervention – therapeutic
recommendations
An early investigation in OSA patients treated with trache-
ostomy reported an improvement in PAP and right ventric-
ular function [62]. In several studies, CPAP did result in a
long-term improvement of PAP in patients with OSA [31,
215] Chaouat et al., for example, did not exclude patients
with chronic obstructive pulmonary diseases, which might
influence the level of PAP [31]. In contrast, Sajkov et al.
studied the effects of CPAP in 20 patients without lung or
cardiovascular disorders. Five of these subjects showed an
elevation in mean PAP at baseline. The authors found that
CPAP improved daytime PAP and total pulmonary vascular
resistance, and the greatest improvement was shown in
patients with sustained daytime PH [198] Alchanatis et al.
described a sample of 21% of patients with PH out of 29
patients with OSA but without further CVD. In both groups,
pulmonary hypertensive and normotensive, PAP fell signifi-
cantly under treatment with CPAP for 6 months [2]. Though
indicative of positive effects of CPAP therapy on PH in OSA,
the therapeutic studies mentioned above have to be regarded
with caution, as there was no control group.
Conclusions and recommendations
Mild PH is present in 20–40% of patients with OSA, but
there is no correlation between the severity of OSA and the
occurrence of PH. Although the pathophysiological back-
ground is still unclear, vascular endothelial dysfunction
associated with increased vascular reactivity might be one
important aspect. There is some evidence for the positive
effect of long-term treatment with CPAP on PH in patients
with OSA.
Pulmonary Hypertension in Chronic Obstructive
Pulmonary Disease
W. Randerath, K. Rasche, K.-H. Ru¨ hle
Introduction
Chronic obstructive pulmonary disease (COPD) is often
associated with nocturnal (i.e. sleep-related) hypoventilation,
ventilation–perfusion mismatching, and consecutive O
2
desaturations [58]. As a consequence of the Euler–Liljestrand
reflex and other mechanisms, pulmonary arterioles in the
pulmonary circulation constrict and vascular resistance
increases [36]. In the following, the pathophysiological
mechanisms leading to an increase in pulmonary artery
pressure will be discussed and the consequences for therapy
elucidated.
Epidemiology
COPD is often diagnosed in patients with chronic cigarette
abuse. The disease can be defined by clinical symptoms such
as exertional dyspnoea, chronic cough and sputum produc-
tion, and by lung function tests with reduced Tiffeneau index.
COPD can be diagnosed in about 50% of all smokers older
than 60 years [188]. In the daytime-hypoxic blue-bloater
type of COPD, we often observe SDB and oxygen
desaturations. In 30% of patients with COPD and daytime
PO
2
values between 60 and 70 mm Hg, oxygen desaturations
during sleep are diagnosed [185]. OSA and COPD are
independent diseases, both possibly leading to PH [187, 244]
(see chapter on pulmonary hypertension in obstructive sleep
apnoea syndrome).
Physiology/pathophysiology
Most patients with COPD present with moderate or severe
daytime hypoxaemia. During sleep onset, alveolar ventila-
tion decreases slightly due to changes of the set point for
CO
2
. Especially during REM sleep, there is a further fall in
ventilation with marked O
2
desaturations [45]. The two
major causes of hypoventilation are a reduction in venti-
latory effort, caused by an altered central nervous stimula-
tion and a relaxation of thoracic muscles during REM sleep,
whereas diaphragmatic ventilatory drive is blunted for
anatomical reasons in COPD, especially in emphysema. The
reduced central drive can be documented by reduced swings
in the oesophageal pressure being observed mainly during
periods of REM sleep with frequent eye movements. This
decrease in ventilation is not counterbalanced by a hypoxic
and hypercapnic ventilatory response because REM sleep
mechanisms are blunting chemosensitivity. There is also a
mild increase of upper airway resistance caused by the
relaxation of the oropharyngeal airway. As a consequence
of these mechanisms, O
2
saturation decreases dependent on
112 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
the resulting ventilation–perfusion mismatch. The duration
of these episodes last as long as 10–20 min and can easily
be discriminated from the apnoea-induced short desatura-
tions with durations of 10–100 s. As a consequence of the
sleep-induced O
2
desaturations, pulmonary artery pressure
increases during these periods. In one study, integrated
pulmonary artery mean pressure increased from 29.6 +/)
10 mm Hg during wakefulness to 41.2 +/)14.4 mm Hg
[194]. Besides the alveolar vascular reflex, the increase of
cardiac output plays a role in the increase of pulmonary
artery pressure [61]. It is controversially discussed whether
the extent of nocturnal hypoxaemia is an additional factor
contributing to the degree of PH. In patients with isolated
sleep-associated hypoxaemia without severe daytime hypox-
aemia, it was shown that despite nocturnal oxygen therapy,
no significant change in daytime PAP could be observed
compared with a control group breathing room air [30]. If
COPD is combined with repetitive upper airway obstruc-
tions, i.e. OSA, the resulting hypoxaemia and pulmonary
hypertension are more severe and the patients are more
likely to develop right heart failure [23, 92, 95, 187, 228,
244].
Impact on clinical practice
COPD promotes development of PH by different pathophys-
iological mechanisms. Concerning sleep, both COPD-asso-
ciated nocturnal hypoxaemia and additional OSA lead to
significant rises in PAP. The severity of COPD-associated
hypoxaemia during sleep can be predicted with sufficient
precision by blood gas measurements in the evening before
sleep onset, because according to one study, PO
2
values
higher than 55 mm Hg during daytime combined with O
2
desaturations during sleep do not contain clinically important
prognostic information concerning the development of PH
[32].
Therapeutic intervention
In most patients with COPD and nocturnal hypoxaemia,
nocturnal O
2
saturation (SaO
2
) is increased to values above
90% by insufflation of O
2
through a nasal cannula at a flow
rate of 2 L/min. Thus, total sleep time can be prolonged and
sleep quality improved. In COPD patients, mean PAP fell
significantly from 29.5 +/)12.7 to 24.9 +/)9.7 mm Hg in
the first night of O
2
therapy [194]. Long-term oxygen therapy
applied during 15–18 h/day led to a significant reduction in
pulmonary artery pressure from 28.0 +/)7.4 to 23.9 +/)
6.6 mm Hg after 31 months of therapy [245]. In a more
recent study, Raeside et al. diagnosed a mean nocturnal PAP
comparable to their PAP at exercise in 10 patients with
COPD. This elevated nocturnal PAP could be reversed with
oxygen [182]. The decrease in PAP could mainly be
attributed to a decrease in pulmonary vascular resistance.
The expectation that patients with resting hypoxaemia and
hypercapnia treated with supplemental oxygen might develop
progressive nocturnal hypercapnia as a consequence of
reduced ventilatory drive caused by hypoxaemia could not
be confirmed. In patients with stable COPD without OSA,
transcutaneously measured PCO
2
did not increase more than
6 mm Hg [69]. In COPD patients with predominantly
ventilatory failure, i.e. elevated levels of PaCO
2
, (non-)
invasive ventilator therapy may be necessary [139]. For
COPD patients with additional OSA, see the chapter on
pulmonary hypertension in obstructive sleep apnoea syn-
drome.
Diagnostic recommendations
Measurements of oxygen saturation during the night do not
yield any additional value in the decision-making of whether
oxygen therapy is indicated or not. Daytime arterial blood
gas measurements are of sufficient prognostic value. Addi-
tional polysomnographic measurements are usually not
indicated in COPD. However, polysomnography should be
performed in COPD patients with a suspicion of coexisting
OSA or in patients with unclear symptoms and findings such
as daytime sleepiness, polycytaemia, cor pulmonale, or
morning headaches.
Therapeutic recommendations
Daytime hypoxaemia in COPD is nearly always associated
with hypoventilation and ventilation–perfusion mismatching
during sleep and should be treated by supplemental oxygen
therapy during the night. It has been shown that 14–16 h
per day of oxygen therapy is superior to only nightly treat-
ment with oxygen. In COPD patients with predominantly
ventilatory failure, i.e. elevated levels of PaCO
2
, (non-)
invasive ventilator therapy may be necessary [139]. In
COPD patients with additional OSA, both diseases should
be treated consequently because these patients are likely to
develop PH.
Conclusions and future perspectives
There is only a moderate correlation between nocturnal O
2
desaturation, hypercapnia severity and PH. Additional
factors responsible for the development of PH, such as
OSA, should be identified [184]. O
2
therapy reduces right-
heart strain and improves life expectancy, but the work of
breathing is only slightly improved. With intermittent
positive pressure ventilation, the diaphragm can be unloaded
in patients with ventilatory failure. Thus physical perform-
ance during the day can be ameliorated. However, especially
in patients with COPD, noninvasive ventilation is not well
tolerated and compliance after 6 months is only about 50%.
We therefore need more intelligent ventilator devices with
servo-ventilation to avoid sleep disturbances induced by
mask and machine. Pharmacological therapy of PH with
nitric oxide donors or endothelin receptor antagonists have to
be studied in COPD patients first, before they can be
considered as a further treatment option in future [92, 94,
228, 236, 244].
Sleep-Disordered Breathing and Cerebrovascular
Disease
P. Clarenbach, A. Nachtmann, T.E. Wessendorf
Introduction – epidemiology
The high prevalence of SDB among patients with stroke
has been confirmed in numerous studies, although meth-
odological differences regarding patient age, time after
stroke, or diagnostic methods somehow reduce the power
of a general conclusion [14, 50, 83, 144, 145, 168, 207,
240, 247]. Most of the authors come to the following
conclusions:
1 The overall prevalence rate of SDB in acute stroke
patients is in the range of 40–60%.
2 OSA is the leading type of SDB; true central sleep
apnoea is comparatively rare.
