THE JOURNAL OF CLINICAL HYPERTENSION VOL. III NO. V SEPTEMBER/OCTOBER 2001
Sleep-disordered breathing, manifested by repetitive
episodes of partial or complete cessation of breathing
during sleep associated with brief arousal and auto-
nomic activation, is estimated to affect as many as
4% of adult men and 2% of adult women. Studies
conducted during the 1980s revealed a strong associ-
ation between sleep-disordered breathing and hyper-
tension. The results of these early studies, which
relied on relatively small samples of patients, have
been confirmed in recent years by large-scale epi-
demiologic studies that are controlled for all possible
confounding factors. This paper reviews the evidence
suggesting a causative relationship between hyperten-
sion and disordered breathing in sleep. The authors
discuss the possible underlying mechanisms of the
two entities and address the clinical implications of
this relationship. They conclude by recommending a
proactive approach to the diagnosis of breathing dis-
orders in sleep, in order to prevent the cardiovascular
sequelae of this syndrome. (J Clin Hypertens. 2001;
3:296–301). ©2001 Le Jacq Communications, Inc.
structions during sleep, causing intermittent noctur-
nal hypoxemia, sleep fragmentation, and daytime
sleepiness. It affects 2%–4% of the adult population1
bstructive Sleep Apnea Syndrome (OSAS) is
characterized by repeated upper airway ob-
and has been described as a major public health
problem.2The association of OSAS with hyperten-
sion (HT) has been noted since the first description
of OSAS in the medical literature.3Approximately
40%–60% of OSAS patients seen in sleep laborato-
ries have HT.4–6This HT rate is two- to three-fold
higher than that in the general population; although
this is a highly select group of patients, early studies
of random groups of hypertensives in the sleep labo-
ratory also disclosed a very high prevalence of OSAS,
ranging from 30%–80%.7–10Furthermore, habitual
snoring, one of the hallmark symptoms of OSAS, has
been reported to be associated with HT in several epi-
demiologic studies.11,12Since OSAS and HT share
certain risk factors, i.e., male gender, obesity, middle
age, and a sedentary lifestyle, questions have been
raised as to how much of this association may be at-
tributable to these confounding variables. This argu-
ment diminishes the importance of the syndrome as a
major public health problem.13This paper reviews
the evidence supporting a causal relationship between
OSAS and HT, discusses some of the mechanisms
that possibly underlie this relationship, and addresses
their clinical implications.
CONTROLLING FOR CONFOUNDERS
As mentioned above, HT and OSAS share the same
risk factors. Figures 1 and 2 illustrate the relation-
ships between HT and body mass index (BMI, ex-
pressed as the square of weight in kg/height in m)
and between HT and the severity of OSAS, as indi-
cated by the respiratory disturbance index (RDI,
expressed as the total number of respiratory distur-
bances during sleep divided by hours of sleep) in
10,000 patients diagnosed in the Technion Sleep
Disorders Center in Israel. The rates of HT linearly
increase as a function of both BMI and RDI.
How can the effects of confounding variables be
disentangled from those of the repeated insult of
multiple episodes of nocturnal apnea? This can be
Obstructive Sleep Apnea and Hypertension:
From Correlative to Causative Relationship
Peretz Lavie, PhD;1Donald Silverberg, MD;2Arie Oksenberg, PhD;2Victor Hoffstein, MD3
From the the Sleep Laboratory, Faculty of
Medicine,Technion-Israel Institute of Technology,
Haifa, Israel;1the Sleep Disorders Unit, Loewenstein
Rehabilitation Hospital, Raanana, Israel;2and Divi-
sion of Respiratory Medicine, St. Michael’s Hospital,
University of Toronto, Ontario, Toronto, Canada3
Address for correspondence/reprint requests:
P. Lavie, PhD, Sleep Laboratory, Gutwirth Bldg.,
Technion-Israel Institute of Technology, Haifa 32000, Israel
Manuscript received January 31, 2001;
accepted March 2, 2001
VOL. III NO. V SEPTEMBER/OCTOBER 2001THE JOURNAL OF CLINICAL HYPERTENSION
achieved either by comparing blood pressure (BP)
in OSAS patients and controls of the same age,
gender, and BMI, as well as all other potential con-
founders, or by using statistical techniques to con-
trol for confounding effects. So far, 47 studies have
examined the association between HT and OSAS,
with attempts to control for potential confounders.
