Sleep Medicine 8 (2007) 668–680

www.elsevier.com/locate/sleep

Role of sleep-wake cycle on blood pressure circadian rhythms

and hypertension
a,*
Michael H. Smolensky , Ramón C. Hermida b, Richard J. Castriotta c,
Francesco Portaluppi d
a
School of Public Health, RAS-W606, The University of Texas-Houston Health Sciences Center, 1200 Herman Pressler, Houston, TX 77030, USA
b
E.T.S.I. Telecomunicación, Campus Universitario, VIGO (Pontevedra) 36200, Spain
c
Division of Pulmonary, Critical Care and Sleep Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin,
MSB 1.274 Houston, TX 77030, USA
d
Hypertension Center, University of Ferrara Via Savonarola 9, I-44100 Ferrara, Italy

Received 23 June 2006; received in revised form 8 November 2006; accepted 11 November 2006
Available online 26 March 2007

Abstract

Stages of different depth characterize the temporal organization of sleep. Each stage exerts an effect on blood pressure (BP) reg-
ulation and contributes to its 24-h variation. The main determinant of the circadian influences of sleep and wakefulness on BP is the
daytime sympathetic and nighttime parasympathetic prevalence, but many other physiologic mechanisms known either to induce
sleep or determine arousal may play an important role in the mediation of sleep influences on BP. Alteration of one or more of such
mechanisms may be reflected in altered circadian BP rhythms. Sleep- and arousal-related mechanisms and phenomena that affect
circadian BP rhythms include neurohumoral sleep factors (arginine vasopressin, vasoactive intestinal peptide, somatotropin, insulin,
steroid hormones and metabolites, and serotonin among others) and waking factors (corticotropin-releasing factor, adrenocortico-
tropin, thyrotropin-releasing hormone, endogenous opioids, and prostaglandin (E2)). Pathologic respiratory variations (sleep-disor-
dered breathing) and insomnia are major causes of the sleep-related alteration of the circadian BP profile, including loss of the
expected normal decline in BP by 10–20% from the daytime level. A great number of medical disorders can cause insomnia, but
objective sleep studies have been performed only in a minority of them. Overall, the sleep-related pathophysiological mechanisms
actually involved in causing altered circadian BP rhythms in different normotensive and hypertensive conditions are not completely
understood. In any case, changes in the circadian BP rhythm are known to be strongly related to one’s risk of cardiovascular mor-
bidity and mortality, thus representing strong prognostic indicators worthy of further investigation.
Ó 2007 Elsevier B.V. All rights reserved.

Keywords: Circadian rhythm; Sleep; Blood pressure; Essential hypertension; Secondary hypertension; Autonomic nervous system; Autonomic
failure; Sleep-disordered breathing; Insomnia

1. Introduction

Day–night patterns in blood pressure (BP) are closely

*
Corresponding author. Tel.: +1 713 500 9237; fax: +1 713 500
9249.
E-mail addresses: michael.h.smolensky@uth.tmc.edu (M.H.
Smolensky), rhermida@tsc.uvigo.es (R.C. Hermida), Richard.J.
Castiotta@uth.tmc.edu (R.J. Castriotta), prf@unife.it (F. Portaluppi).
tied to the 24-h sleep-wake cycle and are influenced by
several endogenous circadian rhythms as well as cyclic
exogenous factors. Moreover, a number of sleep disor-
ders and acute and chronic medical conditions can alter
BP and cause hypertension. Exploration of the topics of
sleep, BP circadian rhythms, and hypertension requires

1389-9457/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.sleep.2006.11.011
 M.H. Smolensky et al. / Sleep Medicine 8 (2007) 668–680
an understanding of the (i) different types of 24-h BP
patterns found in health and disease, (ii) circadian
rhythm and cyclic environmental determinants of such
BP changes, and (iii) definition of hypertension, taking
into account inherent 24-h activity-sleep BP variation.
2. Day–night patterns in blood pressure
The conventional, homeostatic perception is that BP
and heart rate (HR) are relatively constant during the
24-h sleep–wake cycle, except when affected by exercise,
stress, and other ambient influences. Thus, in the
absence of medical complications, such as diabetes or
renal disease, the conventional criteria recommended
for the diagnosis of hypertensive persons is the clinical
diastolic BP (DBP) consistently P90 mmHg and/or
the clinical systolic BP (SBP) consistently P140 mmHg
[1].
However, DBP and SBP in actuality undergo rather
large amplitude 24-h patterning, as documented by
ambulatory BP monitoring (ABPM) technology, which
enables the convenient and reliable automatic around-
the-clock measurement of BP and HR. ABPM criteria
for the differential diagnosis of normotension versus
hypertension differ from conventional ones. The diagno-
sis of hypertension by means of 24-h ABPM is made
when the activity mean SBP P135 mmHg and/or DBP
P 85, sleep-time mean SBP P120 mmHg and/or DBP
P70 (often termed nocturnal hypertension), or 24-h
mean SBP P130 mmHg and/or DBP P80 mmHg [2].
