Hermida

1. Review
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The importance of sleep
blood pressure
Expert Rev. Cardiovasc. Ther. 8(6), 803–809 (2010)
Trefor Owen Morgan Blood pressure (BP) varies throughout the day owing to interactions between the sympathetic
Department of Physiology, University
nervous and the renin–angiotensin systems. When awake BP is controlled by sympathetic
of Melbourne, Victoria 3010, Australia nervous system activity but during sleep the renin–angiotensin system becomes more important.
Tel.: +61 383 445 846 The lower BP during sleep is a more powerful predictor of outcome than the awake BP. Certain
Fax: +61 383 440 189 individuals do not have the fall in BP with sleep and this worsens the outcome. Inadequate
treforom@unimelb.edu.au handling of sodium by the kidney is an important factor preventing this BP fall. The different
drug classes have varying effects on BP during 24 h. Drugs that act independently of the two
controlling systems have a similar effect at day and night. Drugs that act on the sympathetic
nervous system have a greater effect during the day and little effect during sleep unless the
sympathetic system is still active. Drugs that act via the renin–angiotensin system have a greater
effect during sleep. Controlling BP during sleep may improve outcome.
Keywords : cardiac hypertrophy • dippers • myocardial infarction • nondippers • renin–angiotensin system • sleep
blood pressure • stroke • sympathetic nervous system
Blood pressure (BP) varies during the 24 h of adjusting to changes in posture and other
the day. There are variations owing to acute events, and maintains BP relatively constant.
events and an intrinsic variation related to the When an individual sleeps the cardiovascular
sleep-awake cycle. A typical pattern is that BP sympathetic nervous system reduces its activ-
falls when a person sleeps and stays at a low ity. BP and pulse rate both fall. During sleep,
level until they wake [1,2] . BP and pulse rate plasma renin and angiotensin II rise, probably
increase on awakening with a further rise in due to the activation of renal baroreceptors [4] .
BP on getting out of bed. Typically, BP is at BP is now maintained by the renin–angioten-
its highest soon after arising; it then falls with sin system rather than the sympathetic nervous
a rise late in the afternoon. It falls again until system. On awakening in the morning, the
the individual goes to sleep, when there is a sympathetic nervous system is activated, caus-
bigger fall and the cycle repeats. In normo- ing a rise in pulse rate and BP; BP is probably
tensive individuals sleep BP is approximately higher at this time due to both systems being
108/63 mmHg, which is 17/15 mmHg lower active. When the person stands there is a fur-
than the awake BP [2] . The variation during ther rise in renin secretion as well as a further
the day is approximately 10/8 mmHg. The rise in BP to its highest value. With the rise
difference between the lowest (during sleep) in BP renin secretion decreases, the morning
and highest (awakening and arising) BP is surge is finished and BP returns to the daytime
approximately 25/20 mmHg. These are aver- value. If the effect of posture on renin secretion
age values and individual people have much is avoided, plasma renin and probably angio-
greater variation. The aforementioned is the tensin II is higher when asleep compared with
usual pattern but some people do not have a awake [4] . However, in normal living daytime
fall when they sleep. The reason for this dif- renin may be higher than the sleep value, as
ference is not clear. The daily variation in BP is renin and angiotensin levels vary with altera-
predominately owing to altered activity of the tions in posture to control renal blood flow and
cardiovascular sympathetic nervous system and glomerular filtration. However, during the day
associated alterations in activity of the renin– renin is probably not of great importance in the
angiotensin system [3,4] . When awake, the sym- control of BP, as the carotid baroreceptors regu-
pathetic nervous system, activated by carotid late this parameter. In a number of countries,
baroreceptors, controls BP and the pulse rate, people have a siesta during the day and BP falls
www.expert-reviews.com 10.1586/ERC.10.60 © 2010 Expert Reviews Ltd ISSN 1477-9072 803

2. Review Morgan
at this time, and there is a similar rise on awakening [5] . From risk for noncardiovascular mortality [16,17] . In many studies
a study by Brandenberger et al. where the patients slept during night-time BP is the value recorded and reported. It may be
the daytime, there were similar increases in renin secretion as more relevant to report on sleep BP and the time of sleep is
occurred during night-time sleep [4] . best measured with an activgraph. Night-time BP is likely to be
less reproducible than sleep BP because the hours of sleep will
Dippers & nondippers affect the night-time results [18] . Many of the associations that
If a person has a fall of less than 10 mmHg or 10% of the day- have been made with the night-time BP may be even stronger
time BP, they are referred to as nondippers [6] . There is also a with sleep BP.
