Download Assessment and management of blood-pressure variability

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Assessment and management
of blood-pressure variability
Gianfranco Parati, Juan E. Ochoa, Carolina Lombardi and Grzegorz Bilo
Abstract | Blood pressure (BP) is characterized by marked short-term fluctuations occurring within a 24 h period
(beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night changes) and also by long-term fluctuations
occurring over more-prolonged periods of time (days, weeks, months, seasons, and even years). Rather than
representing ‘background noise’ or a randomly occurring phenomenon, these variations have been shown to
be the result of complex interactions between extrinsic environmental and behavioural factors and intrinsic
cardiovascular regulatory mechanisms. Although the adverse cardiovascular consequences of hypertension
largely depend on absolute BP values, evidence from observational studies and post‑hoc analyses of data
from clinical trials have indicated that these outcomes might also depend on increased BP variability (BPV).
Increased short-term and long-term BPV are associated with the development, progression, and severity of
cardiac, vascular, and renal damage and with an increased risk of cardiovascular events and mortality. Of
particular interest are the findings from post‑hoc analyses of large intervention trials in hypertension, showing
that within-patient visit-to-visit BPV is strongly prognostic for cardiovascular morbidity and mortality. This result
has prompted discussion on whether antihypertensive treatment should be targeted not only towards reducing
mean BP levels but also to stabilizing BPV with the aim of achieving consistent BP control over time, which
might favour cardiovascular protection.
Parati, G. et al. Nat. Rev. Cardiol. 10, 143–155; published online 12 February 2013; doi:10.1038/nrcardio.2013.1
Introduction
Blood pressure (BP) is characterized by marked shortterm fluctuations occurring within a 24 h period, including beat-to-beat, minute-to-minute, hour-to-hour, and
day-to-night changes. Long-term, substantial variations in BP have also been shown to occur over more-­
prolonged periods of time, for example days, weeks,
months, seasons, and even years.1 Rather than representing ‘background noise’, or a phenomenon occurring at
random, these variations are thought to be the result of
complex interactions between extrinsic environ­mental
and behavioural factors and intrinsic cardiovascular
regu­latory mechanisms (neural central, neural reflex, and
humoral influences) that are not yet completely understood. Although the adverse cardiovascular consequen­
ces of hypertension are thought to depend largely on
mean BP values, evidence from observational studies
and post‑hoc analyses of clinical trials, many of which are
discussed in this Review, indicates that these outcomes
might also depend on BP variability (BPV). Indeed, these
studies have shown that both short-term and long-term
increases in BPV are associated with the development,
progression, and severity of cardiac, vascular, and renal
damage, and with an increased incidence of cardio­
vascular events and mortality independent of elevated
Competing interests
G. Parati declares an association with the following company:
Pfizer. See the article online for full details of the relationship.
The other authors declare no competing interests.
mean BP. Of particular interest are the findings of a 2010
post‑hoc analysis of large intervention trials in hyper­
tension, which showed that within-patient BPV between
visits to a physician’s office (visit-to-visit) is strongly prognostic for cardiovascular morbidity.2 In some instances,
this associ­ation was reported to be stronger than the
relationship between mean BP and cardiovascular risk.2
Against the background of this evidence, the question has been raised as to whether treatment with anti­
hypertensive agents should be targeted towards stabili­zing
BPV, in addition to obtaining mean BP control, with the
aim of optimizing cardiovascular protection. However,
before being implemented in clinical practice as an additional target of antihypertensive treatment, an improved
understanding and definition of the BPV phenomenon
and of its various components is required. The clinical
relevance and prognostic implications of BPV can vary
substantially depending on the method of assessment and
the time interval examined. This matter is not just semantics; different definitions of BPV and assessment of its
different components can lead to various interpretations
of the physiological and pathophysiological mechanisms
of this phenomenon.
In this Review, the mechanisms of BPV, the methods
currently used for BPV assessment, and the clinical relevance and prognostic importance of various types of
BPV are discussed. In addition, the question of whether
BPV should become a target for antihypertensive treatment
in the prevention of cardiovascular disease is addressed.
NATURE REVIEWS | CARDIOLOGY Department of
Cardiology, S. Luca
Hospital, IRCCS,
Istituto Auxologico
Italiano & University of
Milano-Bicocca Piazza
Brescia 20, Milan
20149, Italy (G. Parati,
J. E. Ochoa,
C. Lombardi, G. Bilo).
Correspondence to:
G. Parati
gianfranco.parati@
unimib.it
VOLUME 10 | MARCH 2013 | 143
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Key points
■■ Blood-pressure variability (BPV) is a complex phenomenon that includes
short-term fluctuations occurring within a 24 h period as well as blood pressure
changes over more-prolonged periods of time
■■ The underlying mechanisms, clinical significance, and prognostic implications
differ between types of BPV; thus, when interpreting BPV, the method and time
interval of its measurement should be taken into account
■■ Mounting evidence indicates that the adverse cardiovascular consequences
of high blood pressure could also be the result of increased BPV, and not only
of elevation of mean blood pressure values
■■ Short-term and long-term BPV are independently associated with the
development, progression, and severity of cardiac, vascular, and renal damage
and with an increased risk of cardiovascular events and mortality
■■ Post-hoc analyses of large intervention trials in patients with hypertension
have shown that intraindividual and interindividual visit-to-visit BPVs are strong
predictors of cardiovascular morbidity and mortality
■■ Whether treatment with antihypertensive agents should be targeted towards
stabilizing BPV in addition to controlling mean blood pressure values, to achieve
maximum cardiovascular protection, is uncertain
Mechanisms and determinants of BPV
Short-term BPV
Several studies have been conducted with the aim of
disentangling the precise contribution of humoral,
neural, and environmental factors to BPV.3–7 The findings have indicated that these factors are often inextricably intertwined; separating them makes scientific sense,
but is pointless in the clinical setting. BP variations in
the very short (beat-to-beat) and short (within a 24 h
period) term mainly reflect the influences of central and
reflex autonomic modulation (increased central sympathetic drive and reduced arterial and cardio­pulmonary
reflexes),3,4,8 elastic properties of arteries (reduced arteri­al
compliance), 9–11 and the effects of humoral (angio­
tensin II, bradykinin, endothelin‑1, insulin, nitric oxide),
rheo­logical (blood viscosity), and emotional factors
(psychological stress) of diverse nature and duration.