In persons with normal BP and uncomplicated essen-
tial hypertension, BP declines to its lowest levels during
nighttime sleep, rises abruptly with morning awakening,
and attains near peak or peak values during the first
hours of diurnal activity [3]. In the so-called normal dip-
pers, the sleep-time BP mean is lower by 10–20% com-
pared to the daytime mean [4]. In addition to this
profound, sleep-related nocturnal decline, the typical
circadian pattern of BP exhibits two daytime peaks,
the first around 9 a.m. and the second around 7 p.m.,
with a small afternoon nadir around 3 p.m. In healthy
young adults, the immediate morning rise of SBP
amounts to about 20–25 mmHg. However, in the
elderly, who have less compliant and elastic arteries,
the morning rise in SBP can be as great as 40–60 mmHg.
Bed-bound subjects, whether normotensive [5] or hyper-
tensive [6], and persons with fixed HR [7] also exhibit
significant BP decline during sleep, which is more pro-
nounced for women than men [8], attesting to the role
of an endogenous circadian mechanism in BP
regulation.
Other 24-h BP patterns are also known. Non-dipping
(<10 mmHg decrease in sleep-time BP mean relative to
daytime mean) and even rising (mean sleep-time BP
greater than daytime mean) patterns are common in sec-
ondary hypertension, that is, hypertension caused by a
669
co-existing medical condition. Super-dipping BP pat-
terns (> 20 mmHg decrease in sleep-time BP mean rela-
tive to daytime mean) may occur in those with
autonomic dysfunction or those treated too aggressively
with antihypertensive medications, particularly when
ingested in the evening, or in those persons who evidence
‘white coat’ – pseudohypertension, which is abnormally
high BP only in the presence of medical personnel in
clinical settings [9], and who are treated aggressively
with BP-lowering medications.
Alteration of the circadian rhythm of the neurohu-
moral factors that affect the autonomic nervous and car-
diovascular (CV) systems, secondary to various
pathological conditions, results in persistent change of
the 24-h BP pattern. A blunted or reversed sleep-time
decline in BP has been reported in persons with ortho-
static autonomic failure [10], Shy-Drager syndrome
[11], vascular dementia [12], Alzheimer-type dementia
[13], cerebral atrophy [14], cerebrovascular disease
[15,16], ischemic arterial disease after carotid endarter-
ectomy [17], neurogenic hypertension [18], fatal familial
insomnia [19], diabetes [20], catecholamine-producing
tumors [21,22], Cushing’s syndrome [23], exogenous glu-
cocorticoid administration [24], mineralocorticoid
excess syndromes [25], Addison’s disease [26], pseudohy-
poparathyroidism [27], sleep apnea syndrome [28], nor-
motensive and hypertensive asthma [29], chronic renal
failure [30,31], severe hypertension [32], salt-sensitive
essential hypertension [33], gestational hypertension
[34], toxemia of pregnancy [35], essential hypertension
with left ventricular hypertrophy [36], renal, liver, or
cardiac transplant [37–39] related to immunosuppressive
treatment, congestive heart failure [40,41], and recombi-
nant human erythropoietin therapy [42]. A circadian
profile characterized by daytime hypertension and
sleep-time hypotension has been described in hemody-
namic brain infarction associated with prolonged distur-
bance of the blood–brain barrier [43]. In these patients,
the range of variation in the BP level between daytime
activity and nighttime sleep is significantly increased
from expected – to 20% for SBP and 23% for DBP.
3. Mechanisms of 24-h BP patterns
The 24-h BP variation is primarily the result of the (i)
exogenous cyclic day–night alteration of physical and
mental activity, stress, and other ambient events coupled
with the sleep–wake cycle and (ii) endogenous circadian
rhythms in neurohumoral and other biological func-
tions. Although it is argued that the former are more
important than the latter, it is impossible to clearly sep-
arate their relative influence upon the BP 24-h variation.
For sure, the effects of physical and mental activity
account for a predominant proportion of the day–night
variation [44–46] as demonstrated by studies of shift
workers who show a close linkage between activity
670 M.H. Smolensky et al. / Sleep Medicine 8 (2007) 668–680
and BP even on the first 24-h of night work [47–51].
However, an intrinsic component of human circadian
BP rhythmicity, which is masked by external influences,
also plays a role [52]. An endogenous basis for the 24-h
BP variation, that is, a relationship between the circa-
dian clock and the BP rhythm, is suggested by labora-
tory rodent studies showing that lesioning of the
suprachiasmatic nucleus (the master pacemaker clock)
abolishes the BP and HR circadian rhythms without
affecting the sleep–wake and motor activity cycles
[53,54]. Rodents are nocturnally active animals and
show increased nighttime BP values compared to
decreased daytime BP values during their rest period.