classification of extreme dippers and of reverse dipping when
the sleep BP is higher than the daytime value. The division Sleep BP
into dippers and nondippers is important because people with A very important study is the Ohasama study [19] , which was a
a nondipping pattern have more cardiovascular events and a community study performed in Japan. A total of 1542 patients
worse outcome [6–10] . over 40 years of age (mean age: 61.3 years) were followed for
It has been postulated [10] that the reason for nondipping is to 10.6 years. The patients were from the general population
allow the kidney to excrete sodium during sleep [11–13] . During and had an ambulatory BP measurement. The 24-h BP was
sleep the kidney tends to conserve both sodium and water, but 122.8/71.8 mmHg, daytime BP was 128.3/75.9 mmHg and
if the intake has been high or the kidney has not returned the night-time BP 111.9/63.8 mmHg. BP was also divided into 2-h
body to its correct sodium balance during the awake hours BP intervals based on the time of awakening. The 24-h, daytime and
stays elevated to excrete the sodium. In addition to the roles of night-time BP, and the BP at each 2-h interval was compared with
the sympathetic nerves and renin–angiotensin system in con- the incidence of various fatal cardiovascular and cerebrovascular
trolling BP, other factors are also probably involved. This may events. Daytime BP and each 2-h period of daytime BP was asso-
be due to an increased circulating plasma volume but it may ciated with an increased incidence of hemorrhagic stroke (Table 1)
also be due to a failure of the sympathetic nervous system to but there was no association with ischemic stroke, ischemic heart
reduce its activity. disease or other cardiac events. Sleep BP was not associated with
There have been relatively few studies of nondipping normo- hemorrhagic stroke but was associated with ischemic cardiac and
tensive patients. However, in patients with elevated BP a num- cerebral events, and with other cardiac events. This association
ber of observations have been made. Sodium-sensitive patients was not only with the mean BP day and night but with the BP at
lose their dipping status when sodium intake is increased [12] . each 2-h interval. BP in the 2-h interval on awakening was not
Patients with impaired renal function are frequently nondip- associated with any adverse events.
pers [14] , and this is in keeping with an impaired ability to excrete Verdecchia et al. has demonstrated that in poorly controlled
sodium. Patients with secondary forms of hypertension (renal hypertensive patients, sleep BP was associated with more car-
artery stenosis, hyperaldosteronism) have a higher prevalence diac hypertrophy events [20] . In the Systolic Hypertension in
of nondipping. There are also more nondippers among diabetic Europe Trial (SYSEUR), sleep BP prior to entry was a better
patients with hypertension [15] , and many diabetics have a low- predictor of outcome than either the clinic or daytime BP [21] .
renin form of hypertension, an indication of a sodium-loaded Likewise, in the Second Australian National Blood Pressure
state. The reasons for the different dipping status are not fully Study (ANBP2) night-time systolic BP both prior to and during
understood and studies are required in which BP, sympathetic treatment was the best predictor of outcome [22,23] . It is not only
nerve activity and renin status are measured throughout 24 h, major cerebro- and cardiovascular events that are associated. In
preferably with the patient recumbent throughout this time to a study of elderly hypertensive patients, Nagai et al. showed
assess the related changes. that sleep systolic BP was more significantly negatively associ-
Patients who do not have a fall in BP at night (nondippers) ated with total brain volume than either 24-h or awake BP [24] .