The majority of these studies (36/47; 76.6%) sup-
port an independent association between OSAS
and HT.14 Since disentangling the contribution of
confounding factors from that of repeated apneic
and hypoxemic events requires large populations,
special attention should be given to studies that
have involved exceptionally large populations of
either sleep laboratory patients or randomly sam-
pled subjects. Our group15 analyzed BP data of
2677 patients recorded over a number of years in
St. Michael’s Hospital sleep laboratory in Toronto.
Using either a history of known HT or a cut-off BP
of 140/90 mm Hg, we found that the risk of HT
increased with increasing OSAS severity, as indi-
cated by the RDI or the level of nocturnal arterial
oxygen desaturation. This relationship was inde-
pendent of all potential confounding factors, such
as BMI, age, gender, and comorbidity. There was a
1% increased risk of HT for each respiratory event
per hour of sleep. Later, we reported16that the as-
sociation between HT and OSAS was limited to
patients aged 40–60 years. Grote et al.17similarly
investigated 1190 patients consecutively referred
for diagnosis of sleep-related breathing disorders
and reported that the relative risk of HT, defined
as BP of 160/95 mm Hg, was 4.15 for an RDI of
>40, in comparison with an RDI of <5, and 1.95
for HT defined as BP of >140/90 mm Hg, after
controlling for confounding variables. As our own
results indicated,15the relative risk of HT was
greater for patients under 50 years of age.
In three recent studies, the association between
HT and breathing disorders in sleep was investi-
gated in large, random cohorts of the general pop-
ulation with wide age ranges. Young et al.18
reported that in an unselected population of 1189
state employees in Wisconsin, breathing disorders
in sleep were a risk factor for HT that was inde-
pendent of age, BMI, or gender. Each apneic event
per hour of sleep increased the HT risk in that
population by approximately 4%. Importantly,
their results show that the risk of HT was associ-
ated with the RDI, which was lower than the com-
monly employed cut-off point for OSAS of five or
10 respiratory events per hour. In a 4-year follow-
up study performed in a subsample of 709 of the
original Wisconsin cohort,19the odds ratio (OR)
for the presence of HT at follow-up (compared to
an OR of 1 for an RDI of 0) was 1.42 for an RDI
of 0.1–4.9 at baseline, and 2.03 and 2.89 for RDIs
of 5.0–14.9 and >15, respectively. This relation-
ship was independent of known confounding
Nieto et al.20investigated 6132 subjects aged
>40 years who were recruited from an ongoing
population-based US study (the Sleep Heart
Health Study, discussed below). Sleep was studied
by unattended home sleep recordings, and the as-
sociation between the RDI and HT (defined as BP
of >140/90 mm Hg) was determined. They
showed that after adjustment for confounding
variables, the ORs for HT increased with escalat-
ing RDI categories in a graded dose-response fash-
Figure 1. Relationship between severity of breathing
disorders in sleep, as indicated by the respiratory dis-
turbance index (RDI)—the total number of apneic plus
hypopneic events divided by the total sleep time in
hours—and self-reported hypertension. Data of 10,000
patients diagnosed in the Technion Sleep Medicine
Center in Israel during 1990–2000 are presented.
Figure 2. Relationship between self-reported hyperten-
sion and the degree of overweight based on the World
Health Organization classification of body mass index
(normal, 18.5–24.9 kg/m2; overweight, 25.0–29.9
kg/m2; obesity class 1, 30.0–34.9 kg/m2; class 2,
35.0–39.9 kg/m2; class 3, >40 kg/m2). Data of 10,000
patients diagnosed in the Technion Sleep Medicine
Center in Israel during 1990–2000 are presented.