Thus, the relationship of BP level to activity level is
underlined in both human beings and laboratory
rodents.
The mechanisms of 24-h BP patterns are clearly influ-
enced also by genetic factors. Using standard quantita-
tive genetic variance component analysis of 260
healthy siblings without antihypertensive medications
from 118 Swedish families, Fava et al. [55,56] demon-
strated that circadian BP variability, and in particular
nighttime BP level, assessed by ambulatory monitoring,
are under genetic control. Hence, BP dipping is a herita-
ble trait which can be mapped by linkage analysis.
Genetic control of arterial stiffness is the likely mecha-
nism of this heritability [55,56].
The sleep–wake cycle is a coordinated process involv-
ing rhythmic changes in sensory, motor, autonomic,
endocrine, and cerebral processes. However, each of
the changes occurring with sleep may also occur inde-
pendently of sleep itself [57]. Hence, sleep seems to be
a biological process or system that integrates and mod-
ulates a variety of other systems. The sleep–wake cycle
results from the alternation of mutually inhibitory inter-
actions of arousing or activating systems (cholinergic,
serotonergic, and histaminergic nuclear groups of the
rostral pons, midbrain, and posterior hypothalamus
plus cholinergic neurons in the basal forebrain) and of
hypnogenic or deactivating systems on the other hand
(medial preoptic–anterior hypothalamic region and
adjacent basal forebrain and medial thalamus and
medulla). Cyclic variation in autonomic nervous system
(ANS) activity plays an important role not only in the
mechanism of the sleep–wake rhythm, but also in medi-
ating the influence of sleep and wakefulness on CV func-
tion and BP, in general.
Serotonin, arginine vasopressin, vasoactive intestinal
peptide, somatotropin, insulin, and steroid hormones
and their metabolites are involved in the induction of
sleep, and CRF, ACTH, TRH, endogenous opioids,
and prostaglandin E2 are involved in activation and
arousal. The cyclic 24-h pattern in these chemical medi-
ators is bound to be reflected in the phasic oscillations of
BP and CV parameters. It is common knowledge that
most biologically active substances (e.g., hormones, pep-
tides, neurotransmitters, etc.) exhibit significant circa-
dian variation in their secretory pattern that is
superimposed on their feedback control systems. While
the secretion of these substances is typically episodic, it
is probable that the secretory episodes are ‘‘gated’’ by
mechanisms that are coupled either to sleep itself, or
to an endogenous pacemaker which usually is predomi-
nantly (though not solely) circadian.
4. Neuroendocrine integration of BP rhythms
Circadian rhythms in ANS function are well known;
sympathetic tone is dominant during the diurnal activity
span, while vagal tone is dominant during most of the
nighttime sleep span [58–61]. This day–night oscillation
of the ANS is strongly linked to the sleep–wake circa-
dian rhythm and plays a dominant role in the observed
24-h BP variation in normotension and in uncompli-
cated essential hypertension. In diurnally active persons,
the plasma level of norepinephrine and epinephrine is
highest in the morning, during the initial hours of day-
time activity and is lowest during nocturnal sleep [62].
Urinary catecholamine excretion also exhibits marked
circadian rhythmicity of comparable phasing [63]. The
relationship between the 24-h variation in plasma dopa-
mine and norepinephrine/epinephrine levels is strong,
indicating a dopaminergic modulation of the circadian
rhythm of sympathetic nervous system activity [64].
In humans, catecholamine sulfates are biologically
inactive. In normotensive recumbent subjects, the circa-
dian pattern is opposite that of the biologically active
free catecholamines [65]. Plasma noradrenaline and
adrenaline sulphates peak during the initial portion of
the sleep span. Before the customary time of daytime
awakening, the concentration of both free noradrenaline
and adrenaline suddenly increases, while their sulpho-
conjugate counterparts decline. Thus, the nocturnal
decrease in the level of biologically active catechola-
mines may be the consequence of the activation of an
endogenous system of sulphoconjugation; conversely,
deactivation of the same system late during the sleep
span may contribute to the significant morning increase
in the concentration of biologically active catechola-
mines. The genetic control of catecholamine sulphocon-
jugation and deconjugation is primarily accomplished
by two enzymes – phenolsulphotransferase and aryl sul-
phatase [65]. Temporal modulation of the gene expres-
sion of these enzymes most likely contributes to the
circadian rhythm in sympathetic activity.
Environmental factors, especially the alternation of
light and darkness in conjunction with the activity-sleep
cycle, significantly influence the day–night pattern of
catecholamine concentration. The level of norepineph-
rine, but not epinephrine, is strongly affected by activity,
arousal, and posture [66]. The circadian rhythm in the
plasma norepinephrine metabolite, 3-methoxy-4-
 M.H. Smolensky et al. / Sleep Medicine 8 (2007) 668–680
hydroxyphenylglycol, also is evoked by day–night differ-
ences in physical activity and posture. In contrast, the
24-h pattern in the plasma dopamine metabolites,
homovanillic acid and 3,4-dihydroxyphenylacetic acid,
is regulated by a circadian oscillator that is unaffected
by the sleep-activity cycle [67]. Indeed, the nocturnal
decrease in norepinephrine is observed even in healthy
volunteers kept awake for 24 hours by a regimented rou-
tine of forced activity and food consumption every hour.