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 113
Somnologie 7: 101–121, 2003
3 There is no correlation between stroke location and the
diagnosis of coexisting SDB apart from a tendency of
Cheyne–Stokes respiration to be more common in
infratentorial strokes.
The Sleep Heart Health Study, a large population-based
epidemiological study, confirmed an increased prevalence of
stroke in SDB; the odds ratio for the highest AHI quartile
(AHI >11/h) was 1.6 times (confidence interval [CI] 1.02–
2.46) higher than that of the lowest quartile (AHI <1.4/h)
[217]. In earlier studies using subjective questionnaires for
evaluating snoring history, an even stronger association
between snoring and stroke had been found [169, 224]. The
fact of a similar prevalence of SDB in patients with transient
ischaemic attacks (TIA) [13] and of similar anthropometric
data in SDB [240, 247] with stroke as in SDB without stroke
suggests that OSA preceded the event in most cases. This is
further underlined by the observation that obstructive events
tend to persist after stroke, whereas central apnoeas improve
[168]. It should be noted that the vast majority of
epidemiological studies investigating the relationship
between SDB and cerebrovascular disease have been
performed in patients suffering from TIA/stroke. In contrast,
there is a paucity of data concerning the prevalence of TIA/
stroke in patients with OSA. So far, only one retrospective
survey addressed this question and found a prevalence rate of
8% [212].
Physiology/pathophysiology
Hypertension is regarded as the most important risk factor for
stroke: The link between SDB and hypertension is now
accepted as independent of other confounding factors (see
above). However, there is evidence of other possible links
apart from hypertension: Cerebral blood flow is impaired by
SDB: During obstructive, but not central, events there is a
significant decline in cerebral blood flow followed by an
increase of up to 216% [12, 163]. Flow reduction correlates
with severity of oxygen desaturation, which would be of
particular relevance during REM sleep when cerebral blood
flow and oxygen demands are normally highest, but when
apnoeas are accompanied by the greatest degrees of hypoxia
[110]. In patients with OSA, cerebrovasodilator reserve
seems to be diminished, which can be restored with CPAP
[44]. Patients with lesions in the intra- and extracranial
circulation could therefore be at higher risk of stroke during
respiratory events [1].
The link between atherosclerosis and OSA has been
discussed above. An increased intima-media thickness as
well as a higher prevalence of stenosis of the extracranial
arteries has been confirmed in stroke patients [154, 219, 255].
Patients with ischaemic stroke and coexisting OSA have
increased fibrinogen plasma levels [248], and the level of
fibrinogen correlates with the severity of SDB. The conse-
quences for increased blood viscosity and coagulability may
further add to the increased risk of thrombotic events Chin
et al. observed a reduction in overnight fibrinogen levels in
OSA patients [34]. An effective treatment of OSA, e.g. with
CPAP, can in fact improve other vascular risk factors beyond
blood pressure, so that the risk/benefit ratio calculated from
blood pressure changes may underestimate the true benefit
[175].
Impact on clinical practice
There are only few data about the course of SDB after
stroke: However, in most patients, SDB tends to persist at
least for a 3-month period [123, 168] but shows a
tendency to improve during the first 6–9 weeks [83]. Using
a screening device without discrimination between
obstructive and central events, Szucs et al. found persistent
events in ischaemic but not in hemorrhagic stroke after
3 months [231]. Using pulse oximetry, Good et al. showed
a worse functional outcome after 3 and 12 months in
patients with higher desaturation indices [70]. This could
not be confirmed in recent studies [101, 123], although
Iranzo et al. found early neurological worsening associated
with OSA. It has been speculated that some of the
neuropsychological sequelae observed after stroke – and
regarded as a consequence of the event – could in fact be
partially due to coexisting SDB. OSA in elderly stroke
patients is associated with delirium, depressed mood,
latency in reaction and in response to verbal stimuli, and
impaired ADL (activities of daily living) ability [202]. The
evidence of an effect of SDB on morbidity and mortality is
weak in patients with stroke, as no study has addressed
this point in particular, and the original strong association
between a positive history of snoring and short-term
survival in acute stroke reported by Spriggs et al. [224]
has not been confirmed by others Good et al. reports a
correlation between mortality and oxygen saturation [70]
and Dyken et al. found a mortality of 21% within 4 years
in their stroke patients with OSA, but 0% in patients
without OSA [50]. Mortality data in patients with CAD
and SDB indicate a higher risk of stroke within the
following 5 years [147].
The importance of central sleep apnoea (CSA) in stroke
patients is an open question: Whereas CSA in heart failure
has been associated with increased mortality, its relevance in
stroke patients is not known. As these patients often have
cardiac disease, too, the question remains whether CSA is a
sign of underlying cardiac dysfunction. No study has
addressed this point so far.
Therapeutic intervention
The role of treatment of SDB in stroke has yet to be
determined: In a consecutive series of patients, Wessendorf
et al. showed that CPAP is an option with an acceptance rate
of up to 66% but with the need for intensive coaching during
rehabilitation after stroke. CPAP was effective without
increasing concomitant central apnoeas, but aphasia and
functional disability predicted negative compliance. In case
of acceptance, better subjective fitness and improved blood
pressure control were observed [249]. This primary compli-
ance rate could not be achieved in every setting [82], but
Milanova et al. reported an acceptance rate of 50% in acute
stroke [140]. One could speculate that treatment may be
particularly important in the acute phase, when the survival
of the penumbra is critical.
Among elderly stroke patients, in whom CPAP could
not be initiated, oxygen treatment (3 vs. 0.5 L/min) for
8 days improved some cognitive symptoms in up to 53%
of patients [65]. In a randomized treatment study,
Sandberg et al. investigated the effects of CPAP in stroke
rehabilitation and found positive effects on depression but
not on functional outcome after 4 weeks of treatment.
Compliance was a particular problem in patients with
delirium and cognitive impairment [201] Hui et al.
reached primary CPAP acceptance in 16 of 34 stroke
patients with OSA, but only four proceeded to home
treatment, with an overall low compliance after 3 months
[96].
114 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
Diagnostic/therapeutic recommendations –
conclusions and future perspectives
The high prevalence of SDB observed after stroke justifies
a screening for SDB in stroke patients [144]. As milder
forms of SDB, e.g. the upper airway resistance syndrome,
are not of concern in this clinical setting of mostly elderly
patients, simple forms of screening with a portable device
or simple pulse oximetry may be sufficient [246].
Polysomnography, however, is the only diagnostic method
to safely diagnose SDB and initiate adequate therapy. But
one may argue that as long as the clinical consequences of
treatment are not clear, diagnosis is useless. Therefore,
randomized studies are needed to answer the important
question about treatment relevance. Such studies are
currently under way.
Conclusion
There is rapidly accumulating evidence for OSA being an
important cardio- and cerebrovascular risk factor independ-
ent of confounding factors such as diabetes mellitus,
hyperlipidaemia, and smoking. In particular, OSA is asso-
ciated with a dose-dependent increase in systemic arterial
blood pressure. Effective treatment of OSA with CPAP
therapy lowers blood pressure values not only while asleep
but also during daytime. Although somewhat less clear, OSA
probably enhances atherosclerosis and thereby contributes to
the emergence of vaso-occlusive disease such as CAD and
TIA/stroke. Pulmonary hypertension and nocturnal cardiac
arrhythmias are further features of OSA-related cardiovas-
cular morbidity; however, they are usually less clinically
important. CSR is frequently observed in the setting of
advanced CHF (in earlier series in up to 50% of patients with
an LVEF below 40%). It mainly occurs in elderly males and
constitutes an adverse prognostic sign. Treatment options for
CSR include medical stabilization of CHF, administration of
nasal oxygen, and various forms of noninvasive ventilatory
support. Another possible consequence of SDB (especially
OSA, pulmonary diseases, or both) is PH, which leads to
dyspnoea and right-heart failure. Depending on the causal
type of SDB, administration of nasal oxygen or various
forms of ventilatory support is recommended in these
patients.
Based on the complexity of the interaction of sleep, SDB,
and CVD, an exact diagnosis is important in order to initiate
adequate therapy. Concerning diagnosis of SDB, full poly-
somnography is the only tool, besides the medical history,
with which to simultaneously detect and analyse sleep
structure, nocturnal arousals, disordered breathing, ECG and
oxygen saturation in patients with CVD. These are the
relevant facts physicians need to precisely define the
underlying type of SDB. Nonlaboratory monitoring systems
(NLMS) may help in risk-stratifying patients with suspected
SDB, but often cannot precisely analyse the underlying sleep
disorder, especially in the complex setting of a patient with
CVD. As detailed above, adequate therapy of SDB can
improve the outcome of CVD and is thus of great medical
and socioeconomic importance.
Based on this review paper, some proposals for future
research on the relationship between SDB and CVD can be
made. First, the pathophysiological basis for the emergence
of CVD in OSA needs to be further clarified. Second, the role
of OSA in the development of atherosclerotic disease has to
be studied further. Third, the long-term effects of CPAP
therapy on cardio- and cerebrovascular end points have to be
investigated. Fourth, the prevalence of Cheyne–Stokes
respiration in chronic heart failure has to be evaluated.
Finally, significant work needs to be done to stratify the value
of different treatment options available for CSR/CHF. In the
near future, at least some of these questions will be addressed
by the members of the working group ‘Kreislauf und Schlaf’
of the German Sleep Society.
References
[1] Aboyans V, Lacroix P, Virot P, Tapie P, Cassat C, Rambaud G,
Laskar M, Bensaid J: Sleep apnoea syndrome and the extent of
atherosclerotic lesions in middle-aged men with myocardial
infarction. Int Angiol 18: 70–73, 1999.