THE JOURNAL OF CLINICAL HYPERTENSIONVOL. III NO. V SEPTEMBER/OCTOBER 2001
ion. Comparison of the highest category of RDI
(>30 per hour) with the lowest (<1.5 per hour)
yielded an OR of 1.37.
Bixler et al.21studied the relationship between
HT and sleep-disordered breathing in 1000
women and 741 men sampled from a much larger
population with specific risk factors for sleep-dis-
ordered breathing. They reported an independent
association between sleep-disordered breathing
and HT that was strongest in young individuals,
especially those of normal weight. The association
was not significant, or was inverted, among older
In addition to these large population studies,
Davies et al.,22in a case-controlled study of 24-hour
ambulatory BP measurements in 45 patients with
OSAS and 45 normal matched controls, recently
found that the OSAS patients had higher diastolic BP
during the day and night, and higher systolic BP at
EFFECTS OF OSAS TREATMENT ON HT
If there is a causative relationship between OSAS
and HT, effective treatment of OSAS can be ex-
pected to reduce daytime or 24-hour levels of BP
in apneic patients. Several studies have provided
support for this. Mayer et al.23reported that 6
months of treatment with nasal continuous posi-
tive airway pressure (nCPAP) significantly de-
creased BP, both during sleep and wakefulness, in
12 patients with severe OSAS. This change could
not be explained by a change in BMI.
Suzuki et al.24performed ambulatory BP monitor-
ing for 48 hours in normotensive and hypertensive
OSAS patients before and after CPAP treatment and
reported a significant decrease in daytime and night-
time BP, but only in hypertensive patients. A possible
selective effect of nCPAP treatment on OSAS pa-
tients was also reported by Engelman et al.,25who
observed a significant improvement in mean daytime
arterial BP only in a subgroup of patients defined as
“nondippers” under placebo treatment conditions.
Others also reported that nCPAP treatment restored
the normal circadian pattern of nocturnal “dipping”
in OSAS patients.26Wilcox et al.,27on the other
hand, showed a significant drop in mean 24-hour BP
in both normotensive and hypertensive patients after
nCPAP treatment. Only diastolic BP, however, was
decreased during the day. Akashiba et al.28reported
that 2 weeks of nCPAP treatment was sufficient to
reduce waking systolic and diastolic BP in 31 OSAS
patients. Minemura et al.29reported that the daytime
and nighttime decreases in BP after nCPAP treatment
were accompanied by significant decreases in day-
time and nighttime levels of urinary noradrenaline.
Interestingly, in comparing the effects of nCPAP
treatment with those of a placebo (nCPAP adminis-
tered at ineffective pressure) on 24-hour BP in OSAS
patients, Dimsdale et al.30found that both treat-
ments reduced daytime BP levels to the same degree,
while only effective nCPAP treatment significantly
reduced nighttime BP. Voogel et al.31measured BP
for 24 hours in OSAS patients before and after 3
weeks of CPAP treatment, in a tightly controlled en-
vironment and with a control group. They showed
reductions in daytime and nighttime BPs only in the
treated OSAS group.
Berger et al.32studied positional OSAS patients
(those in whom most apneic events occurred in
the supine position) and found that avoidance of
the supine posture during sleep for a 1-month pe-
riod resulted in a significant fall in mean 24-hour,
sleeping, and waking BPs.
Perhaps the most convincing evidence that OSAS
can cause HT is found in animal models.33Investi-
gators in Toronto34mechanically produced OSAS
in four dogs. Within a few weeks, the daytime and
sleeping systemic BPs rose and, when they stopped
the apneic events, the BPs reverted to normal with-
in another few weeks. Here, obviously, there were
no “confounding variables.” Persistent HT can also
be produced in animals by intermittent exposure to
hypoxia for several days.34
Acute Effects of OSAS on BP
A patient with severe OSAS can have 400–600 ab-
normal breathing events during the night. Most of
these events are terminated by a brief “arousal”
(lasting several seconds but unnoticed by the pa-
tient), which is associated with an increase in sys-
temic BP.35Because these surges in BP occur so
frequently during the night, the net result is an
increase in mean overall BP in OSAS patients
throughout the night.