These findings suggest the circadian change in norepi-
nephrine secretion is controlled by a biological clock
whose activity is apparent only when the influence of
sleep, posture, and activity is removed [68]. Nonetheless,
the evidence is compelling that the observed 24-h
changes in ANS activity and biogenic amines are not
explained by a single controlling influence. Temporal
patterns in external stimuli are at least as, if not more,
important than endogenous clock mechanisms. Finally,
other humoral factors, such as those of the renin–angio-
tensin–aldosterone system, the hypothalamic–pituitary–
adrenal system, the hypothalamic–pituitary–thyroid sys-
tem, the opioid system, and various vasoactive peptides,
are well known to affect the circadian organization of
the CV system and BP circadian rhythm (for a review
on this subject, see [69]).
Disturbances of the circadian rhythm of ANS activity
and neurohumoral factors that play a role in central
and/or peripheral BP regulation result in alteration of
the typical 24-h BP pattern. An imbalance of sympa-
thetic versus parasympathetic activity is the major deter-
minant of the alteration. This is true not only for the
various forms of neurogenic dysautonomias but in dia-
betes and chronic renal failure in which change in the
circadian BP pattern is minimal [70] or absent [71]
before the onset of autonomic neuropathy. In chronic
heart failure, tonic activation of the sympathetic ner-
vous system throughout both the activity and sleep
spans is present and seems to be the major determinant
of changes to the BP rhythm. Experiments on labora-
tory rats demonstrate that the altered BP 24-h pattern
of heart failure is independent of changes in the locomo-
tor activity rhythm [72]. An identical imbalance of the
circadian rhythm of autonomic activity has been dem-
onstrated in essential hypertensive patients who exhibit
a blunted sleep-time BP decline [73]. However, absence
of the normal sleep-time BP fall does not necessarily
imply an obliteration of the 24-h BP rhythm, as seen
in chronic renal insufficiency [74]; in individuals with
this medical condition, a significant BP circadian
rhythm of reduced amplitude and shift from a day to
sleep-time peak (i.e., reversed dipping pattern) is
common.
A non-dipping BP pattern is also found in those diag-
nosed with the rare medical condition of fatal familial
insomnia (FFI), a prion disease characterized by the
total and sustained disruption of the sleep–wake cycle
671
[75]. This condition constitutes a unique, albeit dra-
matic, opportunity to assess the effect of chronic sleep
deprivation on human circadian rhythms, including
those of BP and HR. In FFI, a dominant 24-h rhythm
is detectable in both CV parameters [19], but the noctur-
nal BP decline is lost during the early stage of the dis-
ease, even though the normal nocturnal HR decline is
preserved. This rhythmic component persists, although
with lower amplitude and shifted phase, for several
months after the total disappearance of sleep. Complete
obliteration of significant 24-h variation is found only
during the terminal stage of FFI. Important features
of FFI are the progressive alterations of neurohormonal
[76,77] and CV rhythms [19], indicating it disturbs, and
eventually obliterates, the endogenous circadian-time
structure. Changes in pituitary–adrenal functioning
seem to play a major role in the pathogenesis of the
hypertensive condition of FFI [19].
5. Circadian organization of human sleep
Normal sleep consists of the non-rapid eye movement
(NREM) and rapid eye movement (REM) states.
NREM predominates during the first half of nighttime
sleep and typically constitutes 75–80% of the total sleep
time. In contrast, REM sleep, which is associated with
dreaming, predominates during the second half of the
sleep span and typically comprises 20–25% of the total
sleep time. The normal adult human enters sleep
through NREM sleep, and typically the first REM sleep
episode does not occur until 80–90 min later. Thereafter,
NREM and REM sleep alternate cyclically with a per-
iod of 80–90 min. The duration and organization of
sleep are strictly circadian-time dependent [78]. REM
sleep, although characterized by poikilothermia, is nev-
ertheless closely coupled with the circadian rhythm of
core temperature [79], which in turn is controlled by
the biologic clock (SCN), independent of the sleep per-
iod [80,81].
6. Role of sleep in circadian BP variation
Sleep is the most important and consistent source of
circadian BP variation. Sleep stages are reflected by con-
sistent changes in BP [82]. The deepest sleep stages, 3
and 4, coincide with the lowest BP levels; whereas, the
less deep stages, 1 and 2 and REM sleep, correspond
to relatively higher BP levels, although these are lower
than awake-state BP level. Fluctuations in BP, amount-
ing to as much as 40 mmHg during REM sleep, do not
originate in the sleep-induction (pontine tegmental) area
of the brain of REM sleep itself; rather, they originate in
the forebrain and, thus, are likely to be uninfluenced by
sleep [83].