[2] Alchantatis M, Tourkohoriti G, Kakouros S, Kosmas E, Pod-
aras S, Jordanoglou JB: Daytime pulmonary hypertension in
patients with obstructive sleep apnea: the effect of nasal con-
tinuous positive airway pressure on pulmonary hemodynam-
ics. Respiration 68: 566–572, 2001.
[3] Andreas S: Central sleep apnea and chronic heart failure. Sleep
23(Suppl 4): 220–223, 1999.
[4] Andreas S: Nocturnal insights in chronic heart failure. Eur
Heart J 20: 1140–1141, 1999.
[5] Andreas S, Hagenah G, Mo¨ ller C, Werner GS, Kreuzer H:
Cheyne–Stokes respiration and prognosis in congestive heart
failure. Am J Cardiol 78: 1260–1264, 1996.
[6] Andreas S, Schulz R, Werner GS, Kreuzer H: Prevalence of
obstructive sleep apnea in patients with coronary artery dis-
ease. Coron Artery Dis 7: 541–545, 1996.
[7] Andreas S, von Breska B, Kopp E, Figulla HR, Kreuzer H:
Periodic respiration in patients with heart failure. Clin Investig
71(4): 281–285, 1993.
[8] Andreas S, von Zur MF, Stevens J, Kreuzer H: Nocturnal
oxygen and hypercapnic ventilatory response in patients with
congestive heart failure. Respir Med 92(3): 426–431, 1998.
[9] Andreas S, Weidel K, Hagenah G, Heindl S: Treatment of
Cheyne–Stokes respiration with nasal oxygen and carbon di-
oxide. Eur Respir J 12(2): 414–419, 1998.
[10] Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J:
Endothelium-derived nitric oxide and vascular physiology and
pathology. Cell Mol Life Sci 55: 1078–1087, 1999.
[11] Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP:
Pulmonary arterial hypertension in patients with sleep apnoea
syndrome. Thorax 55: 934–939, 2000.
[12] Balfors EM, Franklin KA: Impairment of cerebral perfusion
during obstructive sleep apneas. Am J Respir Crit Care Med
150(6 Pt 1): 1587–1591, 1994.
[13] Bassetti C, Aldrich MS: Sleep apnea in acute cerebrovascular
diseases: final report on 128 patients. Sleep 22(2): 217–223,
1999.
[14] Bassetti C, Aldrich MS, Quint D: Sleep-disordered breathing in
patients with acute supra- and infratentorial strokes. A pros-
pective study of 39 patients. Stroke 28(9): 1765–1772, 1997.
[15] Becker HF, Brandenburg U, Peter JH, von Wichert P:
Reversal of sinus arrest and atrioventricular conduction
block in patients with sleep apnea during nasal continuous
positive airway pressure. Am J Respir Crit Care Med 151:
215–218, 1995.
[16] Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan
CE, Peter JH: Effect of nasal continuous positive airway
pressure treatment on blood pressure in patients with
obstructive sleep apnea. Circulation 107: 68–73, 2003.
[17] Becker HF, Koehler U, Stammnitz A, Peter JH: Heart block in
patients with sleep apnoea. Thorax 53: S29–S32, 1998.
[18] Bickler PE, Litt L, Banville DL, Severinghaus JW: Effects of
acetazolamide on cerebral acid–base balance. J Appl Physiol
65(1): 422–427, 1988.
[19] Bishop JE, Reeves JT, Laurent GJ: Pulmonary vascular
remodeling. Portland Press, London, 1995.
[20] Bloch KE, Iseli A, Zhang JN, Xie X, Kaplan V, Stoeckli PW,
Russi EW: A randomized, controlled crossover trial of two
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 115
Somnologie 7: 101–121, 2003
oral appliances for sleep apnea treatment. Am J Respir Crit
Care Med 162: 246–251, 2000.
[21] Bokinsky G, Miller M, Ault K, Husband P, Mitchell J: Spon-
taneous platelet activation and aggregation during obstructive
sleep apnea and its response to therapy with nasal continuous
positive airway pressure. Chest 108: 625–630, 1995.
[22] Bolm-Audorff U, Ko¨ hler U, Becker E, Fuchs E, Mainzer K,
Peter JH, von Wichert P: Na¨ chtliche Herzrhythmussto¨ rungen
bei Schlafapnoe-Syndrom. Dtsch Med Wochenschr 109: 853–
856, 1984.
[23] Bradley TD, Rutherford R, Grossmannn RF, et al.: Role of
daytime hypoxemia in the pathogenesis of right heart failure in
the obstructive sleep apnea syndrome. Am Rev Respir Dis
131: 835–839, 1985.
[24] Bratel T, Wennlund A, Carlstrom K: Pituitary reactivity,
androgens and catecholamines in obstructive sleep apnoea.
Effects of continuous positive airway pressure treatment
(CPAP). Respir Med 93: 1–7, 1999.
[25] Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin
BG: Augmented resting sympathetic activity in awake patients
with obstructive sleep apnea. Chest 103: 1763–1768, 1993.
[26] Carlson JT, Rangemark C, Hedner JA: Attenuated endothe-
lium-dependent vascular relaxation in patients with sleep ap-
nea. J Hypertension 14: 577–584, 1996.
[27] Celermajer DS, Adams MR, Clarkson P, Robinson J,
McCredie R, Donald A, Deanfield JE: Passive smoking and
impaired endothelium-dependent arterial dilation in healthy
young adults. New Engl J Med 334: 1540–1541, 1996.
[28] Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C,
Thomas O, Robinson J, Deanfield JE: Cigarette smoking is
associated with dose-related and potentially reversible
impairment of endothelium-dependent dilation in healthy
young adults. Circulation 88: 2149–2155, 1993.
[29] Chan J, Sanderson J, Chan W, Lai C, Choy D, Ho A, et al.:
Prevalence of sleep-disordered breathing in diastolic heart
failure. Chest 111(6): 1488–1493, 1997.
[30] Chaouat A, Weitzenblum E, Kessler R, Charpentier C, et al.: A
randomized trial of nocturnal oxygen therapy in chronic
obstructive pulmonary disease patients. Eur Respir J 14: 1002–
1008, 1999.
[31] Chaouat A, Weitzenblum E, Kessler R, Oswald M, Sforza E,
Liegeon MN, Krieger J: Five-year effects of nasal continuous
positive airway pressure on daytime lung function and pul-
monary hemodynamics in patients with obstructive sleep
apnoea syndrome. Eur Respir J 10: 2578–2582, 1997.
[32] Chaouat A, Weitzenblum E, Kessler R, Schott R, et al.: Out-
come of COPD patients with mild daytime hypoxaemia with
or without sleep-related oxygen desaturation. Eur Respir J 17:
848–855, 2001.
[33] Chin K, Nakamura T, Shimizu K, Mishima M, Nakamura T,
Miyasaka M, Ohi M: Effects of nasal continuous positive
airway pressure on soluble cell adhesion molecules in patients
with obstructive sleep apnea syndrome. Am J Med 109: 562–
567, 2000.
[34] Chin K, Ohi M, Kita H, Noguchi T, Otsuka N, Tsuboi T,
Mishima M, Kuno K: Effects of CPAP therapy on fibrinogen
levels in obstructive sleep apnea syndrome. Am J Respir Crit
Care Med 153: 1972–1976, 1996.
[35] Cohen RA: Endothelial dysfunction in diabetic vascular dis-
ease. Medicographia 19: 157–161, 1997.
[36] Cutaia M, Rounds S: Hypoxic pulmonary vasoconstriction.
Physiologic significance, mechanism and clinical relevance.
Chest 97: 706–718, 1990.
[37] Dark DS, Pingleton SK, Kerby GR, Crabb JE, Gollub SB,
Glatter TR, et al.: Breathing pattern abnormalities and arterial
oxygen desaturation during sleep in the congestive heart fail-
ure syndrome. Improvement following medical therapy. Chest
91(6): 833–836, 1987.
[38] Dart RA, Gregoire JR, Gutterman DD, Woolf SH: The
association of hypertension and secondary cardiovascular
disease with sleep-disordered breathing. Chest 123: 244–260,
2003.
[39] Dean RT, Wilcox I: Possible atherogenic effects of hypoxia
during obstructive sleep apnea. Sleep 16: S15–S22, 1993.
[40] DeBacker WA, Verbraecken J, Willemen M, Wittesaele W,
DeCock W, Van de Heyning P: Central apnea index decreases
after prolonged treatment with acetazolamide. Am J Respir
Crit Care Med 151(1): 87–91, 1995.
[41] De Olazabal JR, Miller MJ, Cook WR, Mithoefer JC: Disor-
dered breathing and hypoxia during sleep in coronary artery
disease. Chest 82(5): 548–552, 1982.
[42] Dickerson LW, Huang AH, Thurner MM, Nearing BD, Verrier
RL: Relationship between coronary hemodynamic changes
and the phasic events of rapid eye movement sleep. Sleep
16(6): 550–557, 1993.
[43] Dimsdale JE, Loredo JS, Profant J: Effect of continuous pos-
itive airway pressure on blood pressure: a placebo trial.
Hypertension 35: 144–147, 2000.
[44] Diomedi M et al.: Cerebral hemodynamic changes in sleep
apnea syndrome and effect of continuous positive airway
pressure treatment. Neurology 51(4): 1051–1056, 1998.
[45] Douglas NJ, Weitzenblum E: Sleep and chronic obstructive
pulmonary disease. Eur Respir Mon 7: 209–214, 1998.
[46] Dro¨ ge W: Free radicals in the physiological control of cell
function. Physiol Rev 82: 47–95, 2002.