In addition to the surges of systemic BP, each
short arousal, which signals the end of an apneic or
hypopneic event, is associated with an increase in
heart rate, pulmonary artery BP, and sympathetic
activity, all lasting for several seconds. There is still
disagreement as to what is the major trigger of the
arousal—the hypoxia, the hypercapnia, or the in-
creased respiratory effort. It is likely that the arousal
is multifactorial in origin and that all three of these
factors, as well as others as yet unidentified, con-
tribute to its occurrence.
Chronic Effects of OSAS on BP
What are the possible mechanisms by which these
intermittent surges of BP that occur at the end of ab-
VOL. III NO. V SEPTEMBER/OCTOBER 2001 THE JOURNAL OF CLINICAL HYPERTENSION
normal respiratory events eventually lead to perma-
nently elevated BP during the waking hours?
One hypothesis put forward during the early
1990s to explain the persistence of high BP during
the daytime concerns increased sympathetic activity,
which frequently accompanies OSAS, both during
sleep36and waking.37OSAS patients have reduced
baroreceptor sensitivity and increased chemorecep-
tor sensitivity,38both of which could explain the
persistent increase in sympathetic activity.39Systolic
blood pressure is significantly correlated with mus-
cle sympathetic nerve activity (MSNA). Somers et
al.40confirmed these findings and also showed that
sympathetic nerve activity further increased during
sleep in OSAS patients. Interestingly, in 1998,
Narkiewicz et al.41reported that obesity alone, in
the absence of OSAS, is not accompanied by in-
creased sympathetic activation and that treatment
with nCPAP decreased sympathetic activation dur-
ing sleep. Waradekar et al.42recorded waking
MSNA in seven OSAS patients before and after 1
month of treatment with nCPAP, and showed a de-
crease in MSNA that was linearly related to the
nightly use of nCPAP. Tonic activation of excitatory
chemoreflex afferents appeared to contribute to in-
creased daytime MSNA.43,44Thus, in addition to its
effects on BP, effective nCPAP treatment has been
shown to decrease daytime MSNA in OSAS pa-
tients. This effect, however, was evident only after
an extended period of therapy.45
Perhaps as a result of the combination of inter-
mittent HT, increased sympathetic activity, and
hypoxia that occurs with apneic events hundreds
of times a night over a period of several years,
there is an increase in systemic vascular reactivity
in OSAS. The vasoconstrictor response to an-
giotensin II in the forearm vasculature of OSAS
patients is enhanced.46Remsburg et al.47showed
that OSAS patients have an abnormal peripheral
vascular response to isocapnic hypoxia. Kato et
al.48demonstrated impairment of resistance-vessel
endothelium-dependent vasodilatation in OSAS
patients. Duchna et al.49found blunted vasodila-
tory responsiveness to bradykinin in OSAS pa-
tients, which was reversed by nCPAP treatment.
Recent studies have also shown that OSAS pa-
tients have reduced levels of nitric oxide, the most
potent naturally occurring vasodilator.50,51Circulat-
ing levels of nitric oxide were approximately one
half those measured in controls, and significantly in-
creased after nCPAP treatment. Stepwise multiple
linear regression with systolic and diastolic BP as the
dependent variables identified nitric oxide as the
only significant correlate. Similar results were ob-
tained in our laboratory (Lavie et al., manuscript in
preparation); measurement of circulating levels of
nitric oxide at hourly intervals during the night in
OSAS patients and controls revealed that OSAS pa-
tients had consistently lower levels.