A significant BP increase takes places in the morning
in diurnally active persons, and there is considerable
672 M.H. Smolensky et al. / Sleep Medicine 8 (2007) 668–680
debate as to whether it commences before or after awak-
ening and as a consequence of arousal from sleep and
change from supine to upright posture [84]. It is difficult
to determine the precise timing of the arousal status of
individuals who make up group studies, and this might
explain the different interpretations of the BP curves
by authors of various investigations. Deep (delta or
slow-wave) sleep prevails during the first half of night-
time rest, and this is coincident with the nocturnal BP
decline. During the last half of nighttime sleep, REM-
related and brief arousal-related episodes of BP and
HR rises are more frequent. This is the likely explana-
tion of why intra-arterial data for a large group of nor-
mal subjects, aligned relative to the time of waking,
show that the early morning rise of BP commences prior
to awakening; thus, its attribution to arousal alone
seems highly implausible. Wrist actigraphy, a tool com-
monly used in sleep studies, has helped identify two dis-
tinct patterns of morning BP rise – one being defined by
a gradual rise that commences before awakening as seen
most commonly in young persons, and the other being
defined by a steep BP rise that commences after waking
as seen most commonly in elderly persons showing pro-
nounced responses to mental stress [85]. A growing
number of studies indicate that the extent of the BP rate
of rise coincident with the commencement of diurnal
activity constitutes an independent predictor of hyper-
tensive target organ damage and risk of acute CV events
at this time of day [9,86]. Recent investigations reveal
that the 24-h pattern and the characteristic morning
peak in the occurrence of both ischemic [87] and hemor-
rhagic [88] stroke is the same in normotensive and
hypertensive persons. Moreover, other CV events, such
as acute aortic dissection, display prominent 24-h varia-
tion, with a significant morning peak, both in hyperten-
sive and normotensive subjects [89]. Taken together,
these observations favor the hypothesis that the magni-
tude of the morning BP surge (whether in the presence
or absence of hypertension) is a crucial determinant of
one’s risk to rupture of a vulnerable and critically weak-
ened arterial wall [90].
Important additional influences of sleep on BP may
be exerted through variation in respiration. During sleep
onset and light NREM sleep, breathing often becomes
periodic with sporadic central apneas. Oscillations of
3–5 s and 20–30 s in breathing are synchronous with
oscillations of cortical electroencephalographic (EEG)
activity, BP, HR, and oxygen saturation. During deep
NREM sleep, breathing becomes regular, and BP and
HR decline. During REM sleep, breathing and HR
become irregular and central apneas or hypopneas last-
ing a few seconds occur sporadically, often in associa-
tion with bursts of REM. Hypertensive peaks,
sometimes as great as 30–40 mmHg from baseline, occur
abruptly and continue for the entire duration of the
REM episode. During sleep, alveolar ventilation
decreases by 0.4–1.5 l/min and pulmonary arterial pres-
sure rises by 4–5 mmHg, but, nonetheless, remain within
the normal range. Changes in the sensitivity and func-
tioning of homeostatic mechanisms account for the
oscillatory phenomena which also occur, with similar
periodicity, in other pathophysiologic states [91,92] or
with sleep onset [93]. The instability associated with
the transition from the mixed (neurogenic and meta-
bolic) control of breathing typical of wakefulness to
the purely metabolic state typical of NREM sleep is
the underlying cause of the periodic oscillations [94].
7. Sleep-related alterations of the circadian BP profile
Stage organization of sleep is also reflected in varia-
tions of autonomic functioning [60]. On the other hand,
a driving effect of the ANS on the circadian BP profile is
well established [95–97]. Sympathetic-nerve activity dur-
ing deep NREM sleep is lower than it is during wakeful-
ness. It increases during REM sleep to the same, or
greater, level seen in wakefulness. During NREM sleep,
the activity of the sympathoadrenal branch of the sym-
pathetic nervous system decreases, probably due to
entrainment to the sleep–wake cycle; whereas, the low
activity of the noradrenergic branches seems mainly
dependent on the assumption of horizontal body pos-
ture during sleep [98]. Sympathetic nervous system activ-
ity, overall, seems to be down-regulated during REM
sleep, whereas awakening selectively enhances epineph-
rine levels and subsequent orthostasis activates promi-
nently the noradrenergic branches [98]. During REM
sleep, a concomitant reduction in coronary blood flow
[99] and increased occurrence of coronary spasm [100]
can be demonstrated. Not surprisingly, therefore,
REM sleep is associated with an elevated risk of myo-
cardial ischemia in individuals with coronary artery dis-
ease or vasospastic angina [100,101]. Thus, REM sleep
constitutes a period of potential CV risk due to the dra-
matic phasic sympathetic, BP, and HR fluctuation.