[47] Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL, Yuan
JX, Deutsch R, Jamieson SW, Thistlethwaite PA: Signaling
molecules in nonfamilial pulmonary hypertension. N Engl J
Med 348: 500–509, 2003.
[48] Duchna H-W, Guilleminault C, Stoohs RA, Faul JL, Moreno
H, Hoffman BB, Blaschke TF: Vascular reactivity in
obstructive sleep apnea syndrome. Am J Respir Crit Care Med
161: 187–191, 2000.
[49] Duchna H-W, Guilleminault C, Stoohs RA, Orth M, De Zeeuw
J, Schultze-Werninghaus G, Rasche K: Das obstruktive
Schlafapnoe-Syndrom: Ein kardiovaskula¨rer Risikofaktor? Z
Kardiol 90: 568–575, 2001.
[50] Dyken ME et al.: Investigating the relationship between stroke
and obstructive sleep apnea. Stroke 27(3): 401–407, 1996.
[51] Dyugovskaya L, Lavie P, Lavie L: Increased adhesion mole-
cules expression and production of reactive oxygen species in
leukocytes of sleep apnea patients. Am J Respir Crit Care Med
165: 934–939, 2002.
[52] Eddahibi S, Morell N, d’Ortho MP, Naeije R, Adnot S:
Pathobiology of pulmonary arterial hypertension. Eur Respir J
20: 1559–1572, 2002.
[53] Eldridge FL, Millhorn DE, Waldrop TG, Kiley JP: Mechanism
of respiratory effects of methylxanthines. Respir Physiol
53(2): 239–261, 1983.
[54] Engleman HM, Gough K, Martin SE, Kingshott RN, Padfield
PL, Douglas NJ: Ambulatory blood pressure on and off con-
tinuous positive airway pressure therapy for the sleep apnea/
hypopnea syndrome: effects in ‘non-dippers’. Sleep 19: 378–
381, 1996.
[55] European Study Group on Diastolic Heart Failure: How to
diagnose diastolic heart failure. Eur Heart J 19(7): 990–1003,
1998.
[56] Faller DV: Endothelial responses to hypoxic stress. Clin Exp
Pharmacol Physiol 26: 74–84, 1999.
[57] Fathi R, Marwick TH: Noninvasive tests of vascular function
and structure: why and how to perform them. Am Heart J 141:
694–703, 2001.
[58] Fischer J, Mayer G, Peter JH, Riemann D, Sitter H: Leitlinie
S2, Nicht-erholsamer Schlaf. Blackwell Wissenschafts-Verlag,
Berlin, 2001.
[59] Flemons WW, Remmers JE, Gillis AM: Sleep apnea and
cardiac arrhythmias. Is there a relationship? Am Rev Respir
Dis 148: 618–621, 1993.
[60] Fletcher EC: Effect of episodic hypoxia on sympa-
thetic activity and blood pressure. Respir Physiol 119: 189–
197, 2000.
[61] Fletcher EC, Levin DC: Cardiopulmonary hemodynamics dur-
ing sleep in subjects with chronic obstructive pulmonary
116 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
disease. The effect of short and longterm oxygen. Chest 85: 6–
14, 1984.
[62] Fletcher EC, Miller J, Schaaf JW, Fletcher JG: Urinary cate-
cholamines before and after tracheostomy in patients with
obstructive sleep apnea and hypertension. Sleep 10: 35–44,
1987.
[63] Franklin KA, Nilsson JB, Sahlin C, Na¨ slund U: Sleep apnoea
and nocturnal angina. Lancet 345: 1085–1087, 1995.
[64] Friedlander AH, Friedlander IK, Yueh R, Littner MR: The
prevalence of carotid atheromas seen on panoramic radio-
graphs of patients with obstructive sleep apnea and their
relation to risk factors for atherosclerosis. J Oral Maxillofac
Surg 57: 516–521, 1999.
[65] Frohnhofen H et al.: Na¨chtliche Sauerstofftherapie und kog-
nitive Funktion bei bewußtseinsklaren, a¨lteren Patienten mit
Hirninfarkt und obstruktiver Schlafapnoe – Eine kontrollierte
Studie. Somnologie 2: 172–183, 1998.
[66] Fung JW, Li TS, Choy DK, Yip GW, Ko FW, Sanderson JE,
et al.: Severe obstructive sleep apnea is associated with left
ventricular diastolic dysfunction. Chest 121(2): 422–429, 2002.
[67] Gainer JL: Hypoxia and atherosclerosis: re-evaluation of an
old hypothesis. Atherosclerosis 68: 263–266, 1987.
[68] Garrigue S, Bordier P, Jais P, Shah DC, Hcini M, Raherisson C,
De Lara MT,Haisaguerre M, Clementy J: Benefit of atrial pacing
in sleep apnea syndrome. N Engl J Med 346: 404–412, 2002.
[69] Goldstein RS, Ramcharan VR, Bowes G, McNicholas WT
et al.: Effect of supplemental nocturnal oxygen on gas ex-
change in patients with severe obstructive lung disease. N Engl
J Med 310: 425–429, 1984.
[70] Good DC et al.: Sleep-disordered breathing and poor func-
tional outcome after stroke. Stroke 27(2): 252–259, 1996.
[71] Gotsopoulos H, Chen C, Qian J, Cistulli PA: Oral appliance
therapy improves symptoms in obstructive sleep apnea: a
randomized, controlled trial. Am J Respir Crit Care Med 166:
743–748, 2002.
[72] Grimm W, Koehler U, Fus E, Hoffmann J, Menz V, Funck R,
Peter JH, Maisch B: Outcome of patients with sleep apnea-
associated severe bradyarrhythmias after continuous positive
airway pressure therapy. Am J Cardiol 86: 688–692, 2000.
[73] Grimpen F, Kanne P, Schulz E, Hagenah G, Hasenfuß G,
Andreas S: Endothelin-1 plasma levels are not elevated in
patients with obstructive sleep apnoea. Eur Respir J 15: 320–
325, 2000.
[74] Grossman W, Braunwald E: Pulmonary hypertension. In:
Braunwald E (ed.): Heart disease. 4
th
edn. W.B. Saunders,
Philadelphia, pp 790–816, 1992.
[75] Grote L, Hedner J, Peter JH: Sleep-related breathing disorder
is an independent risk factor for uncontrolled hypertension.
J Hypertens 18: 679–685, 2000.
[76] Grote L, Ploch T, Heitmann J, Knaack L, Penzel T, Peter JH:
Sleep-related breathing disorder is an independent risk factor
for systemic hypertension. Am J Respir Crit Care Med 160:
1875–1882, 1999.
[77] Hall MJ, Xie A, Rutherford R, Ando S, Floras JS, Bradley TD:
Cycle length of periodic breathing in patients with and without
heart failure. Am J Respir Crit Care Med 154: 376–381, 1996.
[78] Hanly PA, Millar TW, Steljes DG, Baert R, Frais MA, Kryger
MH: The effect of oxygen on respiration and sleep in patients
with congestive heart failure. Ann Intern Med 111(10): 777–
782, 1989.
[79] Hanly PA, Sasson Z, Zuberi N, Lunn K: ST-segment depres-
sion during sleep in obstructive sleep apnea. Am J Cardiol 71:
1341–1345, 1993.
[80] Hanly PA, Zuberi-Khokhar N: Daytime sleepiness in patients
with congestive heart failure and Cheyne–Stokes respiration.
Chest 107(4): 952–958, 1995.
[81] Hanly PA, Zuberi-Khokhar NS: Increased mortality associated
with Cheyne–Stokes respiration in patients with congestive
heart failure. Am J Respir Crit Care Med 153(1): 272–276, 1996.
[82] Harbison J, Ford GA, Gibson GJ: Nasal continuous positive
airway pressure for sleep apnoea following stroke [letter]. Eur
Respir J 19(6): 1216–1217, 2002.
[83] Harbison J, Ford GA, James OF, Gibson GJ: Sleep-disordered
breathing following acute stroke. QJM 95(11): 741–747, 2002.
[84] Harbison JA, O’Reilly P, McNicholas WT: Cardiac rhythm
disturbances in the obstructive sleep apnea syndrome: effects
of nasal continuous positive airway pressure therapy. Chest
118: 591–595, 2000.
[85] Hedner J: Regulation of systemic vasculature in obstructive
sleep apnea syndrome. Sleep 23(Suppl 4): S132–S135, 2000.
[86] Hedner J, Darpo B, Ejnell H, Carlson J, Caidahl K: Reduction
in sympathetic activity after long-term CPAP treatment in
sleep apnoea: cardiovascular implications. Eur Respir J 8:
222–229, 1995.
[87] Hedner J, Grote L: Cardiovascular consequences of obs-
tructive sleep apnea. In: McNicholas WT (ed.): Respiratory
disorders during sleep, vol. 3. European Respiratory Mono-
graph Sheffield, European Respiratory Society Journals Ltd.,
pp 227–265, 1998.
[88] Hedner J, Grote L: The link between sleep apnea and car-
diovascular disease – time to target the nonsleepy sleep ap-
neics? [Editorial] Am J Respir Crit Care Med 163: 5–6, 2001.
[89] Hein H, Raschke F, Koehler D, Mayer G, Peter JH, Ruehle
KH: Leitlinie zur Diagnostik und Therapie schlafbezogener
Atmungssto¨ rungen beim Erwachsenen. Pneumologie 55: 339–
342, 2001.
[90] Heindl S, Lehnert M, Criee CP, Hasenfuss G, Andreas S: Marked
sympathetic activation in patients with chronic respiratory fail-
ure. Am J Respir Crit Care Med 164(4): 597–601, 2001.
[91] Henderson AH: Endothelium in control. Br Heart J 65: 116–
125, 1991.