have an increased morbidity and mortality from all cardio- Kanemaru et al. showed that high nocturnal systolic BP was
and cerebrovascular causes [6–10] . Such patients have a higher associated with cognitive impairment [25] . These increased asso-
24-h BP and cardiac workload, and this may contribute to the ciations of sleep BP with events are present despite the fact that
adverse outcome. An important question is whether it is the sleep BP is lower than daytime BP, indicating that the hormonal
total 24-h BP and workload that is important or, alternatively, and/or neural activity of the person is important in determining
the specific BP level during sleep. It is probably the latter [16] , the outcome.
and it may be more appropriate to classify this in terms of the The powerful effect of nondipping status on outcome was
achievement of an ideal sleep BP rather than dippers and non- demonstrated in an observational study in diabetic patients [26] .
dippers. Night-time BP is a more powerful predictor of outcome In this study, 104 diabetic patients had an ambulatory blood
than daytime BP and predicts total, cardiovascular and non- pressure monitoring and were classified as risers, reduced dippers
cardiovascular mortality even after adjusting for daytime BP. or dippers. There were 16 risers, and 14 individuals died com-
Daytime BP predicts all cardiovascular events and strokes, but pared with 40 deaths in the remaining 88 patients. A mortality
when adjusted for night-time BP it loses its predictability and rate of 88% was found in the reverse dipping pattern (risers)
the only prediction is that low BP is associated with a greater compared with 45% in the remainder. No data are available for
804 Expert Rev. Cardiovasc. Ther. 8(6), (2010)

3. The importance of sleep blood pressure Review
night-time BP during the follow-up period, but if the hypothesis
Table 1. Hazard ratio for each standard deviation
that sodium status controls dipping is correct, most of these
increase in blood pressure.
patients would have continued as nondippers as it was unlikely
that a diuretic, which may have altered the dipping status, would Cause of death 24-h BP Awake BP Sleep BP
have been used in these diabetic patients. Total mortality risk 1.76* 1.59* 1.78*
There are studies that indicate that it is not be as simple as the Mortality H stroke 2.37* 2.73* 1.42
absolute level of sleep BP. Thus, extreme dippers who may have
a very low sleep BP have an increased number of adverse cardiac Mortality I stroke 1.60 1.19 1.94*
events [27] . Studies indicate that the BP surge may be an important Mortality I cardiac 1.94* 1.58 2.38*
predictor of events [28,29] . At the time of awakening when BP rises Mortality NI cardiac 1.51* 1.34 1.70*
acutely and reaches its highest level, there are an increased number *p < 0.05.
of cerebral and cardiac events [30,31] . However, in the Ohasama BP: Blood pressure; H: Hemorrhagic; I: Ischemic; NI: Nonischemic.
Data from [19].
study the BP at this time did not predict outcome [19] . This article
does not address whether sleep BP is more or less important than
BP surges and both probably predict outcome. This may relate associated with increased vascular and cardiac disease [38] .
to interactions between the sympathetic and renin–angiotensin Disturbed sleep, such as the sleep apnea syndrome, causes ele-
systems at the different times (box 1) . vated BP that is difficult to treat [39] . Depression is associated
While this article discusses BP, it is also important to remem- with increased sympathetic activity, decreased and disturbed
ber that pulse rate falls during sleep, which may also lead to an sleep patterns and increased cardiac mortality [40] . A small study
improvement in outcome [32] . from Japan indicated that sleep BP was elevated in depressed
patients and it is possible that BP elevation at night may be
Cardiac hypertrophy the precursor causing cardiac hypertrophy as well as increased
A number of human studies indicate that sleep BP is associated morbidity and mortality [41] .
with cardiac enlargement [20] . In rats when BP was increased by
angiotensin for 6 h during sleep there was cardiac hypertrophy sim- Effect of different drug classes on sleep BP
ilar to that achieved by increasing the BP over 24 h [33] . However, if A number of drug classes interfere with the sympathetic nervous
the same dose of angiotensin was given during the awake interval, system while others interrupt the renin–angiotensin system.
there was no increase in cardiac size. In rats with hypertension As these two systems have different activities over 24 h and
induced using the 2-kidney 1-clip model cardiac hypertrophy was make different contributions to BP, it is likely that drugs that
able to be reversed by reducing BP with
captopril for 6 h during the sleep period
to a similar extent as achieved with 24-h Box 1. Unresolved conundrum: sleep blood pressure.