Behavioural influences (physical activity, sleep, postural
changes) can induce marked variations in BP over a 24 h
period. In addition, spontaneous and rhythmic BP fluctuations at various frequencies occur independently of
behaviour throughout the day and night, presumably
because of influences originating in the central nervous
system, for example, the so-called Mayer waves (10 s
rhythm in BP oscillations).8,12 BP fluctuations also occur
in response to the mechanical forces generated by venti­
lation. All types of BP variation, whether induced by
behavioural or postural challenges, or by thoracic movements with ventilation, are modulated by arterial and
cardio­pulmonary reflexes, the reduced efficacy of which
can result in increased BPV. Despite the large number
of studies in which the effects of genetic variation on BP
levels have been explored, the effects of genetic variation
on short-term BPV or on circadian BP fluctuations have
been examined in only a few investigations.13–18
In the general population, BP falls by an average of
10–20% of daytime values during sleep.19 This phenom­
enon is referred to as ‘dipping’. However, in some indivi­
duals, the nocturnal decrease in BP is blunted (a fall in
night-time systolic and diastolic BP <10% of daytime BP;
these individuals are known as ‘nondippers’) or BP even
144 | MARCH 2013 | VOLUME 10
increases (these individuals are referred to as ‘risers’ or
‘inverted dippers’). Dippers exhibiting a nocturnal BP
fall >20% of daytime BP are known as ‘extreme dippers’.20
Nondipping is frequently accompanied by higher noctur­
nal mean BP than in ‘dippers’ (>125/75 mmHg).20 Such
alterations in day-to-night BP profiles are heavily influenced by both an indivi­dual’s level of activity during the
day and by the sleep–­wakefulness cycle. Proposed mecha­
nisms for these changes include increased sympa­thetic
nervous system activity during the night,21 decreased
renal sodium excretory ability,22 salt sensiti­vity,23 altered
breathing patterns during sleep (for example, obstructive
sleep apnoea), leptin and insulin resistance,24 endothelial
dysfunction,25 and g­lucocorticoid use.26,27
Long-term BPV
Information on the factors involved in long-term BPV,
(day-to-day, visit-to-visit, or seasonal) is still limited.
Behavioural changes are considered to have a major
role in day-to-day BPV, as indicated by the substantial
changes observed in 24 h ambulatory BP monitoring
(ABPM) values between working days and the weekend.28
Long-term BPV has been shown to be a reproducible
and not a random phenomenon. 29 However, little is
known about the factors responsible for BPV observed
over months or years in observational studies and clinical trials of antihypertensive drugs.2,30,31 Some potential
mechanisms for long-term BPV, particularly increased
arterial stiffness, have been postulated in studies published in the past 2 years.32,33 Long-term BPV might not
entirely consist of spontaneous BP variations, nor reflect
the same physiological cardiovascular control mechanisms as short-term BP fluctuations; it might also be the
result of poor BP control in treated patients (in particular
visit-to-visit BP variations during follow-up) or reflect
inconsistent office BP (OBP) r­eadings (Table 1).34
Thus, factors influencing the degree of BP control,
such as compliance with the prescribed therapeutic regimen, and correct dosing and titration of anti­
hypertensive treatment, or errors in BP measurement can
influence day-to-day and visit-to-visit BPV. Long-term
BPV has also been reported to occur as a consequence
of seasonal climatic changes. Systolic and diastolic BP
have been reported to be lower during summer and
higher during winter,35 mainly as a result of changes in
outdoor temperature.36 This finding is consistent across
the various methods of monitoring BP (OBP measurement [OBPM], average values from home BP monitoring
[HBPM], and mean values from 24 h ABPM). In addition, inappropriate downward titration of antihypertensive drugs on the basis of variations of OBPM during the
summer can reduce the extension of BP control over 24 h,
and contribute to the paradoxical increase in night-time
BP levels reported during hot weather in some studies.36
Assessment of BPV
Measures of BPV can be obtained by various methods,
for example continuous beat-to-beat BP recordings,
repeated OBPM, 24 h ABPM, or HBPM over long periods
of time. BP fluctuations can be assessed in the very short
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Table 1 | Types of BPV: methods of measurement, prognostic relevance, and proposed mechanisms
Characteristic
Very short-term BPV
(beat-by-beat)
Short-term BPV
(within 24 h)
Long-term BPV
(day-by-day)
Long-term BPV
(visit-to-visit)
Method of BP
measurement
Continuous BP recordings in a
laboratory setting or under
ambulatory conditions
ABPM
ABPM over ≥48 h
HBPM
ABPM
OBPM
HBPM
Measurement
intervals
Beat-to-beat over variable recording
periods (1 min to 24 h)
Every 15–20 min over 24 h
Day-by-day, over several
days, weeks, or months
Spaced by visit over
weeks, months, and years
Advantages
Assessment of indices of autonomic
cardiovascular modulation
Extensive information on 24 h BP profile
Identification of patterns of circadian
BP variation
Appropriate for long-term
monitoring
Appropriate for long-term
monitoring
Disadvantages
Stability of measurements might not
be guaranteed outside the
laboratory setting
Cannot be repeated frequently
Patient training and
involvement is required for
HBPM
ABPM over 48 h is neither
always well tolerated or
accepted by patients
OBPM and HBPM provide
limited information on BP
profiles
Indices of BPV
SD
Indices of autonomic modulation can
be calculated (that is, fluctuations in
very low, low, and high frequency
bands [spectral analysis])
24 h, daytime, and night-time SD and CV
24 h weighted SD
Day-to-night BP changes
ARV
SD
CV
SD
CV
Proposed
mechanisms
Increased central sympathetic drive
Reduced arterial/cardiopulmonary
reflex
Humoral and rheological factors
Behavioural and emotional factors
Activity/sleep
Ventilation
Increased central sympathetic drive
Reduced arterial/cardiopulmonary reflex
Humoral and rheological factors
Behavioural and emotional factors
Activity/sleep
Reduced arterial compliance
Improper dosing/titration of AHT
Reduced arterial
compliance
Improper dosing/titration
of AHT
Reduced adherence to AHT
BP measurement errors
Improper dosing/titration
of AHT
Reduced adherence to
AHT
BP measurement errors
Seasonal change
Abbreviations: ABPM, ambulatory blood pressure monitoring; AHT, antihypertensive treatment; ARV, average real variability; BP, blood pressure; BPV, blood pressure variability; CV, coefficient
of variation; HBPM, home blood pressure monitoring; OBPM, office blood pressure measurement.
or short-term, and in the mid-to-long term (day-to-day,
visit-to-visit, or between seasons). These components of
BPV can be characterized by various mechanisms and
might differently affect prognosi­s (Figure 1).