[92] Hida W, Tun Y, Kikuchi Y, Okabe S, Shirato K: Pulmonary
hypertension in patients with chronic obstructive pulmonary
disease: recent advances in pathophysiology and management.
Respirology 7: 3–13, 2002.
[93] Hilton MF, Chappell MJ, Bartlett WA, Malhotra A, Beattie
JM, Cayton RM: The sleep apnoea/hypopnoea syndrome
depresses waking vagal tone independent of sympathetic
activation. Eur Respir J 17: 1258–1266, 2001.
[94] Hoeper MM, Galie N, Simonneau G, Rubin LJ: New treat-
ments for pulmonary arterial hypertension. Am J Respir Crit
Care Med 165: 1209–1216, 2002.
[95] Hopkins N, McLoughlin P: The structural basis of pulmonary
hypertension in chronic lung disease: remodelling, rarefaction
or angiogenesis? J Anat 201: 335–348, 2002.
[96] Hui DS et al.: Prevalence of sleep-disordered breathing and
continuous positive airway pressure compliance: results in
Chinese patients with first-ever ischemic stroke. Chest 122(3):
852–860, 2002.
[97] Hung J, Whitford EG, Parsons RW, Hillman DR: Association
of sleep apnoea with myocardial infarction in men. Lancet
336(8710): 261–264, 1990.
[98] Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman
AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G,
Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW,
Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V,
Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO,
Smith SC Jr: ACC/AHA guidelines for the evaluation and
management of chronic heart failure in the adult: executive
summary. A report of the American College of Cardiology/
American Heart Association Task Force on Practice Guide-
lines (Committee to Revise the 1995 Guidelines for the
Evaluation and Management of Heart Failure): developed in
collaboration with the International Society for Heart and
Lung Transplantation; endorsed by the Heart Failure Society
of America. Circulation 104(24): 2996–3007, 2001.
[99] Imadojemu VA, Gleeson K, Quraishi SA, Kunselman AR,
Sinoway LI, Leuenberger UA: Impaired vasodilator responses
in obstructive sleep apnea are improved with continuous
positive airway pressure therapy. Am J Respir Crit Care Med
165: 950–953, 2002.
[100] Ip MS, Lam B, Chan LY, Zheng L, Tsang KW, Fung PC, Lam
WK: Circulating nitric oxide is suppressed in obstructive sleep
apnea and is reversed by nasal continuous positive airway
pressure. Am J Respir Crit Care Med 162: 2166–2171, 2000.
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 117
Somnologie 7: 101–121, 2003
[101] Iranzo A, et al.: Prevalence and clinical importance of sleep
apnea in the first night after cerebral infarction. Neurology
58(6): 911–916, 2002.
[102] Javaheri S: Effects of continuous positive airway pressure on
sleep apnea and ventricular irritability in patients with heart
failure. Circulation 101: 392–397, 2000.
[103] Javaheri S: Treatment of central sleep apnea in heart failure.
Sleep 23(Suppl 4): S224–S227, 2000.
[104] Javaheri S, Corbett WS: Association of low PaCO2 with
central sleep apnea and ventricular arrhythmias in ambulatory
patients with stable heart failure. Ann Intern Med 128(3): 204–
207, 1998.
[105] Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H,
Lindower P, et al.: Sleep apnea in 81 ambulatory patients with
stable heart failure. Types and their prevalences, consequences
and presentations. Circulation 97: 2154–2159, 1998.
[106] Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P,
Roselle GA: Effect of theophylline on sleep-disordered brea-
thing in heart failure. N Engl J Med 335(8): 562–567, 1996.
[107] Kato M, Roberts-Thomson P, Phillips BG, Haynes WG,
Winnicki M, Accurso V, Somers VK: Impairment of endothe-
lium-dependent vasodilation of resistance vessels in patients
with obstructive sleep apnea. Circulation 102: 2607–2610, 2000.
[108] Khoo MC, Belozeroff V, Berry RB, Sassoon CS: Cardiac
autonomic control in obstructive sleep apnea. Effects of long-
term CPAP therapy. Am J Respir Crit Care Med 164: 807–812,
2001.
[109] Khoo MC, Kronauer RE, Strohl KP, Slutsky AS: Factors
inducing periodic breathing in humans: a general model. J
Appl Physiol 53(3): 644–659, 1982.
[110] Klingelhofer J et al.: Assessment of intracranial hemodynam-
ics in sleep apnea syndrome. Stroke 23(10): 1427–1433, 1992.
[111] Koehler U, Becker HF, Grimm W, Heitmann J, Peter JH,
Schafer H: Relations among hypoxemia, sleep stage, and
bradyarrhythmia during obstructive sleep apnea. Am Heart J
139: 142–148, 2000.
[112] Koehler U, Fus E, Grimm W, Pankow W, Schafer H,
Stammnitz A, Peter JH: Heart block in patients with
obstructive sleep apnoea: pathogenetic factors and effects of
treatment. Eur Respir J 11: 434–439, 1998.
[113] Koehler U, Schafer H: Is obstructive sleep apnea (OSA) a risk
factor for myocardial infarction and cardiac arrhythmias in
patients with coronary heart disease (CHD)? Sleep 19(4):
283–286, 1996.
[114] Koehler U, Trautmann M, Trautmann R, Tabarelli O, Cassel
W, Heitmann J, Peter JH: Do patients with sleep apnea have a
higher risk for myocardial infarction during sleep? Z Kardiol
88: 410–417, 1999.
[115] Kourembanas S, Marsden PA, McQuillan LP, Faller DV:
Hypoxia induces endothelin gene expression and secretion in
cultured human endothelium. J Clin Invest 88: 1054–1057,
1991.
[116] Krachman SL, Crocetti J, Berger TJ, Chatila W, Eisen HJ,
D’Alonzo GE: Effects of nasal continuous positive airway
pressure on oxygen body stores in patients with Cheyne–
Stokes respiration and congestive heart failure. Chest 123(1):
59–66, 2003.
[117] Kraiczi H, Hedner J, Peker Y, Carlson J: Increased vasocon-
strictor sensitivity in obstructive sleep apnea. J Appl Physiol
89: 493–498, 2000.
[118] Kraiczi H, Hedner J, Peker Y, Grote L: Comparison of
atenolol, amlodipine, enalapril, hydrochlorothiazide, and lo-
sartan for antihypertensive treatment in patients with
obstructive sleep apnea. Am J Respir Crit Care Med 161:
1423–1428, 2000.
[119] Laaban JP, Cassuto D, Orvoe¨ n-Frija E, Iliou MC, Mundler O,
Le´ger D, Oppert JM: Cardiorespiratory consequences of sleep
apnoea syndrome in patients with massive obesity. Eur Respir
J 11: 20–27, 1998.
[120] Lanfranchi PA, Braghiroli A, Bosimini E, Mazzuero G,
Colombo R, Donner CF, et al.: Prognostic value of Cheyne–
Stokes respiration in chronic heart failure. Circulation 99:
1435–1440, 1999.
[121] Lanfranchi P, Somers VA: Obstructive sleep apnea and vas-
cular disease. Respir Res 2: 315–319, 2001.
[122] Lavie P, Herer P, Hoffstein V: Obstructive sleep apnoea syn-
drome as a risk factor for hypertension: population study. BMJ
320: 479–482, 2000.
[123] Lawrence E et al.: The natural history and associations of sleep
disordered breathing in first ever stroke. Int J Clin Pract 55(9):
584–588, 2001.
[124] Leung RS, Bradley TD: Sleep apnea and cardiovascular dis-
ease. Am J Respir Crit Care Med 164: 2147–2165, 2001.
[125] Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HAJ:
Microcirculation in hypertension – a new target for treatment?.
Circulation 104: 735–740, 2001.
[126] Liao JK, Zulueta JJ, Yu FS, Peng HB, Cote CG, Hassoun PM:
Regulation of bovine endothelial constitutive nitric oxide
synthase by oxygen. J Clin Invest 96: 2661–2666, 1995.
[127] Lofaso F, Verschueren P, Rande JL, Harf A, Goldenberg F:
Prevalence of sleep-disordered breathing in patients on a heart
transplant waiting list. Chest 106(6): 1689–1694, 1994.
[128] Lorenzi-Filho G, Rankin F, Bies I, Douglas Bradley T: Effects
of inhaled carbon dioxide and oxygen on Cheyne–Stokes
respiration in patients with heart failure. Am J Respir Crit Care
Med 159(5 Pt 1): 1490–1498, 1999.
[129] Loube DI, Gay PC, Strohl KP, Pack AI, White DP, Collop NA:
Indications for positive airway pressure treatment of adult
obstructive sleep apnea patients: a consensus statement. Chest
115(3): 863–866, 1999.
[130] Lupattelli G, Lombardini R, Schillaci G, Ciuffetti G, Marchesi
S, Siepi D, Mannarino E: Flow-mediated vasoactivity and
circulating adhesion molecules in hypertriglyceridemia:
association with small dense LDL cholesterol particles. Am
Heart J 140: 521–526, 2000.
[131] Lu¨ scher TF: The endothelium as a target and mediator of
cardiovascular disease. Eur J Clin Invest 23: 670–685, 1993.
[132] Marchant B, Stevenson R, Vaishnav S, Wilkinson P, Ranja-
dayalan K, Timmis AD: Influence of the autonomic nervous
system on circadian patterns of myocardial ischaemia: com-
parison of stable angina with the early postinfarction period.
Br Heart J 71: 329–333, 1994.
[133] Marin JM, Carrizo SJ, Kogan I: Obstructive sleep apnea and
acute myocardial infarction: clinical implications of the
association. Sleep 21: 809–815, 1998.