BP reduction [34] . However, administering • Sleep BP predicts outcome. The lower the better
the same dose of captopril and reducing • BP surge predicts outcome. The greater the surge the worse the outcome. A large BP
BP during the awake hours had no effect surge frequently has a low sleep BP
on cardiac size, despite a similar or greater • An acute increase in BP with awakening and standing up normally occurs, but at this
reduction in 24-h BP (Table 2). time there is an increased incidence of cardio- and cerebrovascular events
How do we reconcile the above?
Renal disease • The lower the sleep BP in people without vascular disease, the better
Patients with renal damage frequently the outcome
exhibit a nondipping status, but there is also • Studies in which the BP surge predicts outcome are usually in older patients who
evidence that in Type 2 diabetes elevated already have vascular disease with stiff blood vessels
nocturnal BP makes it more likely that a • At night during sleep cardiac output is decreased and pulse rate falls. This leads to a
low systolic BP and also a low diastolic BP owing to the stiff blood vessels and a
patient will develop microalbuminuria.
prolonged diastolic time
Thus it is important that in diabetic patients,
• On awakening, sympathetic activitation increases cardiac output and pulse rate, leading
sleep BP is controlled [35] . If diabetic patients
to a greater rise in systolic and diastolic pressure than in people without vascular
have a reversed circadian rhythm (risers), disease, and thus a greater surge. The combination of a higher BP and a more rapid
there is an increased incidence of fatal and pulse rate increases myocardial work
nonfatal vascular event occurence [36] . • Coronary arteries in these people have a limited capacity to vasodilate and are not able
to deliver the required amount of oxygen, leading to angina, myocardial infarctions,
Sleep, depression, sympathetic arrhymias and sudden death. Thus, the cause for the apparent discrepancy may relate
activity & cardiac disease to the presence of stiff arteries
There are a number of complex interac- • It should be noted that the definition of BP surge varies and is not the same as the
tions between these variables [37] . Reduced acute rise in BP seen with awakening and arising
and interrupted hours of sleep have been BP: Blood pressure.
www.expert-reviews.com 805

4. Review Morgan
which ARB drugs in doses that have a
Table 2. Effect of different time of treatment on 24-h, sleep and
full 24-h response have been compared
awake blood pressure, and cardiac hypertrophy.
with amlodipine, the fall in BP during
Treatment Systolic BP (mmHg) Cardiac index sleep has been greater with the ARB [43] ,
(mg/g) even though both drugs would have
24‑h Awake Sleep
had a plasma level that would produce
Control normotensive 117 132 109 2.14
hypertensive rats maximal effect.
The probable reason for the greater sleep
Control 184 193 171 2.78
BP fall with ACE inhibitors and ARBs is
Captopril 75 mg 143 156 124 2.21* that sleep BP is maintained by circulat-
Captopril 15 mg 8 AM 172 198 116 2.24* ing levels of angiotensin II. A cross-over
Captopril 15 mg 8 PM 169 162 166 2.69
design study comparing perindopril given
*p < 0.01 compared with hypertensive control and rats treated during the awake period (8 PM).