Short-term BPV
The dynamic behaviour of BP over a 24 h period was
first shown through the use of intra-arterial BP monitoring in ambulant individuals.37–39 These recordings
identified both beat-to-beat and day-to-night BP variations.37 Accurate assessment of short-term BPV within a
24 h period requires continuous BP recording. However,
such evaluation is now also possible (although less precisely) through the use of intermittent, noninvasive 24 h
ABPM. From these recordings, the standard deviation
(SD) of the mean systolic, diastolic, and arterial pressure
values over a 24 h period can be calculated.40 Daytime
and night-time periods can be considered separately.40
Calculation of the ‘weighted’ SD of the 24 h mean value,
(that is, the average of the daytime and night-time BP SD,
each weighted for the duration of the respective day or
night period) has been proposed as a method of excluding day-to-night BP changes from the quantifi­cation
of overall 24 h SD, without discarding either daytime
or night-time values.41 The average SD of BP can also
be divided by the corres­ponding mean BP and multiplied by 100 to express a normalized measure of BPV
as a coeffi­cient of variation. Other measures include the
‘residual’ BPV, representing the fast BP fluctuations that
remain after exclusion of the slower components of the
24 h BP profile through spectral analysis,42 and ‘average
real varia­bility’, which is the average of the absolute differences between consecutive BP measurements.43 These
parameters, which focus on short-term BP changes and
are not affected by the ‘dipping’ phenom­e non, have
been shown to be better predictors of organ damage and
cardio­vascular risk than the conventional 24 h SD of
BP.41,43,44 Slow fluctuations in BP levels occurring between
day and night can be assessed using 24 h ABPM to identify patterns of circadian BP variation, which are relevant
to cardiovascular prognosis.23,45–48
Mid-term and long-term BPV
Day-to-day
Measures of day-to-day BPV can be obtained using
ABPM performed over consecutive days (that is, over a
48 h period). However, this strategy is not always well tolerated or accepted by patients. As an alternative, HBPM
can be performed by patients in fairly standardized conditions. Although HBPM might not provide the same
extensive information on 24 h BP behaviour as ABPM, it
can be used to monitor BP changes over a time window
(several days) when a patient’s physiological characteristics and treatment regimen both remain stable. Notably,
measurement of day-to-day BPV enables a physician to
optimize antihypertensive treatment earlier than if BPV
were measured on a visit-to-visit basis. Information on
BPV can be collected quickly, rather than over a period
of months or years, by which time the subclinical damage
associated with inconsistent BP control would have
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Central sympathetic drive
Arterial or cardiopulmonary reflex
Humoral, rheological, behavioural
and emotional factors
Activity or sleep
Arterial compliance
Inappropriate dosing or
titration of AHT
Adherence to AHT
BP measurement errors
Seasonal
change
Ventilation
Very short-term BPV
(beat to beat)*
Short-term BPV
(over 24 h)
Subclinical organ damage‡
Cardiovascular events
and mortality?§
Renal outcomes?§
Subclinical organ damage‡
Cardiovascular events
Cardiovascular mortality
All-cause mortality
Progression of
microalbuminuria, proteinuria
eGFR, progression to ESRD
Mid-term BPV
(day-to-day)
Subclinical organ damage‡
Cardiovascular events
Cardiovascular mortality
All-cause mortality
Microalbuminuria
eGFR
Long-term BPV
(visit-to-visit)
Subclinical organ damage‡
Cardiovascular events
All-cause mortality
Microalbuminuria and
proteinuria
eGFR
Figure 1 | Various types of BPV, their determinants, and prognostic relevance for cardiovascular and renal outcomes.
*Assessed in laboratory conditions; ‡cardiac, vascular, and renal subclinical organ damage; §BPV on a beat-to-beat basis
has not been routinely measured in population studies. Abbreviations: AHT, antihypertensive treatment; BP, blood pressure;
BPV, blood-pressure variability; ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate. Springer and
Current Hypertension Reports, 14 (5), 2012, 421–431, Blood pressure variability, cardiovascular risk, and risk for renal
disease progression, Parati, G., Ochoa, J. E. & Bilo, G. with kind permission from Springer Science and Business Media.
already progressed and treatment modifications would
be too late to be effective.
In daily clinical practice, the assessment of BPV by
HBPM might be more cost-effective and more feasible
for repeated assessment during long-term follow-up of
patients with hypertension than the use of either OBPM
or ABPM.49,50 In patients who are receiving antihypertensive treatment, we cannot exclude the possibility that
day-to-day BPV might be influenced by adherence to
prescribed medication. The extent of this effect, and
whether day-to-day and visit-to-visit BPV are similarly
or differently affected by reduced adherence to treatment,
are issues that warrant assessment in future studies.
Visit-to-visit BPV
BP has been shown to exhibit important variations
between office visits. 2,30 Meta-analyses and post‑hoc
interpretations of data from clinical trials on anti­
hypertensive treatment have shown the clinical relevance
of visit-to-visit BPV, as assessed by OBPM or betweenvisit ABPM, especially in predicting cerebro­vascular
events.2 However, in the clinical setting, obtaining BP
measurements over a consistent number of visits to
achieve a meaningful estimate of visit-to-visit BPV is
usually difficult. Moreover, OBPM might not provide
information on BP during a patient’s usual activities over
a long period of time and is, therefore, not representative
of actual BP burden. OBPM is thus an imperfect indicator of BP control, and is far from being an ideal means to
assess visit-to-visit BPV.
Intraindividual visit-to-visit BPV assessed by 24 h
ABPM has been shown to be lower than when consi­
dering BP values measured in a physician’s office. 51
Therefore, during long-term treatment, BP is noticeably more stable when assessed with ABPM during
daily life than when assessed on the basis of OBPM.
This phenomenon is partly the result of OBP alteration
146 | MARCH 2013 | VOLUME 10
by environmental stimuli, and by the emotional BP rise
induced in a patient by a doctor’s visit in the clinical
setting (the white-coat effect). These factors have no
effect on 24 h mean BP. Thus, visit-to-visit variability in
24 h mean BP cannot easily be predicted from variability
in BP values obtained from OBPM.
Although ABPM provides extensive information on BP
levels within a given 24 h period, it cannot be repeated
frequently and, thus, cannot be routinely used to assess
visit-to-visit BPV. As mentioned above, although HBPM
does not provide information on 24 h BP profiles, this
strategy is an appropriate alternative approach for the
assessment of mid-term and long-term BPV. HBPM
allows day-to-day BP measures to be obtained in fairly
standardized conditions (stable treatment regimen, no
substantial physiological changes are likely), without
the confounding influence of the white-coat effect, and
with less modification by daily activity levels compared
with ABPM.52 Thus, HBPM seems more appropriate for
the mid-term and long-term assessment of BPV and
BP control than repeated OBPM or ABPM. Indeed,
when properly implemented, HBPM has been shown
in several studies to significantly improve BP control
among patients receiving long-term anti­hypertensive
therapy when compared with conventional OBPM.53,54
In the light of this evidence, and its prognostic and
clinical advantages, the use of HBPM is recommended
in current international guidelines 20,49,55–57 as part of
the routine diagnostic and therapeutic approach to
hypertension, to define the BP normalization rate
achieved with various drug regimens.49 In clinical practice, HBPM might identify patients with false resistant
hypertension (that is, individuals with normal home
BP whose OBP cannot be easily controlled despite the
use of several antihypertensive agents), thus preventing
unnecessary up-titration or addition of antihypertensive drugs, and reducing the need for follow-up visits.50
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180
19
2116
10 7
90
7 6
60
100
P <0.05
75
11
16
10
50
25
P <0.01
16
16
10
11
13
6
10
10
10
21
7
10
7
0
10 10
7
7 6
21
10
0
1st
2nd
3rd
Group
4th
5th
Severity of target-organ damage (%)
0
Rate of target-organ damage (%)
Short-term BPV
The degree of BPV is generally directly correlated with
mean BP values. 37 Early studies using intra-arterial
ABPM over a 24 h period, showed for the first time
that BPV (SD of the 24 h, day, and night mean BPs) is
increased in patients with hypertension compared with
individuals who are normotensive.37 The increase in the
SD of BP is proportional to the increase in mean BP, with
no change in the coefficient of variation.37 Interestingly,
an increase in BPV was also shown within individuals, as
their mean BP increased between subperiods over 24 h.
The majority of the available data confirm the superior
prognostic value of mean BP over BPV, although evidence from longitudinal and observational studies has
indicated that short-term BPV within a 24 h period
might be an important contributory factor in cardio­
vascular risk. Several studies, in which either intraarterial or noninvasive BP monitoring was used, have
indeed shown that cardiac, vascular, and renal damage
for a given mean 24 h BP value is more prevalent and
severe as 24 h BPV increases.38,59–64 (Figures 2,3).