[134] Marrone O, Bellia V, Ferrara G et al.: Transmural pressure
measurements: importance in the assessment of pulmonary
hypertension in obstructive sleep apnoeas. Chest 95: 338–342,
1989.
[135] Marrone O, Bellia V, Pieri D, Salvaggio A, Bonsignore G:
Acute effects of oxygen administration on transmural pul-
monary pressure in obstructive sleep apnoea. Chest 101:
1023–1027, 1992.
[136] Marrone O, Bonsignore MR, Romano S, Bonsignore G:
Slow and fast changes in transmural pulmonary artery
pressure in obstructive sleep apnoea. Eur Respir J 7: 2192–
2198, 1994.
[137] Mayer J, Becker H, Brandenburg U, Penzel T, Peter JH, von
Wichert P: Blood pressure and sleep apnea: results of long-
term nasal continuous positive airway pressure therapy. Car-
diology 79: 84–89, 1991.
[138] McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kow-
embanas S: Hypoxia inhibits expression of eNOS via tran-
scriptional and post-transcriptional mechanisms. Am J Physiol
267: H1921–H1927, 1994.
[139] Mehta S, Hill NS: Noninvasive ventilation – state-of-the-art.
Am J Respir Crit Care Med 163: 540–577, 2001.
[140] Milanova M et al.: Sleep apnea in acute stroke: Diagnosis,
treatment, and follow-up in 100 patients. Sleep Res Online
2(Suppl 1): 405, 1999.
[141] Miller A, Granada M: In-hospital mortality in the pickwickian
syndrome. Am J Med 56: 144–150, 1974.
[142] Miller WP: Cardiac arrhythmias and conduction disturbances
in the sleep apnea syndrome. Prevalence and significance. Am
J Med 73: 317–321, 1982.
118 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
[143] Minemura H, Akashiba T, Yamamoto H, Akahoshi T, Kosaka
N, Horie T: Acute effects of nasal continuous positive airway
pressure on 24-hour blood pressure and catecholamines in
patients with obstructive sleep apnea. Intern Med 37: 1009–
1013, 1998.
[144] Mohsenin V: Sleep-related breathing disorders and risk of
stroke. Stroke 32(6): 1271–1278, 2001.
[145] Mohsenin V, Valor R: Sleep apnea in patients with hemi-
spheric stroke. Arch Phys Med Rehabil 76(1): 71–76, 1995.
[146] Monasterio C, Vidal S, Duran J, Ferrer M, Carmona C, Barbe
F, Mayos M, Gonzalez-Mangado N, Juncadella M, Navarro A,
et al.: Effectiveness of continuous positive airway pressure in
mild sleep apnea–hypopnea syndrome. Am J Respir Crit Care
Med 164: 939–943, 2001.
[147] Mooe T, Franklin KA, Holmstrom K, Rabben T, Wiklund U:
Sleep-disordered breathing and coronary artery disease: long-
term prognosis. Am J Respir Crit Care Med 164: 1910–1913,
2001.
[148] Mooe T, Franklin KA, Wiklund U, Rabben T, Holmstrom K:
Sleep-disordered breathing and myocardial ischemia in patients
with coronary artery disease. Chest 117(6): 1597–1602, 2000.
[149] Mooe T, Rabben T, Wiklund U, Franklin KA, Eriksson P:
Sleep-disordered breathing in men with coronary artery dis-
ease. Chest 109(3): 659–663, 1996.
[150] Morera J, Hoadley SD, Roland JM, Pasipoularides A, Darragh
R, Gaitan G, Pieroni DR: Estimation of the ratio of pulmonary
to systemic pressures by pulsed wave Doppler echocardiog-
raphy for assessment of pulmonary artery pressures. Am J
Cardiol 63: 862–866, 1989.
[151] Morgan BJ, Crabtree DC, Puleo DS, Badr MS, Toiber F,
Skatrud JB: Neurocirculatory consequences of abrupt change
in sleep state in humans. J Appl Physiol 80: 1627–1636, 1996.
[152] Moruzzi P, Sarzi-Braga S, Rossi M, Contini M: Sleep apnoea
in ischaemic heart disease: differences between acute and
chronic coronary syndromes. Heart 82: 343–347, 1999.
[153] Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA,
Parker C, Poole WK, Passamani E, Roberts R, Robertson T:
Circadian variation in the frequency of onset of myocardial
infarction. N Engl J Med 313: 1315–1322, 1985.
[154] Nachtmann A et al.: Positive Korrelation von obstruktiver
Schlafapnoe mit Gefa¨ssprozessen bei Schlaganfallpatienten.
Aktuelle Neurologie 27(Suppl S2): 241, 2000.
[155] Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R:
Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-
prone sites on the endothelium in the APO-E deficient mouse.
Arterioscler Thromb Vasc Biol 18: 842–851, 1998.
[156] Naughton M, Benard D, Tam A, Rutherford R, Bradley TD:
Role of hyperventilation in the pathogenesis of central sleep
apneas in patients with congestive heart failure. Am Rev Re-
spir Dis 148(2): 330–338, 1993.
[157] Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F,
Bradley TD: Effects of nasal CPAP on sympathetic activity in
patients with heart failure and central sleep apnea. Am J Respir
Crit Care Med 152(2): 473–479, 1995.
[158] Naughton MT, Benard DC, Rutherford R, Bradley TD: Effect
of continuous positive airway pressure on central sleep apnea
and nocturnal PCO2 in heart failure. Am J Respir Crit Care
Med 150(6 Pt 1): 1598–1604, 1994.
[159] Naughton MT, Bradley TD: Sleep apnea in congestive heart
failure. Clin Chest Med 19(1): 99–113, 1998.
[160] Naughton MT, Liu PP, Bernard DC, Goldstein RS, Bradley
TD: Treatment of congestive heart failure and Cheyne–Stokes
respiration during sleep by continuous positive airway pres-
sure. Am J Respir Crit Care Med 151(1): 92–97, 1995.
[161] Naum CC, Sciurba FC, Rogers RM: Pulmonary function
abnormalities in chronic severe cardiomyopathy preceding
cardiac transplantation. Am Rev Respir Dis 145(6): 1334–
1338, 1992.
[162] Nelesen RA, Yu H, Ziegler MG, Mills PJ, Clausen JL,
Dimsdale JE: Continuous positive airway pressure normalizes
cardiac autonomic and hemodynamic responses to a laboratory
stressor in apneic patients. Chest 119: 1092–1101, 2001.
[163] Netzer N, Werner P, Jochums I, Lehmann M, Strohl KP: Blood
flow of the middle cerebral artery with sleep-disordered
breathing: correlation with obstructive hypopneas. Stroke
29(1): 87–93, 1998.
[164] Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P,
Mullen M, Baig W, Flapan AD, Cowley A, Prescott RJ,
Neilson JM, Fox KA: Prospective study of heart rate variab-
ility and mortality in chronic heart failure: results of the United
Kingdom heart failure evaluation and assessment of risk trial
(UK-heart). Circulation 98(15): 1510–1516, 1998.
[165] Nowlin JB, Troyer WG, Collins WS: The association of
nocturnal angina with dreaming. Ann Intern Med 63: 1040–
1046, 1965.
[166] Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T, Kat-
ayama H, Ouchi Y: Increased levels of circulating ICAM-1,
VCAM-1, and L-selectin in obstructive sleep apnea syndrome.
J Appl Physiol 87: 10–14, 1999.
[167] Otsuka K, Sadakane N, Ozawa T: Arrhythmogenic properties
of disordered breathing during sleep in patients with cardio-
vascular disorders. Clin Cardiol 10: 771–782, 1987.
[168] Parra O et al.: Time course of sleep-related breathing disorders
in first-ever stroke or transient ischemic attack. Am J Respir
Crit Care Med 161: 375–380, 2000.
[169] Partinen M, Palomaki H: Snoring and cerebral infarction.
Lancet 2(8468): 1325–1326, 1985.
[170] Peker Y, Hedner J, Kraiczi H, Loth S: Respiratory disturbance
index: an independent predictor of mortality in coronary artery
disease. Am J Respir Crit Care Med 162(1): 81–86, 2000.
[171] Peker Y, Kraiczi H, Hedner J, Loth S, Johansson A, Bende M:
An independent association between obstructive sleep apnoea
and coronary artery disease. Eur Respir J 14(1): 179–184, 1999.
[172] Peled N, Abinader EG, Pillar G, Sharif D, Lavie P: Nocturnal
ischemic events in patients with obstructive sleep apnea syn-
drome and ischemic heart disease: effects of continuous pos-
itive air pressure treatment. J Am Coll Cardiol 34(6): 1744–
1749, 1999.
[173] Penzel T, McNames J, Murray A, de Chazal P, Moody G,
Raymond B: Systematic comparison of different algorithms
for apnoea detection based on electrocardiogram recordings.
Med Biol Eng Comput 40: 402–407, 2002.
[174] Peppard PE, Young T, Palta M, Skatrud J: Prospective study of
the association between sleep-disordered breathing and
hypertension. N Engl J Med 342: 1378–1384, 2000.
[175] Pepperell JC et al.: Ambulatory blood pressure after thera-
peutic and subtherapeutic nasal continuous positive airway
pressure for obstructive sleep apnoea: a randomised parallel
trial. Lancet 359(9302): 204–210, 2002.
[176] Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken
ME, Somers VK: Effects of obstructive sleep apnea on end-
othelin-1 and blood pressure. J Hypertens 17: 61–66, 1999.
[177] Podszus T, Greenberg H, Scharf S: Influence of sleep state and
sleep disordered breathing on cardiovascular function. In:
Saunders NA, Sullivan CE (eds): Sleep and breathing. Marcel
Decker, New York, pp 257–310, 1994.