Loss or reversal of the expected normal physiologic
sleep-time BP decline may result from a large number
of medical disorders that can cause insomnia. Unfortu-
nately, objective studies have not been performed in the
majority of these conditions, even though polysomno-
graphic data demonstrating sleep disturbances are avail-
able in CV diseases [102,103], autonomic failure [11,104–
107], rheumatoid arthritis possibly in relation to cortico-
steroid therapy [108,109], chronic renal failure [110],
hyperthyroidism [111], Cushing’s disease, exogenous
glucocorticoid administration [112–115], and FFI
[116,117]. It is worth mentioning that sleep disturbances
may be induced also by a variety of acute and chronic
common medical conditions, such as allergic rhinitis
(sleep-time exacerbation of nasal obstruction often
accompanied by sleep-disordered breathing) [118,119],
atopic dermatitis [120,121], asthma (which occurs
 M.H. Smolensky et al. / Sleep Medicine 8 (2007) 668–680
nocturnally in 75% or so of sufferers) [122,123], osteoar-
thritis (an arthritic condition characterized by inflamma-
tion and pain that builds during the course of daytime
activity and in many is most severe at night) [124],
chronic pain syndrome (pain threshold is lowest over-
night) [125], peptic ulcer disease and gastric–esophageal
reflux disorder (which tend to be most severe in the late
evening and very early morning hours after midnight)
[126], congestive heart failure (dyspnea and increased
work of breathing become worse overnight) [127], noc-
turnal polyuria [128–130], and voluntary chronic sleep
loss/deprivation [131]. If chronic, these medical condi-
tions result in persistent sleep onset insomnia and/or dis-
turbed and discontinuous nighttime sleep, and, as a
consequence, increased risk of higher than normal noc-
turnal BP levels (i.e., nocturnal hypertension) and end-
organ injury to the blood vessels, brain, eye, kidney,
and heart. It is usually assumed that discomfort is the
major cause of poor sleep, sometimes leading to a gener-
alized stress from disruption of sleep [132–134].
Although relatively little is known of the pathophysio-
logic mechanisms involved in the genesis of the sleep dis-
turbances of many of these pathologic conditions,
circadian processes have been determined to play a dom-
inant role in the pathophysiology in some; however, this
is beyond the scope of this article. On the other hand,
two conditions, namely sleep-disordered breathing and
autonomic failure, for which the relationships between
sleep and BP have been extensively, though not com-
pletely, investigated, are reviewed below in detail.
8. Sleep-disordered breathing and circadian BP profile
Sleep-disordered breathing includes snoring and sleep
apnea [135] and upper airway resistance syndrome
(UARS) [136]. These can be distinguished from primary
snoring disorder (PSD), in which there is snoring with-
out apneas, hypopneas, hypoventilation, sleep disrup-
tion, or daytime sleepiness. An obstructive apnea in
adults is a complete cessation of airflow lasting P5 s
with continued effort to breathe; a hypopnea is P50%
decrease in airflow for P5 s; and a respiratory-related
arousal (RERA) is a transient arousal which terminates
an episode of breathing with flow limitation or exagger-
ated effort by esophageal pressure monitoring, but does
not meet the criteria of apnea or hypopnea. The average
number of abnormal events per hour of sleep (apnea
index, apnea/hypopnea index, and RERA index) serves
to quantify sleep-disordered breathing. A snoring index
P10 conventionally defines the presence of snoring, and
an apnea/hypopnea index P10 defines the presence of
sleep apnea. Based on these criteria, PSD and non-
apneic sleep-disordered breathing (UARS) can be differ-
entiated from obstructive sleep apnea syndrome
(OSAS), in which alterations of the circadian BP profile
are found (i.e., obliteration of the sleep-related BP fall
673
and increase in BP variability) [137]. Some have postu-
lated that snoring alone is a risk factor for hypertension
and cardiovascular disease, but this is based on older
epidemiological questionnaire studies conducted with-
out polysomnography and before Guilleminault’s
description of UARS [138,139]. A more recent study
failed to find an increased risk of hypertension or CV
disease in polysomnographically verified PSD with the
exclusion of OSA and UARS [140].
The changes in CV function that accompany OSA
events are now well recognized. HR and BP initially fall
with the onset of apnea but then rise acutely with termi-
nation of apnea. As a result, BP variability and average
BP levels are increased [137]. CV reflex tests [141] reveal
significantly higher HR and plasma levels of norepi-
nephrine in subjects at rest and greater BP response to
head-up tilting, with significantly reduced respiratory
arrhythmia, lower baroreflex sensitivity index, and lower
Valsalva ratio associated with an enhanced HR brady-
cardia induced by the cold face test. Collectively, these
findings reveal sympathetic overactivity that is associ-
ated with the blunting of reflexes dependent on barore-
ceptor or pulmonary afferents and normal or greater
than normal cardiac vagal efferent activity.