Most importantly, prospective studies have provided
evidence that an initial increase in BPV within 24 h
independently predicts progression of subclinical organ
damage, structural cardiac and vascular alterations (such
as increased left ventricular mass index or carotid–intima
media thickness),64,65 cardiovascular events,42,44,65–71 and
cardiovascular mortality.42,44,71,72 Overall, this evidence
supports the concept that the adverse cardiovascular
consequences of high BP depend on BPV as well as
on mean BP. A report from the International Database on
Ambulatory Blood Pressure in relation to Cardiovascular
Outcome, showed that indices of BPV, such as the
average of the daytime and night-time mean BP SD
weighted for the duration of the daytime and nighttime intervals and the average real variability, predict
outcome.73 However, these indices improve prediction of
the composite cardiovascular events by mean BP by only
0.1%,73 confirming the superior role of 24 h mean BP for
prediction of outcomes in clinical practice. The results
of this study, however, might have been affected by the
different methods of 24 h ABPM used in the various
p­opulations whose data were pooled in the analysis.
As previously mentioned, ABPM provides information on diurnal BP changes. The prognostic relevance
of nocturnal BP and reduced night-time BP dipping
has been assessed in several studies. Observational and
longi­tudinal analyses have shown the superior prognostic value of nocturnal BP when compared with daytime
or 24 h BP in predicting cardiovascular morbid and
fatal events45,46,74–80 and all-cause mortality,74,75,77,79,81,82
both in patients with hypertension and among healthy
individuals in the general population. These findings
are not surprising given that nocturnal BP, without the
Inter-half-hour SD (mmHg)
1011
120
Prognostic importance of BPV
7
1010
150
24 h MAP (mmHg)
A memory-equipped HBPM device, or a combination
of HBPM and telemedicine, could facilitate the routine
use of this strategy in daily practice without unduly
increasing the burden on the health-care provider.49,58
3
10
P <0.01
10
2
11
16
7
1
21
6
7
10
10
0
1st
2nd
3rd
Group
4th
5th
MAP variability < group average
MAP variability > group average
Figure 2 | Short-term BPV and subclinical organ damage (cross-sectional study).
Rate and severity of target-organ damage in patients with essential hypertension
divided into quintiles of increasing 24 h MAP. Patients in each group were further
classified into two categories according to whether the inter-half-hour SD of MAP
was below or above the average variability of the group. Within each group, the two
classes had similar 24 h MAP values. For each class, the severity of target-organ
damage was expressed as the average score accounting for both the presence
and extent of target-organ damage. The score ranged in each patient from 0
(no clinical events, or electrocardiogram, chest radiograph, fundus, or renal
function alterations) to 3 (major alterations in the electrocardiogram, chest
radiograph, or fundus plus a clinical event, renal abnormality, or both). For any
level of 24 h MAP, patients in whom 24 h BPV was low had a lower prevalence
and severity of target-organ damage than those in whom 24 h BPV was high.
The number at the top of each bar represents the number of patients in each
subgroup. Abbreviations: BPV, blood-pressure variability; MAP, mean intra-arterial
blood pressure. Permission obtained from Wolters Kluwer Health © Parati, G. et al.
Relationship of 24-hour blood pressure mean and variability to severity of
target‑organ damage in hypertension. J. Hypertens. 5, 93–98 (1987).
pressor effects of physical activity, emotional stress,
and environmental stimuli that are present during the
day, might be more reproducible and representative of
true BP and organ-damage status. In addition, a ‘nondipping’ pattern of BP has also been shown to have a
prognostic role. Individuals who experience a ‘blunted’
nocturnal decrease in BP have been reported to have
a higher preva­lence of subclinical organ damage47,65,83
and an increased risk of cardiovascular events 84 and
death,46 compared with those with a normal night-time
BP decrease. Among ‘risers’ or ‘inverted dippers’, the
c­ardiovascular risk is even greater.85
Evidence also exists that the incidence of cardiac and
cerebrovascular events peaks in the morning,86–89 possi­
bly in relation to the sharp BP rise that occurs in some
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150
a key predictor of cardiovascular outcomes. Indeed, the
risk of cardiovascular events was increased rather than
decreased, as would be expected in patients with a blunted
prewaking BP surge, which is associated with reduced or
absent night-time BP dipping. According to the investigators, this finding could be partly attributed to the superior
reproducibility of nocturnal BP compared with the early
morning surge.48
17
P <0.01
Inter-half-hour SD (mmHg)
24 h MAP (mmHg)
130
110
90
70
0
14
11
8
5
0
Severity of target-organ damage (%)
170
P <0.01
LVMI (g/m2)
150
130
110
90
0
1st
2nd
3rd
4th
Group
3
P <0.01
2
1
0
1st
2nd
3rd
4th
Group
MAP variability < group average
MAP variability > group average
Figure 3 | Short-term BPV and subclinical organ damage (longitudinal study).
Rate and severity of target-organ damage and LVMI in the same patients as in
Figure 2 after 7.4 years of follow-up. Patients were divided into quartiles of
increasing 24 h MAP. Patients in each group were further classified into two
categories according to whether the inter-half-hour SD of MAP was below or above
the average variability of the group. Within each group, the two classes had similar
24 h MAP values. For each class, the severity of target-organ damage was
expressed as the average score, as assessed in Figure 2 with the addition of
echocardiographic data. BPV (among half-hour SD of 24 h MAP) at the initial
evaluation was a significant predictor of target-organ damage at follow-up,
indicating that the cardiovascular complications of hypertension might depend on
the degree of 24 h BPV. Abbreviations: BPV, blood-pressure variability; LVMI, left
ventricular mass index; MAP, mean intra-arterial blood pressure. Permission
obtained from Wolters Kluwer Health © Frattola, A. et al. Prognostic value of
24‑hour blood pressure variability. J. Hypertens. 11, 1133–1137 (1993).
individuals upon waking. In support of this concept,
several studies, most of which were conducted in Japan,
have provided evidence that an increased morning BP
surge is associated with a higher incidence of cardio­
vascular events and mortality.68,69,84,90 However, the actual
prognostic value of morning BP surge is still a matter of
debate owing to the difficulties in defining and assessing
this parameter and the significant correlation between the
degree of morning BP surge (a potentially high-risk phenomenon) and the degree of BP fall at night (a potentially
protective phenomenon). Thus, the adverse prognostic
impact of a blunted or inverted night-time BP fall seems
difficult to reconcile with the hypothesis that an excessive
morning BP surge is also predictive of a worse outcome.