[178] Ponikowski P, Anker SD, Chua TP, Francis D, Banasiak W,
Poole-Wilson PA, Coats AJ, Piepoli M: Oscillatory breathing
patterns during wakefulness in patients with chronic heart
failure: clinical implications and role of augmented peripheral
chemosensitivity. Circulation 100(24): 2418–2424, 1999.
[179] Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-
Peploe K, Harrington D, Anker SD, Volterrani M, Colombo R,
Mazzuero G, Giordano A, Coats AJ: Augmented peripheral
chemosensitivity as a potential input to baroreflex impairment
and autonomic imbalance in chronic heart failure. Circulation
96(8): 2586–2594, 1997.
[180] Poston L, Taylor PD: Endothelium-mediated vascular function
in insulin-dependent diabetes mellitus. Clin Sci 88: 245–255,
1995.
[181] Quyyumi AA, Efthimiou J, Quyyumi A, Mockus LJ, Spiro
SG, Fox KM: Nocturnal angina: precipitating factors in
patients with coronary artery disease and those with variant
angina. Br Heart J 56: 346–352, 1986.
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 119
Somnologie 7: 101–121, 2003
[182] Raeside DA, Brown A, Patel KR, Welsh D, Peacock AJ:
Ambulatory pulmonary artery pressure monitoring during
sleep and exercise in normal individuals and patients with
COPD. Thorax 57: 1050–1053, 2002.
[183] Randerath WJ, Heise M, Hinz R, Ruehle KH: An individually
adjustable oral appliance vs continuous positive airway pres-
sure in mild-to-moderate obstructive sleep apnea syndrome.
Chest 122: 569–575, 2002.
[184] Rasche K, Duchna HW, Orth M, DeZeeuw J, et al.: Der
Einfluss verschiedener Hypoxa¨miedefinitionen auf die Bezie-
hung zwischen Pulmonalisdruck im Wachzustand und Hy-
poxa¨ mie im Schlaf. Pneumologie 55: 289–294, 2001.
[185] Rasche K, Orth M, Duchna HW, Podbregar D, et al.: Ha¨u-
figkeit na¨chtlicher Hypoxa¨mien bei in Ruhe und Wachzustand
normoxa¨ mischen und normokapnischen Patienten mit chro-
nisch obstruktiver Lungenerkrankung. Atemw-Lungenkrkh
21: 383–385, 1995.
[186] Remme WJ, Swedberg K: Guidelines for the diagnosis and
treatment of chronic heart failure. Eur Heart J 22(17): 1527–
1560, 2001.
[187] Richter P, Gottwik M: Cor pulmonale: interaction with pul-
monary hypertension, sleep apnea and lung diseases. Internist
43(Suppl 1): S19–20, S23–32, 2002.
[188] Rijcken B, Britton J: Epidemiology of chronic obstructive
pulmonary disease. Eur Respir Mon 7: 41–73, 1988.
[189] Roche F, Court-Fortune I, Pichot V, Duverney D, Costes F,
Emonot A, Vergnon JM, Geyssant A, Lacour JR, Barthelemy
JC: Reduced cardiac sympathetic autonomic tone after long-
term nasal continuous positive airway pressure in obstructive
sleep apnoea syndrome. Clin Physiol 19: 127–134, 1999.
[190] Rose EC, Staats R, Virchow C Jr, Jonas IE: Occlusal and
skeletal effects of an oral appliance in the treatment of
obstructive sleep apnea. Chest 122: 871–877, 2002.
[191] Ross R: Atherosclerosis – an inflammatory disease. N Engl J
Med 340: 115–126, 1999.
[192] Ross R: The pathogenesis of atherosclerosis: a perspective for
the 1990s. Nature 362: 801–809, 1993.
[193] Rubanyi GM: The role of endothelium in cardiovascular
homeostasis and diseases. J Cardiovasc Pharmacol 22(Suppl
4): S1–S14, 1993.
[194] Ru¨ hle KH, Matthys H: Nocturnal hypoxemia and pulmonary
arterial blood pressure. In: Peter JH, Podszus T, v Wichert P
(eds): Sleep related disorders and internal diseases. Springer,
Berlin, pp 271–278, 1987.
[195] Saarelainen S, Seppala E, Laasonen K, Hasan J: Circulating
endothelin-1 in obstructive sleep apnea. Endothelium 5: 115–
118, 1997.
[196] Sajkov D, Cowie RJ, Bradley JA, Mahar L, McEvoy RD:
Validation of new pulsed Doppler echocardiographic tech-
niques for assessment of pulmonary hemodynamics. Chest
103: 1348–1353, 1993.
[197] Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, McEvoy
RD: Pulmonary hypertension and hypoxemia in obstructive
sleep apnea syndrome. Am J Respir Crit Care Med 149: 416–
422, 1994.
[198] Sajkov D, Wang T, Saunders NA, Bune AJ, McEvoy RD:
Continuous positive airway pressure treatment improves pul-
monary hemodynamics in patients with obstructive sleep
apnea. Am J Respir Crit Care Med 165: 152–158, 2002.
[199] Sajkov D, Wang T, Saunders NA, Bune AJ, Neil AM, McEvoy
RD: Daytime pulmonary hemodynamics in patients with
obstructive sleep apnea syndrome. Am J Respir Crit Care Med
159: 1518–1526, 1999.
[200] Sakamoto T, Nakazawa Y, Hashizume Y, Tsutsumi Y, Mizuma
H, Hirano T et al.: Effects of acetazolamide on the sleep apnea
syndrome and its therapeutic mechanism. Psychiatry Clin
Neurosci 49(1): 59–64, 1995.
[201] Sandberg O, Franklin KA, Bucht G, Eriksson S, Gustafson Y:
Nasal continuous positive airway pressure in stroke patients
with sleep apnoea: a randomized treatment study. Eur Respir J
18(4): 630–634, 2001.
[202] Sandberg O, Franklin KA, Bucht G, Gustafson Y: Sleep apnea,
delirium, depressed mood, cognition, and ADL ability after
stroke. J Am Geriatr Soc 49(4): 391–397, 2001.
[203] Sanner B, Sturm A, Konermann M: Koronare Herzerkrankung
bei Patienten mit obstruktiver Schlafapnoe. Dtsch Med
Wochenschr 121(30): 931–935, 1996.
[204] Sanner B, Tepel M, Markmann A, Zidek W: Effect of CPAP
therapy on 24-hour blood pressure in patients with obstructive
sleep apnea syndrome. Am J Hypertens 15: 251–257, 2002.
[205] Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W:
Pulmonary hypertension in patients with obstructive sleep
apnea syndrome. Arch Intern Med 157: 2483–2487, 1997.
[206] Sanner BM, Konermann M, Tepel M, Groetz J, Mummenhoff
C, Zidek W: Platelet function in patients with obstructive sleep
apnoea syndrome. Eur Respir J 16: 648–652, 2000.
[207] Scha¨fer D et al.: Polygraphic screening after ischemic stroke: a
consecutive study on 258 patients. Somnologie 5(4): 135–140,
2001.
[208] Scha¨fer H, Hasper E, Ewig S, Koehler U, Latzelsberger J,
Tasci S, Lu¨ deritz B: Pulmonary haemodynamics in obstructive
sleep apnoea: time course and associated factors. Eur Respir J
12: 679–684, 1998.
[209] Scha¨fer H, Koehler U, Ploch T, Peter JH: Sleep-related myo-
cardial ischemia and sleep structure in patients with obstruct-
ive sleep apnea and coronary heart disease. Chest 111: 387–
393, 1997.
[210] Schulz R, Grebe M, Hummel C, Grimminger F, Seeger W:
Common carotid artery intima media thickness is increased in
obstructive sleep apnea. Am J Respir Crit Care Med 165(8):
A512, 2002.
[211] Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H,
Mayer K, Seeger W, Grimminger F: Enhanced release of
superoxide from polymorphonuclear neutrophils in obstructive
sleep apnea. Impact of continuous positive airway pressure
therapy. Am J Respir Crit Care Med 162: 566–570, 2000.
[212] Schulz R, Olschewski H, Grimminger F, Seeger W:
Schlaganfall und transitorischer ischa¨mischer Attacke (TIA) bei
obstruktiver Schlaf-Apnoe: eine retrospektive Erhebung an
187 konsekutiven Patienten. Pneumologie 54: 575–579, 2000.
[213] Schulz R, Schmidt D, Blum A, Lopes-Ribeiro X, Lu¨ cke C,
Mayer K, Olschewski H, Seeger W, Grimminger F: Decreased
plasma levels of nitric oxide derivatives in obstructive sleep
apnoea – response to CPAP therapy. Thorax 55: 1046–1051,
2000.
[214] Sebel J, Kolenda D: Pra¨valenz der obstruktiven Schlafapnoe
bei Patienten mit koronarer Herzerkrankung. Herz Kreis 27:
153–158, 1995.
[215] Sforza E, Krieger J, Weitzenblum E, Apprill M, Lampert E,
Ratomaharo J: Long-term effects of treatment with nasal
continuous positive airway pressure on daytime lung function
and pulmonary hemodynamics in patients with obstructive
sleep apnea. Am Rev Respir Dis 141: 866–870, 1990.
[216] Sforza E, Laks L, Grunstein RR, Krieger J, Sullivan CE: Time
course of pulmonary artery pressure during sleep in sleep
apnoea syndrome: role of recurrent apnoeas. Eur Respir J 11:
440–446, 1998.