in the morning or in the evening inferred
BP: Blood pressure. that during sleep, a lower level of drug was
Data from [34]. needed to obtain the BP fall [44] . Likewise,
a study by Smith et al. with trandolopril,
act on these systems may have different effects on awake and a very long-acting ACE inhibitor, showed the following over a
sleep BP. In a randomized, blinded, crossover study Morgan 48-h period [45] . There was a similar fall in day and night-time
et al. compared the effects of different drug classes on day and BP over the first 30 h. The response disappeared 30–40 h after
night-time BP in elderly patients with systolic hypertension who dosing during the day but reappeared 40–48 h after dosing
had not been treated for hypertension [42] . Drugs were used in when the patients slept. During the day carotid baroreceptors
a dose that was known to provide a 24-h or longer duration of predominately control BP, and ACE inhibitors or ARBs require
full BP response. A dihydropyridine calcium-blocking drug a greater blockade of the renin–angiotensin system to reduce
(amlodipine 10 mg) and a thiazide diuretic (hydrochlorthiazide BP. However, at night when circulating angiotensin II controls
50 mg) lowered daytime BP slightly more than night-time BP, BP, even a small degree of blockade of angiotensin II formation
but when corrected for the different BPs at these times prior to in plasma will alter BP.
medication the falls were similar (Table 3) . A b-blocking drug The importance of different activities of the sympathetic ner-
(atenolol 100 mg) lowered daytime BP but had no significant vous system was shown in a study of an a-receptor-blocking
effect on sleep BP. An ACE inhibitor (perindopril 8 mg) low- drug, doxazosin [46] . In patients who were dippers, doxazosin
ered sleep BP more than daytime BP (Table 3) . Thus, diuretics given at night caused no significant fall in night-time BP, and in
and calcium channel-blocking drugs that act independently of fact there was a rise. In nondippers there was a fall of 12 mmHg
the sympathetic nervous and renin–angiotensin systems have a and in risers a fall of 18 mmHg. This indicated that in most
similar effect day and night. However, b-blocking drugs had no individuals who are dippers there is an absence of sympathetic
effect on night-time BP because the sympathetic nervous system nervous activity during sleep. However, the persistence of sym-
makes little contribution to BP. Conversely, ACE inhibitors pathetic activity during sleep leads to a disturbance of the usual
caused a greater drop in sleep BP than in awake BP. This dif- BP pattern.
ference in response would mean that with the same daytime BP
control b-blocking drugs convert individuals into nondippers, Importance of time of dosing
while ACE inhibitors cause individuals to become dippers. This If a drug is used in a dose that provides levels throughout the
may explain in part the beneficial effect of ACE inhibitors, 24 h that adequately block the renin–angiotensin system, the
particularly on cardiac hypertrophy. In a number of studies in time of dosing should theoretically not matter. However, many
drugs do not have a full 24-h effect. In a study by Hermida
Table 3. Effect of different drug classes on day and et al., ramipril 5 mg was given morning or night [47] . The great-
night blood pressure. est fall in BP (13.5/11.5 mmHg) occurred in sleep BP with
night-time administration. Whether this would translate into
Fall in BP (mmHg)
different prognostic outcomes is unknown. The Heart Outcome
24‑h Day Night Prevention Evaluation (HOPE) study administered ramipril
Diuretics 14.9 15.5 12.5 10 mg at night and had a 22% improvement in a number of
CCBDs 14.4 14.8 12.7 events, despite little fall in the clinical (daytime) BP (Table 4) [48] .
However, a HOPE substudy indicated a large fall in night-time
b-blockers 8.1 11.6 4.4*
BP (17/8 mmHg) [49] . In the Perindopril Protection Against
ACE inhibitors 11.5 9.5 16.3* Recurrent Stroke Study (PROGRESS) study perindopril 4 mg
*p < 0.01 compared with daytime value. given in the morning caused no improvement in the same type
ACE: Angiotensin-converting enzyme; BP: Blood pressure; CCBD: Calcium
channel-blocking drug. of events [50] . However, in the European Trial on Reduction
Data from [42]. of Cardiac Events with Perindopril in Stable Coronary Artery
806 Expert Rev. Cardiovasc. Ther. 8(6), (2010)

5. The importance of sleep blood pressure Review
Disease (EUROPA) perindopril 8 mg
Table 4. Effect of treatment with angiotensin converting enzyme
given in the morning improved outcome
inhibitors according to dose and time of administration.