In a study of 3,012 patients with hypertension,48 a blunted
day-to-night BP dip, but not an increased morning BP
surge (in contrast to earlier studies68,84), was shown to be
148 | MARCH 2013 | VOLUME 10
Mid-term and long-term BPV
Day-to-day
Most studies on the prognostic relevance of BPV have
focused on short-term BP changes assessed with 24 h
ABPM. However, evidence also suggests that increased
day-to-day BPV identified by HBPM is associated with
increased prevalence and severity of cardiac, vascular,
and renal damage,91 and with an increased risk of fatal
and nonfatal cardiovascular events.92,93 A cross-sectional
analysis of individuals with untreated hypertension
showed that increased day-to-day BPV (assessed as the
maximum mean triplicate in home systolic BP over a
14 day period) was associated with the severity of cardiac
(left ventricular mass index), macrovascular (increased
carotid intima–media thickness), and microvascular
(urinary albumin:creatinine ratio) damage regardless
of the mean HBPM value. This finding suggests that
maximum home systolic BP might improve the prediction of hypertensive subclinical organ damage beyond
mean home systolic BP.91
The Ohasama study 92 provided the first evidence that
an increased day-to-day variability in systolic BP assessed
by HBPM is associated with an increased risk of the
compo­site of cardiac-related and stroke-related mortality.
Only the risk of stroke-related mortality was significant
when the components of the primary end point were considered separately.92 Further evidence on the prognostic
value of day-to-day BPV assessed by HBPM in the general
population was provided by the Finn-Home Study.93
After 7.8 years of follow-up, increasing levels of home-­
measured BPV (defined as the SDs of morning minus
evening and day-to-day home BP levels during 7 consecutive days) were found to be significant and independent
predictors of cardiovascular events, even after adjustment
for age and mean home BP.93 This study, therefore, supports the additive value of day-to-day home-measured
BPV in predicting cardiovascular prognosis.
Visit-to-visit
Visit-to-visit measures of BPV spaced by months, or
even years, have also been shown to have prognostic
value.2,30,31 In treated patients, whereas ABPM might
reflect BP control by antihypertensive medication over
a single 24 h period, visit-to-visit BPV reflects the degree
of BP control and the BP burden on the cardiovascular
system in the long term. Increased visit-to-visit BPV is
associated with cardiac (diastolic dysfunction),94 macro­
vascular (increased intima–media thickness and stiffness),33 microvascular (micro and macro albuminuria,
renal vascular atherosclerosis),95–97 and cerebral (white
matter hyperintensity volume and brain infarctions)98
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damage, as well as with endothelial dysfunction,99 and
impairment in cognitive function in the elderly. 100
Longitudinal studies and post‑hoc analyses of clinical
trials in patients with hypertension have shown that
increasing values of intraindividual visit-to-visit variability in OBP or ambulatory BP is predictive of fatal and
nonfatal cerebro­vascular 2,101–103 and coronary 102–104 events,
and of all-cause mortality,30 independent of mean OBP
or ambulatory BP. In some analyses, the predictive value
of intraindividual visit-to-visit BPV is even greater than
that of average BP during treatment,2 suggesting that the
protective effect of antihypertensive treatment depends
not only on the magni­tude of mean BP reduction, but
also on the consistency of on-treatment BP control in
the long term. Evidence in support of this hypothesis has
been provided by the INVEST study,31 conducted in a
population of high-risk patients with hypertension and
a history of coro­nary artery disease. The incidence of fatal
and non­fatal cardiovascular events, particularly stroke,
fell sharply as the percentage of clinic visits at which BP
was deemed to be controlled (<140/90 mmHg) increased
throughout the treatment period. This relationship was
independent of the control of mean OBP (Figure 4).31
The prognostic relevance of visit-to-visit BPV shown
in these studies supports the recommendation to avoid
inconsistent BP control and large BP differences from
one clinic visit to the next, by adequate dosing and titration of antihypertensive treatment and by impro­ving
adherence to treatment. However, these data relate only
to patients with hypertension who are at high cardiovascular risk.31 By contrast, a post‑hoc analysis of data
from ELSA 51 showed that, in treated patients with
mild-to-moderate hypertension who were at fairly low
cardio­vascular risk, visit-to-visit BPV made little or no
contribution to cardiovascular risk prediction over that
provided by mean BP. Neither was visit-to-visit BPV
associated with progression of organ damage or with
cardiovascular outcomes.51 Furthermore, in a study of
healthy individuals representative of the general population followed-up over a 12-year period, intraindividual
visit-to-visit BPV did not contribute to risk stratification
beyond mean systolic BP.105 Taken together, these findings suggest that the clinical relevance of visit-to-visit
BPV might, at least in part, depend on the level of total
cardiovascular risk.
The prognostic role of within-visit BPV (defined as
the SD of three OBP readings performed during a single
medical evaluation), which might reflect the white-coat
effect, was investigated by Muntner and colleagues.106 In
marked contrast to studies of visit-to-visit systolic BPV,
in which strong associations with outcomes and high
levels of reproducibility have been reported for highrisk patients, short-term within-visit BPV was neither
reproducible nor associated with an increased risk of allcause or cardiovascular mortality in a sample of 15,317
individuals from the general population.106 Although
more data are needed to clarify this issue, current evidence suggests that assessment of BPV based on values
obtained during office or clinic visits should focus on
measurements taken over longer periods of follow-up.
Clinic visits with
BP <140/90 mmHg (%)
HR (95% CI) for MI
<25 (n = 3,838)
1.00
25 to <50 (n = 3,757)
0.70 (0.57–0.86)
50 to <75 (n = 6,664)
0.68 (0.56–0.81)
≥75 (n = 8,316)
0.58 (0.48–0.69)
HR (95% CI)
HR (95% CI) for stroke
<25 (n = 3,838)
1.00
25 to <50 (n = 3,757)
0.89 (0.67–1.19)
50 to <75 (n = 6,664)
0.70 (0.52–0.92)
≥75 (n = 8,316)
0.50 (0.37–0.68)
0.4
0.6
0.8
Reduced
risk
1
1.2
Increased
risk
Figure 4 | Hazard ratio (HR) for MI or stroke according to the percentage of clinic
visits with BP <140/90 mmHg. The group in which this occurred in <25% of the
visits was taken as reference. Data were adjusted for differences in baseline
demographics, BP, and cardiovascular risk factors, as well as for in-treatment
average BP. As the proportion of visits with BP control increases, an associated
steep reduction in cardiovascular risk occurs, independent of baseline
characteristics and mean on-treatment BP. These data indicate that consistency of
BP control during treatment provides additional information on the protective effect
of antihypertensive treatment. Abbreviations: BP, blood pressure; MI, myocardial
infarction. Permission obtained from Wolters Kluwer Health © Mancia, G. et al.
Blood pressure control and improved cardiovascular outcomes in the International
Verapamil SR–Trandolapril Study. Hypertension 50, 299–305 (2007).
Target for antihypertensive therapy?
Experimental studies in rats have indicated a beneficial
effect of some drug classes, such as calcium-channel
blockers, in reducing short-term BPV and preventing
cardiac, renal, and brain damage.107 Such studies also
suggest plausible mechanisms for these benefits, for
example, restoration of baroreflex sensitivity.108,109 Most
studies in humans, using either intra-arterial or non­
invasive ABPM, have shown that 24 h BPV decreases
proportionally to reductions in mean BP with a variety of
antihypertensive treatments.110–117 Therefore, the effects
of antihypertensive therapy on short-term BPV are likely
to be the result of BP lowering per se. Additional longitudinal evidence is needed to determine whether some
drugs or treatment strategies have greater effects on 24 h
BPV than others, and whether a treatment-induced
reduction in short-term BPV might also reduce the
development or progression of organ damage and the
risk of cardiovascular events independently of mean BP.9
At present, the only evidence that modulation of 24 h
BPV with antihypertensive treatment in humans might
be cardioprotective comes from studies in which smoothness index (SI) was used to assess the distri­bution over
time of BP reduction by treatment.39,118 From analysis
of duplicated 24 h ABPM performed before and during
pharmacological treatment, the average of the 24-hourly
BP changes and its SD are determined. The SI is the
ratio between the average of the 24-hourly BP changes
induced by a given medication and its SD (Figure 5a).