[217] Shahar E, Whitney CW, Redline S, Lee ET, Newman AB,
Nieto FJ, O’Connor GT, Boland LL, Schwartz JE, Samet JM:
Sleep-disordered breathing and cardiovascular disease. Cross-
sectional results of the Sleep Heart Health Study. Am J Respir
Crit Care Med 163: 19–25, 2001.
[218] Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara
T, Accurso V, Somers VK: Elevated C-reactive protein in
patients with obstructive sleep apnea. Circulation 105: 2462–
2464, 2002.
[219] Silvestrini M, Rizzato B, Placidi F, Baruffaldi R, Bianconi A,
Diomedi M: Carotid artery wall thickness in patients with
obstructive sleep apnea syndrome. Stroke 33: 1782–1785, 2002.
[220] Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley
TD: Risk factors for central and obstructive sleep apnea in 450
men and women with congestive heart failure. Am J Respir
Crit Care Med 160(4): 1101–1106, 1999.
120 Hans-Werner Duchna et al.
Somnologie 7: 101–121, 2003
[221] Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD: Ef-
fects of continuous positive airway pressure on cardiovascular
outcomes in heart failure patients with and without Cheyne–
Stokes respiration. Circulation 102(1): 61–66, 2000.
[222] Sin DD, Mayers I, Man GC, Pawluk L: Long-term compliance
rates to continuous positive airway pressure in obstructive
sleep apnea: a population-based study. Chest 121: 430–435,
2002.
[223] Solin P, Bergin P, Richardson M, Kaye DM, Walters EH,
Naughton MT: Influence of pulmonary capillary wedge pres-
sure on central apnea in heart failure. Circulation 99(12):
1574–1579, 1999.
[224] Spriggs DA et al.: Snoring increases the risk of stroke and
adversely affects prognosis. QJM 83(303): 555–562, 1992.
[225] Staniforth AD, Kinnear WJ, Starling R, Cowley AJ: Nocturnal
desaturation in patients with stable heart failure. Heart 79(4):
394–399, 1998.
[226] Staniforth AD, Kinnear WJ, Starling R, Hetmanski DJ,
Cowley AJ: Effect of oxygen on sleep quality, cognitive
function and sympathetic activity in patients with chronic heart
failure and Cheyne–Stokes respiration. Eur Heart J 19(6):
922–928, 1998.
[227] Steering Committee of the Physicians’ Health Study Research
Group: Final report on the aspirin component of the ongoing
Physicians’ Health Study. N Engl J Med 321(3): 129–135,
1989.
[228] Strange JW, Wharton J, Phillips PG, Wilkins MR: Recent
insights into the pathogenesis and therapeutics of pulmonary
hypertension. Clin Sci 102: 253–268, 2002.
[229] Stu¨ hlinger MC, Tsao PS, Her J-H, Kimoto M, Balint RF,
Cooke JP: Homocysteine impairs the nitric oxide synthase
pathway – role of asymmetric dimethylarginine. Circulation
104: 2569–2575, 2001.
[230] Suzuki M, Otsuka K, Guilleminault C: Long-term nasal con-
tinuous positive airway pressure administration can normalize
hypertension in obstructive sleep apnea patients. Sleep 16:
545–549, 1993.
[231] Szucs A et al.: Pathological sleep apnoea frequency remains
permanent in ischaemic stroke and it is transient in haemor-
rhagic stroke. Eur Neurol 47(1): 15–19, 2002.
[232] Tahawi Z, Orolinova N, Joshua IG, Bader M, Fletcher EC:
Altered vascular reactivity in arterioles of chronic intermittent
hypoxic rats. J Appl Physiol 90: 2007–2013, 2001.
[233] Takasaki Y, Orr D, Popkin J, Rutherford R, Liu P, Bradley TD:
Effect of nasal continuous positive airway pressure on sleep
apnea in congestive heart failure. Am Rev Respir Dis 140(6):
1578–1584, 1989.
[234] Teschler H, Dohring J, Wang YM, Berthon-Jones M: Adaptive
pressure support servo-ventilation: a novel treatment for
Cheyne–Stokes respiration in heart failure. Am J Respir Crit
Care Med 164(4): 614–619, 2001.
[235] Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL,
Simmons FB, Dement WC: Sleep-induced apnea syndrome.
Prevalence of cardiac arrhythmias and their reversal after
tracheostomy. Am J Med 63: 348–358, 1977.
[236] Tilton RG, Brock TA, Dixon RA: Therapeutic potential of
endothelin receptor antagonists and nitric oxide donors in
pulmonary hypertension. Expert Opin Investig Drugs 10:
1291–1308, 2001.
[237] Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TD:
Overnight shift from obstructive to central apneas in patients
with heart failure: role of PCO(2) and circulatory delay. Cir-
culation 103(2): 238–243, 2001.
[238] Tojima H, Kunitomo F, Kimura H, Tatsumi K, Kuriyama T,
Honda Y: Effects of acetazolamide in patients with the sleep
apnoea syndrome. Thorax 43(2): 113–119, 1988.
[239] Tremel F, Pepin JL, Veale D, Wuyam B, Siche JP, Mallion
JM, et al.: High prevalence and persistence of sleep apnoea
in patients referred for acute left ventricular failure and
medically treated over 2 months. Eur Heart J 20(16): 1201–
1209, 1999.
[240] Turkington PM et al.: Prevalence and predictors of upper
airway obstruction in the first 24 hours after acute stroke.
Stroke 33(8): 2037–2042, 2002.
[241] Van de Borne P, Oren R, Abouassaly C, Anderson E, Somers
VK: Effect of Cheyne–Stokes respiration on muscle sympa-
thetic nerve activity in severe congestive heart failure secon-
dary to ischemic or idiopathic dilated cardiomyopathy. Am J
Cardiol 81(4): 432–436, 1998.
[242] Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson
K, Chrousos GP: Elevation of plasma cytokines in disorders of
excessive daytime sleepiness: role of sleep disturbance and
obesity. J Clin Endocrinol Metab 82: 1313–1316, 1997.
[243] Walsh JT, Andrews R, Starling R, Cowley AJ, Johnston ID,
Kinnear WJ: Effects of captopril and oxygen on sleep apnoea
in patients with mild to moderate congestive cardiac failure. Br
Heart J 73(3): 237–241, 1995.
[244] Weitzenblum E: Chronic cor pulmonale. Heart 89: 225–230,
2003.
[245] Weitzenblum E, Sautegau A, Ehrhart M, Mammosser M: Long
term oxygen therapy can reverse the progression of pulmonary
hypertension in patients with chronic obstructive lung disease.
Am Rev Respir Dis 131: 493–498, 1985.
[246] Wessendorf TE, Alymov G, et al.: Pulsoximetrie als
Schlafapnoescreening bei Schlaganfallpatienten. Pneumologie
56(6): 357–362, 2002.
[247] Wessendorf TE, Teschler H, et al.: Sleep-disordered breathing
among patients with first-ever stroke. J Neurol 247(1): 41–47,
2000.
[248] Wessendorf TE, Thilmann AF, Wang YM, Schreiber A,
Konietzko N, Teschler H: Fibrinogen levels and obstructive
sleep apnea in ischemic stroke. Am J Respir Crit Care Med
162: 2039–2042, 2000.
[249] Wessendorf TE, Wang YM, et al.: Treatment of obstructive
sleep apnoea with nasal continuous positive airway pressure in
stroke. Eur Respir J 18(4): 623–629, 2001.
[250] White DP, Zwillich CW, Pickett CK, Douglas NJ, Findley LJ,
Weil JV: Central sleep apnea. Improvement with acetazola-
mide therapy. Arch Intern Med 142(10): 1816–1819, 1982.
[251] Wilcox I, McNamara SG, Collins FL, Grunstein RR, Sul-
livan CE: ‘Syndrome Z’: the interaction of sleep apnoea,
vascular risk factors and heart disease. Thorax 53(Suppl 3):
S25–S28, 1998.
[252] Willich SN, Lo¨ wel H, Mey W, Trautner C: Regionale
Unterschiede der Herz-Kreislauf-Mortalita¨t. Dtsch A
¨rzteblatt
96: 378–383, 1999.
[253] Willson GN, Wilcox I, Piper AJ, Flynn WE, Grunstein RR,
Sullivan CE: Treatment of central sleep apnoea in congestive
heart failure with nasal ventilation. Thorax 53(Suppl 3): S41–
S46, 1998.
[254] Willson GN, Wilcox I, Piper AJ, Flynn WE, Norman M,
Grunstein RR, et al.: Noninvasive pressure preset ventilation
for the treatment of Cheyne–Stokes respiration during sleep.
Eur Respir J 17(6): 1250–1257, 2001.
[255] Wondzinski E et al.: Einfluss der Obstruktiven Schlafapnoe auf
die Intima-Media-Dicke der A. carotis communis bei
Schlaganfallpatienten. Aktuelle Neurologie 27(Suppl S2):
P541, 2000.
[256] Yi G, Keeling PJ, Goldman JH, Hnatkova K, Malik M,
McKenna WJ: Comparison of time domain and spectral tur-
bulence analysis of the signal-averaged electrocardiogram for
the prediction of prognosis in idiopathic dilated cardiomyop-
athy. Clin Cardiol 19(10): 800–808, 1996.
[257] Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B,
Skatrud J: Population-based study of sleep-disordered brea-
thing as a risk factor for hypertension. Arch Intern Med 157:
1746–1752, 1997.
[258] Ziegler MG, Mills PJ, Loredo JS, Ancoli-Israel S, Dimsdale
JE: Effect of continuous positive airway pressure and placebo
treatment on sympathetic nervous activity in patients with
obstructive sleep apnea. Chest 120: 887–893, 2001.
Sleep-Disordered Breathing and Cardio- and Cerebrovascular Diseases 121
Somnologie 7: 101–121, 2003