One-half or more of all those diagnosed with OSAS
are hypertensive, not only during nighttime sleep but
also during daytime activity [28,142,143]. Conversely,
several studies have found an approximately 30% prev-
alence of sleep apnea among individuals diagnosed with
primary hypertension [144–147]. Several hypotheses
have been advanced to explain how snoring and sleep
apnea result in the sustained daytime elevation of BP
and ultimately daytime hypertension. Several factors
are candidate mechanisms for the long-term diurnal ele-
vation of BP, including the direct effects of episodic hyp-
oxaemia and hypercapnia on chemoreceptors and
sympathetic activity [148,149], modification of the CV
system (including fluid balance) in response to marked
fluctuations in intrathoracic pressure during obstructed
breathing [150], generalized stress from sleep disruption
(‘arousal effect’) [132–134], genetic factors, and age. The
relative contribution of each factor is unknown, and the
role of recurrent hypoxia is particularly controversial
[151–154]. Conceivably, the concerted action of several
factors hypoxia, negative intrathoracic pressure, inter-
mittent BP changes, sleep arousals, and metabolic or
endocrine factors possibly only in conjunction with a
particular age and specific genetically determined char-
acteristics could cause hypertension. Whatever the cau-
sal factors, the common mechanism shared by
hypertension and OSAS is sympathetic system activa-
tion [134,141,155–158], which somehow becomes
chronic or acts as an intermediary, changing hormonal
balance and/or causing vascular remodeling.
Recent studies suggest that OSA leads to endothelial
dysfunction with impaired endothelium-dependent
674 M.H. Smolensky et al. / Sleep Medicine 8 (2007) 668–680
flow-mediated dilation, which improves with continuous
positive airway pressure (CPAP) [159]. This may be
related to the intermittent hypoxia of OSA [160]. The
OSA-associated endothelial dysfunction may be more
closely related to the apnea-hypopnea index in women
than men, suggesting more vulnerability to associated
CV disease in women than men [161]. Intermittent
hypoxia also induces long-term facilitation of carotid
body sensory activity, which may contribute to persis-
tent reflex activation of sympathetic nerve activity and
BP in OSA [162].
The data of various investigations suggest that undi-
agnosed sleep-disordered breathing might play a role in
the genesis of BP pattern alteration in some, if not all,
non-dippers diagnosed as essential hypertensives. This
is more likely to be the case for males, since in the adult
population the prevalence of sleep apnea is much higher
among men than women [163–167]. To test this hypoth-
esis, a polysomnographic study was undertaken on a
representative population of male essential hypertensive
non-dippers [168]; the study documented the blunted
sleep-related fall and increased variability in BP in rela-
tion to apneic snoring in 10 of 11 non-dippers. Hence,
undiagnosed apneic snoring appears to play a role also
in the genesis of the non-dipper circadian BP profile.
9. Autonomic failure and circadian BP Profile
Autonomic failure can occur in a ‘‘pure’’ form (PAF),
previously termed ‘‘idiopathic orthostatic hypotension’’
[169], or in association with a neurodegenerative disease
termed multiple system artrophy (MSA), without other
neurological signs. The term MSA, first used by Graham
and Oppenheimer in 1969 [170], refers to a sporadic
adult-onset neurodegenerative disease variously
described in the past as striatonigral degeneration, olivo-
pontocerebellar atrophy, or Shy-Drager syndrome,
according to the clinical predominance of parkinsonism,
cerebellar signs, and autonomic failure, respectively
[171–173]. The prognosis of MSA with autonomic fail-
ure is usually determined by the progression of neuro-
logic features over the course of six or so years. On
the other hand, the natural history of PAF is slow, grad-
ually progressing over some 10–15 years.
Everyone with autonomic failure evidences severe
symptomatic postural hypotension, but persons with
MSA and autonomic failure show normal plasma nor-
epinephrine levels when resting in the supine position
without significant increase when subjected to ortho-
static stress. Subjects with PAF differ, evidencing very
low plasma norepinephrine levels when resting in supine
position without increase when subjected to orthostatic
stress [137]. Patients with autonomic failure reveal a
sympathetic efferent defect which is more pronounced
in PAF, suggesting the lesion is more completely distal
in this group. In both PAF and MSA patients, the para-
sympathetic efferent lesion is less severe than the sympa-
thetic efferent lesion. A greater increase in sensitivity to
norepinephrine infusion is detectable more in PAF than
MSA patients with autonomic failure, providing further
evidence that the lesion in PAF is more distal. Patients
with MSA alone have normal responses to physiologic
and pharmacologic tests [137].