This index provides a measure of both the amplitude and
the time distribution of the BP reduction obtained by a
given drug or drug combi­nation. SI has also been shown
NATURE REVIEWS | CARDIOLOGY VOLUME 10 | MARCH 2013 | 149
© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
∆BP (mmHg)
a
∆H/SD = 3.7
SI
0
–5
–10
∆H = 8.6
SD = 2.3
–15
0
b 25
8
12
16
Time from drug intake (h)
60
r = 0.25
P <0.01
17
13
9
5
24
0
–30
–60
–90
0
–110
–6
∆CBmax IMT 12 months (mm)
20
r = –0.35
P <0.01
30
∆LVMI 12 months (mmHg)
21
SD 12 months (mmHg)
4
–3
0
3
SI 12 months
6
–6
–3
0
3
SI 12 months
6
0.5
y = –0.041x + 0.0718
r = –0.31, P <0.01
0.3
0.1
0.1
0.3
0.5
–2
–1
0
1
2
SI 12 months
3
4
5
6
to be related to drug-induced regression of myocardial
damage (for example, left ventricular hypertrophy)39 and
reduced progression of carotid artery wall thickening,
independently of basal mean BP (Figure 5b).118
Target for cardiovascular prevention?
The primary goals of antihypertensive treatment are to
protect against the development and progression of subclinical organ damage, which confers increased cardio­
vascular risk, and to directly prevent cardiovascular
events. Targeting of antihypertensive treatment towards
stabilizing long-term BPV, in addition to reducing
average BP to optimize cardiovascular protection, has
been suggested.60 However, data from most controlled
trials of various antihypertensive agents strongly support
the preponderant role of mean BP reduction in reducing
c­ardiovascular risk.119,120
A post‑hoc analysis of data from ASCOT and
MRC-elderly showed that long-term intraindividual
150 | MARCH 2013 | VOLUME 10
▶ Figure 5 | Measurement and prognostic relevance of SI.
a | Calculation of the SI from hourly BP values obtained
before and during treatment by 24 h ambulatory BP
monitoring. The SI is obtained by first calculating the
average BP values for each hour of the 24 h monitoring
period, both before and during treatment. From these
values, all hourly changes in BP induced by treatment are
obtained, and the average of these hourly values (∆H) is
computed together with its SD, which represents the
dispersion of the antihypertensive effect over the 24 hourly
values. Finally, the SD is normalized by dividing its value for
∆H, and the inverse of this ratio indicating the degree of
‘smoothness’ of BP reduction by treatment is termed
‘smoothness index’. Permission obtained from Wolters
Kluwer Health © Parati, G. et al. The smoothness index: a
new, reproducible and clinically relevant measure of the
homogeneity of the blood pressure reduction with
treatment for hypertension. J. Hypertens. 16, 1685–1691
(1998). b | Relationship between SI of systolic BP, with
changes in 24 h SD of systolic BP (left panel), in LVMI (right
panel) and in CBmax IMT (bottom panel) after 12 months of
antihypertensive treatment. Higher values of SI were
associated with significant reductions in indices of carotid
artery intima–media thickness during therapy, independent
of basal BP values suggesting that, for carotid artery
morphology, the smoothness of BP reduction is even more
important than its absolute change. Permission obtained
from Wolters Kluwer Health © Rizzoni, D. et al. The
smoothness index, but not the trough-to-peak ratio predicts
changes in carotid artery wall thickness during
antihypertensive treatment. J. Hypertens. 19, 703–711
(2001). Abbreviations: BP, blood pressure; CBmax IMT,
maximum value of common carotid artery plus bifurcation
mean maximum intima–media thickness; ∆H, average of
treatment-induced BP reductions for each hour over 24 h;
LVMI, left ventricular mass index; SI, smoothness index.
visit-to-visit BPV might be differentially affected by
various classes of antihypertensive drug, and that
these differences might explain the variable effects
of BP-lowering drugs in preventing cardiovascular
events.102 The most-important finding of this analysis was that a regimen based on the calcium-channel
antagonist amlodipine was also associated with lower
intraindividual BPV and a lower incidence of stroke than
a regimen based on the β‑blocker atenolol, in­dependent
of mean BP. The investi­gators concluded that β‑blockers
do not control BP to the same extent as calcium-­channel
antagonists. 102 Contrasting results were observed in
a post‑hoc analysis of the ELSA study in patients with
mild-to-moderate hypertension, in which no substantial differences in intra­i ndividual visit-to-visit BPV
were observed between use of a β‑blocker or a calciumchannel antagonist. 51 When the pooled data of this
study were analyzed, carotid intima–media thickness
and cardiovascular outcomes were related to the mean
office or ambulatory systolic BP achieved by treatment,
but not to on-treatment visit-to-visit office or 24 h BPV
(Figure 6).121 A post‑hoc analysis of data from the J‑CORE
study, provided evidence that combination therapy with
a calcium-channel blocker and renin–­angiotensinsystem blockers decreased day-to-day home-measured
BPV (defined as within-individual SD of BP measures
performed over 5 consecutive days) and aortic pulse
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a 1.7
CIMT (mm)
1.5
Unadjusted P = 0.0001
Adjusted P = 0.048
Unadjusted P = 0.039
Adjusted P = 0.055
Unadjusted P = 0.925
Adjusted P = 0.011
≤5.8
≤4.2
1.3
1.1
0.9
0
≤134.0 134.0 to 140.5 to ≥146.9
<140.5 <146.9
Clinic SBP mean (mmHg)
1.7
CIMT (mm)
1.5
5.8 to
8.0 to ≥10.6
<8.0
<10.6
Clinic SBP SD (mmHg)
Unadjusted P = 0.0002
Adjusted P = 0.455
Unadjusted P = 0.0001
Adjusted P = 0.046
4.2 to 5.7 to
<5.7
<7.5
Clinic SBP CV (%)
≥7.5
Unadjusted P = 0.042
Adjusted P = 0.645
1.3
1.1
0.9
0
≤123.8 123.8 to 130.9 to ≥138.8
<130.9 <138.8
24 h SBP mean (mmHg)
Events (%)
b 8
≤3.8
3.8 to
5.6 to ≥8.2
<5.6
<8.2
24 h SBP SD (mmHg)
≤2.9
P = 0.0003
NS
6
NS
≥6.2
Below median
Above median
P = 0.0066
NS
4
2.9 to 4.3 to
<4.3
<6.2
24 h SBP CV (%)
NS
2
0
≤141 >141
≤7.8 >7.8
≤5.5 >5.5
≤131 >131
≤5.3 >5.3
≤4.0 >4.0
Clinic SBP mean
(mmHg)
Clinic SBP SD
(mmHg)
Clinic SBP CV
(%)
24 h SBP mean
(mmHg)
24 h SBP SD
(mmHg)
24 h SBP CV
(%)
Figure 6 | Visit-to-visit BPV, carotid atherosclerosis, and cardiovascular events in the European Lacidipine Study on
Atherosclerosis.121 a | CIMT at the end of the 4‑year treatment period in quartiles of on-treatment office (upper panel) and
24 h (lower panel) SBP mean, SD, or CV. CIMT was related to the mean clinic or ambulatory SBP achieved by treatment, but
not to the on-treatment visit-to-visit clinic or 24 h BPV (assessed either with the SD of the mean on-treatment SBP or with
the CV). b | Rate of cardiovascular events in patients with an on-treatment clinic or 24 h SBP mean, SD, or CV above or
below the median value for the group as a whole. Cardiovascular events were related to the mean clinic or ambulatory SBP
achieved by treatment, but not to the on-treatment visit-to-visit clinic or 24 h BPV (assessed either with the SD of the mean
on-treatment SBP or with the CV). The findings in both (a) and (b) suggest that, when BP is only modestly elevated, the
average long-term BP level is more prognostically relevant than the difference in BP between visits. Abbreviations: BPV,
blood-pressure variability; CIMT, carotid intima–media thickness; CV, coefficient of variation; SBP, systolic BP. Permission
obtained from Wolters Kluwer Health © Mancia, G. et al. Visit-to-visit blood pressure variability, carotid atherosclerosis, and
cardiovascular events in the European Lacidipine Study on Atherosclerosis. Circulation 126, 569–578 (2012).