Thus, a cascade of events occurs in OSAS by
which the peripheral vasculature is progressively
damaged by chronic exposure to surges of hyper-
tension, sympathetic activity, and hypoxia. The
associated endothelial dysfunction promotes fur-
ther vasoconstriction and this leads to chronic
The accumulated findings from large-scale studies of
sleep laboratory-diagnosed OSAS patients monitored
with all-night polysomnography, as well as studies of
random cohorts of the general population, case-con-
trolled studies, and intervention studies, all suggest
that OSAS constitutes a major contributor to the de-
velopment of HT. In 1995, our group52reported that
HT was a significant independent predictor of car-
diopulmonary mortality in OSAS patients. The re-
cently reported US Sleep Heart Health Study53
demonstrated that OSAS is an independent risk factor
not only for HT but also for heart failure, stroke, and
coronary heart disease. These findings have important
clinical implications concerning diagnosis and treat-
ment of OSAS patients, as well as patients with essen-
tial HT. At the time of OSAS diagnosis, more than
one quarter of the patients were already aware of
having HT. This is probably an underestimation of
the true prevalence of HT among OSAS patients,
since a large number of patients have elevated BP
without being aware of it. Figure 3 depicts the per-
centage of OSAS patients who reported having HT at
Figure 3. Comparison between the percentage of pa-
tients with breathing disorders in sleep who reported
on hypertension or used antihypertensive medications
and the percentage of patients who were found to have
blood pressures >140/90 mm Hg either during morning
or evening measurements. Data of 2677 adult patients
diagnosed in St. Michael’s Hospital Sleep Laboratory
in Toronto are presented.
THE JOURNAL OF CLINICAL HYPERTENSION VOL. III NO. V SEPTEMBER/OCTOBER 2001
the time of their diagnosis, and the percentage who
were found to have BP levels of >140/90 mm Hg by
objective measurements obtained just before sleep
monitoring. Thus, the actual percentage of patients
with elevated BP is much higher than the percentage
of patients who report a history of HT.
Another clue to the presence of OSAS may be
refractoriness to antihypertensive therapy. There
is evidence that hypertensive OSAS patients are
more resistant to antihypertensive therapy than
non-OSAS patients with HT.54–57This phenome-
non may extend to the sleeping as well as the
waking BP. On the other hand, as was mentioned
before, nCPAP effectively lowers BP in hyperten-
sive OSAS patients, and in one study,58 termina-
tion of CPAP treatment resulted in an immediate
increase in BP.
Currently, most OSAS patients are referred to a
sleep laboratory for diagnosis only after experienc-
ing symptoms severe enough to affect their quality
of life, or when they attract the attention of family
members (usually because of loud snoring). Snorers
themselves, even with clear daytime sleepiness, are
reportedly passive in terms of seeking medical help
for their symptoms.59The average age of patients
diagnosed in sleep laboratories is approximately 50
years. The impact of the apnea on the cardiovascu-
lar system is gradual and cumulative. If we assume
that in most patients the interval from the first ap-
pearance of frequent apneic events during sleep to
the formal diagnosis of OSAS is about 10 years, by
the time of diagnosis it may be too late to prevent
the impact of the apnea on the cardiovascular sys-
tem. The Wisconsin data and those of the Sleep
Heart Health Study demonstrated that even a very
mild breathing disorder in sleep is associated with a
significant HT risk. Thus, a proactive attitude to-
ward the diagnosis of OSAS should be taken. In-
stead of waiting for patients to complain about
heavy snoring and excessive daytime sleepiness,
physicians should actively seek out symptoms sug-
gestive of OSAS in all patients. In view of the close
associations between OSAS and obesity, HT, and a
family history of OSAS, those with these three risk
factors in particular should be questioned routinely
about symptoms of sleep-related breathing disor-
ders. The three most important subjects on which to
question patients are:
1) Snoring. Do you snore a lot, and is the snoring
independent of the body position? Is the snoring
quiet and steady (which suggests that it is mild in na-
ture) or loud, of variable intensity, and with many
gasps or grunts (suggesting that it is more severe and
accompanied by apneic episodes)?
2) Excessive daytime sleepiness. Do you tend to
fall asleep quickly during passive activities, such as
reading an interesting book, watching an interesting
television program, or driving a car? Sometimes the
complaint may be “fatigue” or “tiredness” rather
3) Apneic episodes at night. Does your bed part-
ner or other family member say that you stop
breathing or gasp a lot during sleep?
Starting effective treatment at the earliest possible
age may prevent the cumulative impact of the apnea
on the cardiovascular system, as well as improve pa-
tients’ wakefulness and quality of life.
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