Complete obliteration of the circadian changes in BP
is found in PAF patients, whereas the normal circadian
profile of BP is reversed in MSA patients with auto-
nomic failure. This is in contrast to those of the MSA
group without autonomic failure, who have a normal
dipper BP pattern [137]. This finding is consistent with
the notion that normal day–night BP changes depend
on proper functioning of the sympathetic nervous sys-
tem. The low morning BP level, which corresponds to
the peak incidence of postural symptoms, is thought to
result from nocturnal polyuria and natriuresis; this is
substantiated by the improvement obtained with admin-
istration of desmopressin (synthetic antidiuretic hor-
mone) [174].
Sleep abnormalities (fragmentation of sleep with
greater than normal sleep latency, muscle tone, and
abnormal movements, decreases in REM and stage 3
and 4 sleep, and REM sleep behavior disorder) are com-
mon in MSA, in the presence or absence of autonomic
failure. However, they are not found in PAF patients,
suggesting not only that the disruption of sleep is mainly
due to central nervous system lesions [137], but also that
autonomic failure can induce nocturnal BP dysregula-
tion, independent of sleep abnormalities. Whether the
effect of MSA on sleep is primary or secondary to the
discomfort caused by neurologic signs is a matter of
continuing debate [175]. When OSAS is present, no
change in BP or HR is found in persons with autonomic
failure, in contrast to the usual brady-tachyarrhythmia
and increased BP after a single apnea found in the
MSA group without autonomic failure [137]. This find-
ing suggests that autonomic vasomotor reflexes play an
important mediator role in the hypertensive response to
apnea.
10. Prognostic relevance of altered circadian BP rhythms
The sleep-time BP level is the most sensitive predictor
of CV mortality – stroke, acute myocardial infarct, and
sudden cardiac death [176]. Absence of the normal 10–
20% decline in BP during sleep appears to carry a higher
heart and cerebral risk since the amount of time during
the 24 h when BP is elevated and impacts target tissues
and organs is prolonged. Accordingly, the average
sleep-time BP level and the magnitude of the sleep-time
BP decline are significantly correlated with target organ
damage to the heart [36,177–182], brain [9,15,183,184],
and kidney [185–189]. A large prospective study demon-
strated that CV morbidity is higher in non-dipper than
 M.H. Smolensky et al. / Sleep Medicine 8 (2007) 668–680
dipper hypertensive women [190]. The left ventricular
structure of the heart seems to be more BP load-depen-
dent in women than men with essential hypertension, as
demonstrated by higher echocardiographic indexes of
left ventricular hypertrophy in female, but not male,
non-dippers compared to dippers [182]. BP sodium-sen-
sitivity may be a marker of enhanced risk of kidney and
CV complications, and it is of interest that sodium-sen-
sitive essential hypertensive patients show loss of the
normal (10–20%) sleep-time BP decline [191].
11. Conclusions
Many different mechanisms appear to mediate sleep
influences on the circadian BP rhythms of normal and
disease states; however, only a few have been identified.
Disrupted ANS activity, sleep-disordered breathing, and
altered sleep structure and sleep duration are established
causes of changes to the circadian BP profile, in partic-
ular nocturnal hypertension. In many diseases to which
this finding applies, however, the pathophysiologic
mechanisms actually involved either in altering the
sleep-related changes in BP or underlying the sleep dis-
order are unknown. For this purpose, objective poly-
somnographic and continuous ABPM data are
required. Only by this comprehensive approach are
complete and simultaneous information about sleep
architecture, breathing events, BP, and sleep–wake dif-
ferentiation derived, thus permitting separation of
non-dippers with actual abnormalities in sleep-related
changes in BP from non-dippers with sleep anomalies
(e.g., insomnia, sometimes induced by the monitoring
procedure itself) of entirely different pathophysiologic
relevance.
This article reviewed the relationship between sleep,
BP circadian rhythms, and hypertension. The literature
shows that the sleep-time BP level is a determinant
and predictor of one’s risk of end-organ damage and
CV accidents and that the extent of the BP rise occurring
at the transition of nighttime sleep to daytime activity
may be a determinant of morning stroke, acute myocar-
dial infarct, and sudden cardiac death. Thus, individuals
who show 24-h BP patterns that exhibit an abnormal
(either too little or too great) sleep-time dipping or an
enhanced morning BP rise are at increased risk of tar-
get-organ injury (related to the BP load) as well as car-
diovascular mortality. We believe ABPM ought to be
applied more routinely to differentiate normotension
from hypertension and, in particular, to diagnose noc-
turnal, that is sleep-time, hypertension. Indeed, ABPM
is the only accurate means of diagnosing abnormal
sleep-time BP patterns. Finally, based on increasing epi-
demiology and case series studies linking abnormalities
or obliteration of the 24-h BP patterns to CV events,
we propose that restoration of the normal circadian
BP pattern should be one of the goals of therapeutic
675
interventions. However, the feasibility and means of
achieving this, and the manner of conducting an evalu-
ation of the prospective significance of such a normali-
zation, has yet to be sufficiently addressed [192].
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