wave velocity more effectively than the combination
of a diuretic and renin–angiotensin-system blockers.122
Reductions in home BP were, however, similar with both
regimens after a 24‑week follow-up period.122
Meta-analyses of a large number of post‑hoc studies
have shown that differences exist in the effectiveness of
stroke prevention between classes of antihypertensive
drugs, despite little or no difference in their effect on mean
BP. This finding might be the result of differential class
effects on interindividual BPV (that is, between-patient
dispersion of mean BP during treatment).123,124 However,
a major limitation of interindividual BPV is that it represents the effect of BP treatment in a group of patients and
does not accurately reflect visit-to-visit BPV in individual
patients. Moreover, reports from inter­ventional trials have
indicated that interindividual BPV might be substantially
greater than intraindividual BPV,51 suggesting that factors
other than intraindividual oscillations might be important
components of inter­individual BPV and explain the difference between treatments. Since interindividual BPV is
likely to be a marker of a different individual characteristics in cardio­vascular regulation, it should be clinically
interpreted as an unsatisfactory surrogate of visit-to-visit
intraindividual BPV.125 More-reliable measurements,
such as HBPM with long-term treatment, must be implemented in upcoming clinical trials to better determine the
efficacy of various antihypertensive drug classes on ‘real’
day-to-day BPV and cardiovascular outcomes.
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Given the prognostic relevance of visit-to-visit BPV,
consistency of BP control could be inferred to represent
an additional important goal of antihypertensive treatment. Indeed, the INVEST study 31 has shown that an
increase in the proportion of clinic visits at which BP
is controlled is accompanied by a progressive reduction in the risk of cardiovascular events, independent
of mean BP during treatment. However, most evidence
for visit-to-visit BPV in relation to progression of organ
damage or incidence of cardiovascular events has been
obtained from post‑hoc analyses of trial data and based
on comparisons between nonrandomized groups, which
might introduce a large number of potential confounders. Furthermore, BPV has not always been quantified
using a sufficient number of measurements, nor using
standardized methodologies (that is, visit-to-visit BPV
measured in the office has only a very limited relationship with visit-to-visit BPV measured over 24 h with
ABPM).51 The consistency of OBP control might not,
therefore, reflect that of 24 h BP control—a measure of
recognized prognostic importance.74,75,81
Conclusions
Current knowledge on the mechanisms of short-term
BPV within a 24 h period is limited, and additional
studies will be needed to improve our understanding
of its potential determinants, such as reduced arterial
compliance and genetic variation. Similarly, we still have
much to learn about the factors responsible for long-term
BPV during antihypertensive treatment. The influence
of neurohumoral and cardiovascular functional and
structural alterations cannot be disregarded. However,
determining the extent to which the timing of clinic BP
measurements in relation to drug administration, as
well as patient adherence to antihypertensive treatment,
i­nfluence visit‑to-visit BPV is also important.
Accumulating evidence indicates that both short-term
and long-term BPV are associated with the development,
progression, and severity of cardiac, vascular, and renal
damage, and with an increased risk of cardiovascular
events and mortality, independent of elevated mean
BP. In clinical trials, long-term BPV is associated with
cardiovascular outcomes to a far greater extent than
1.
2.
3.
4.
5.
Mancia, G. Short- and long-term blood pressure
variability: present and future. Hypertension 60,
512–517 (2012).
Rothwell, P. M. et al. Prognostic significance of
visit‑to‑visit variability, maximum systolic blood
pressure, and episodic hypertension. Lancet
375, 895–905 (2010).
Mancia, G. et al. Arterial baroreflexes and blood
pressure and heart rate variabilities in humans.
Hypertension 8, 147–153 (1986).
Conway, J., Boon, N., Davies, C., Jones, J. V.
& Sleight, P. Neural and humoral mechanisms
involved in blood pressure variability.
J. Hypertens. 2, 203–208 (1984).
Schillaci, G. et al. Relationship between shortterm blood pressure variability and large-artery
stiffness in human hypertension: findings from 2
large databases. Hypertension 60, 369–377
(2012).
152 | MARCH 2013 | VOLUME 10
short-term BPV. Although the suggestion has been made
to target antihypertensive treatment towards both normalizing 24 h BPV and reducing average 24 h BP, evidence
about optimal BPV targets is still limited. In large-scale
trials of antihypertensive treatment, 24 h ABPM has not
been routinely used. Therefore, the protective effect of
treatment-­induced changes in 24 h BPV, with respect
to the concomitant changes in mean BP levels, is still to
be adequately documented. Regarding long-term BPV,
meta-analyses of clinical trials on hypertension have
shown that visit-to-visit BPV, or lack of BP control at any
given clinic visit, is associated with an adverse cardio­
vascular prognosis. This finding draws attention to the
importance of consistent BP control over time. In practi­
cal terms, assessment of long-term BPV, ideally on a
day-to-day basis using HBPM, might help physicians to
optimize antihypertensive treatment at every clinic visit,
thus improving long-term BP stabilization.
Although meta-analyses have suggested that the
cardio­protective effects of specific drug classes might be
explained by their capacity to reduce BPV, this matter is
still up for debate and will require additional research to
reach a definitive conclusion. Before BPV is recommen­
ded as a target for antihypertensive treatment in daily
clinical practice, further prospective outcome studies
should be conducted to determine whether a treatmentinduced reduction in BPV is accompanied by a corres­
ponding reduction in cardiovascular risk, and to clarify
the magnitude of the increase in the event rate conferred
by BPV independently of elevated mean BP.71
Review criteria
References for this Review were retrieved from the
PUBMED-MEDLINE databases. Search terms included
“blood pressure variability”, “short-term blood pressure
variability”, “circadian blood pressure profiles”, “visitto-visit blood pressure variability”, “day-by-day blood
pressure variability”, “blood pressure variability
and outcome”, and “blood pressure variability and
antihypertensive treatment”. Most papers considered
were full-text papers published in English language
between 2002 and 2012.