similar to the HOPE study [51] . Perindopril
4 mg given in the morning may not have Drug used Dose Time Reduction in primary Ref.
reduced sleep BP as much as in the other (mg) given end points (%)
two studies, and this may explain the Ramipril 10 PM 22 [48]
results. When a diuretic was given together Perindopril 4 AM 4 [50]
with perindopril there was a greater ben-
[50]
efit obtained, probably because the diuretic Perindopril + indapamide 4 AM 40
increased the fall in BP and increased the Perindopril 8 AM 20 [51]
duration of action of perindopril so that it
reduced BP during sleep. control of sleep BP and improve prognosis. However, the time
An argument can be made that it would be preferable to admin- of administration is of less importance if the drugs are used in
ister ACE inhibitors and ARBs in the evening. This applies par- a dose that clearly provides 24-h control. Sleep BP should be
ticularly to the shorter acting drugs, but should be unnecessary measured and it should be normalized.
with longer acting drugs given in adequate doses. There would
appear little reason to administer diuretics and calcium-blocking Expert commentary
drugs in the morning or evening related to their effect on BP, Sleep BP is an important predictor of outcome. A major question
although other reasons will influence the choice. b-blocking is whether the absolute level of BP or the variation in BP (dippers,
drugs and a-blocking drugs have little effect on sleep BP and nondippers or surge) is more important. The different drug classes
thus having a higher concentration during sleep is probably irrel- alter BP differently at various times of the day due to the activities
evant [37,41] . However, if administered in the evening they would of the control systems. It is important to control BP throughout
have a higher concentration in the morning during the initial 24 h, but control during sleep and on awakening may be more
period of increased sympathetic activity. This may reduce the critical than daytime control. This raises the question of whether
early morning rise in pulse and BP and protect from both overt it may be preferable to give medication in the evening to achieve
and silent angina and heart attacks. these aims, and to tailor the drugs used and their time of dosing
When comparisons are made between the effect of night-time to achieve the greatest effect.
and morning dosing of drugs, it is critical that drugs are used in
a dose known to exert its full effect for 24 h. If this is not carried Five-year view
out, spurious conclusions may be drawn. It is also important Sleep BP needs to be controlled. This requires an easy way to
to recognize that the pharmacokinetics of drugs may alter the measure BP during sleep and choosing drugs based on their
rates of metabolism during asleep and awake states. Studies action on the controlling systems. It is possible that medications
are required in which plasma concentrations of the drugs are will be packaged that release their drug components at different
measured to determine the fall in BP associated with the same times and rates, allowing effective 24-h BP control.
drug concentration.
Financial & competing interests disclosure
Conclusion The author has no relevant affiliations or financial involvement with any
Blood pressure measured during sleep is a more powerful predic- organization or entity with a financial interest in or financial conflict with
tor of outcome than when measured at other times of the day. the subject matter or materials discussed in the manuscript. This includes
During sleep a lower level of BP appears to activate processes employment, consultancies, honoraria, stock ownership or options, expert
that cause vascular disease. ACE inhibitors and ARBs lower testimony, grants or patents received or pending, or royalties.
sleep BP preferentially, and this may have significant outcome No writing assistance was utilized in the production of this
benefits. Administering drugs in the evening may improve the manuscript.
Key issues
• Sleep blood pressure (BP) predicts cardio- and cerebrovascular events.
• Sleep BP is reproducible and is preferred to night-time BP.
• Awake BP is controlled by the sympathetic nervous system.
• Sleep BP is controlled by the renin–angiotensin system; renin is elevated during sleep.
• A lack of a fall in BP during sleep is associated with adverse outcomes.
• Failure to excrete sodium during the day due to either excess salt intake or defective renal function leads to an elevated sleep BP.
• Drugs that act on the sympathetic nervous system have reduced activity during sleep.
• Drugs that act via the renin–angiotensin system have a greater effect during sleep.
• Controlling sleep BP has been shown to improve outcome better than controlling daytime BP.
www.expert-reviews.com 807

6. Review Morgan
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