6.
Mancia, G. et al. in Handbook of Hypertension:
Pathophysiology of Hypertension (eds Mancia, G.
& Zanchetti, A.) 117–169 (Elsevier Science,
Amsterdam, 1997).
7. Mancia, G. & Grassi, G. Mechanisms and clinical
implications of blood pressure variability.
J. Cardiovasc. Pharmacol. 35, S15–S19 (2000).
8. Parati, G., Saul, J. P., Di Rienzo, M. & Mancia, G.
Spectral analysis of blood pressure and heart
rate variability in evaluating cardiovascular
regulation. A critical appraisal. Hypertension 25,
1276–1286 (1995).
9. Parati, G., Faini, A. & Valentini, M. Blood
pressure variability: its measurement and
significance in hypertension. Curr. Hypertens.
Rep. 8, 199–204 (2006).
10. Kotsis, V. et al. Arterial stiffness and 24 h
ambulatory blood pressure monitoring in young
healthy volunteers: the early vascular ageing
11.
12.
13.
14.
Aristotle University Thessaloniki Study
(EVA-ARIS Study). Atherosclerosis 219, 194–199
(2011).
Fukui, M. et al. Home blood pressure variability
on one occasion is a novel factor associated
with arterial stiffness in patients with type 2
diabetes. Hypertens. Res. http://
dx.doi.org/10.1038/hr.2012.177.
Parati, G. et al. Sequential spectral analysis of
24-hour blood pressure and pulse interval in
humans. Hypertension 16, 414–421 (1990).
Berge, K. E. & Berg, K. No effect of a BglI
polymorphism at the renin (REN) locus on blood
pressure level or variability. Clin. Genet. 46,
436–438 (1994).
Berge, K. E. & Berg, K. No effect on blood
pressure level or variability of polymorphisms
in DNA at the locus for atrial natriuretic factor
(ANF). Clin. Genet. 46, 433–435 (1994).
www.nature.com/nrcardio
© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
15. Berge, K. E. & Berg, K. No effect of insertion/
deletion polymorphism at the ACE locus on
normal blood pressure level or variability.
Clin. Genet. 45, 169–174 (1994).
16. Julve, R. et al. Polymorphism insertion/deletion
of the ACE gene and ambulatory blood pressure
circadian variability in essential hypertension.
Blood Press. Monit. 6, 27–32 (2001).
17. Etzel, J. P. et al. Genetic variation at the human
alpha2B-adrenergic receptor locus: role in
blood pressure variation and yohimbine
response. Hypertension 45, 1207–1213
(2005).
18. Jira, M. et al. Association of eNOS gene
polymorphisms T‑786C and G894T with blood
pressure variability in man. Physiol. Res. 60,
193–197 (2011).
19. Friedman, O. & Logan, A. G. Nocturnal blood
pressure profiles among normotensive,
controlled hypertensive and refractory
hypertensive subjects. Can. J. Cardiol. 25,
e312–e316 (2009).
20. Pickering, T. G. et al. Recommendations for
blood pressure measurement in humans and
experimental animals: Part 1: blood pressure
measurement in humans: a statement for
professionals from the Subcommittee of
Professional and Public Education of the
American Heart Association Council on High
Blood Pressure Research. Hypertension 45,
142–161 (2005).
21. Narkiewicz, K. et al. Relationship between
muscle sympathetic nerve activity and diurnal
blood pressure profile. Hypertension 39,
168–172 (2002).
22. Fujii, T. et al. Circadian rhythm of natriuresis is
disturbed in nondipper type of essential
hypertension. Am. J. Kidney Dis. 33, 29–35
(1999).
23. Verdecchia, P. et al. Blunted nocturnal fall in
blood pressure in hypertensive women with
future cardiovascular morbid events. Circulation
88, 986–992 (1993).
24. Haynes, W. G. Role of leptin in obesity-related
hypertension. Exp. Physiol. 90, 683–688
(2005).
25. Quinaglia, T. et al. Non-dipping pattern relates
to endothelial dysfunction in patients with
uncontrolled resistant hypertension. J. Hum.
Hypertens. 25, 656–664 (2011).
26. Holt-Lunstad, J. & Steffen, P. R. Diurnal cortisol
variation is associated with nocturnal blood
pressure dipping. Psychosom. Med. 69,
339–343 (2007).
27. Panarelli, M. et al. 24-hour profiles of blood
pressure and heart rate in Cushing’s syndrome.
Evidence for differential control of
cardiovascular variables by glucocorticoids.
Ann. Ital. Med. Int. 5, 18–25 (1990).
28. Murakami, S. et al. Weekly variation of home
and ambulatory blood pressure and relation
between arterial stiffness and blood pressure
measurements in community-dwelling
hypertensives. Clin. Exp. Hypertens. 27,
231–239 (2005).
29. Muntner, P. et al. Reproducibility of visit‑to‑visit
variability of blood pressure measured as part
of routine clinical care. J. Hypertens. 29,
2332–2338 (2011).
30. Muntner, P. et al. The relationship between
visit‑to‑visit variability in systolic blood pressure
and all-cause mortality in the general
population: findings from NHANES III, 1988 to
1994. Hypertension 57, 160–166 (2011).
31. Mancia, G. et al. Blood pressure control and
improved cardiovascular outcomes in the
International Verapamil SR‑Trandolapril Study.
Hypertension 50, 299–305 (2007).
32. Okada, H. et al. Visit‑to‑visit variability in systolic
blood pressure is correlated with diabetic
nephropathy and atherosclerosis in patients with
type 2 diabetes. Atherosclerosis 220, 155–159
(2012).
33. Nagai, M., Hoshide, S., Ishikawa, J., Shimada, K.
& Kario, K. Visit‑to‑visit blood pressure
variations: new independent determinants for
carotid artery measures in the elderly at high
risk of cardiovascular disease. J. Am.
Soc. Hypertens. 5, 184–192 (2011).
34. Parati, G. & Bilo, G. Calcium antagonist added to
angiotensin receptor blocker: a recipe for
reducing blood pressure variability? Evidence
from day‑by‑day home blood pressure
monitoring. Hypertension 59, 1091–1093
(2012).
35. Sega, R. et al. Seasonal variations in home and
ambulatory blood pressure in the PAMELA
population. Pressione Arteriose Monitorate E
Loro Associazioni. J. Hypertens. 16, 1585–1592
(1998).
36. Modesti, P. A. et al. Weather-related changes in
24-hour blood pressure profile: effects of age
and implications for hypertension management.
Hypertension 47, 155–161 (2006).
37. Mancia, G. et al. Blood pressure and heart rate
variabilities in normotensive and hypertensive
human beings. Circ. Res. 53, 96–104 (1983).
38. Parati, G., Pomidossi, G., Albini, F., Malaspina, D.
& Mancia, G. Relationship of 24-hour blood
pressure mean and variability to severity of
target-organ damage in hypertension.
J. Hypertens. 5, 93–98 (1987).
39. Parati, G., Omboni, S., Rizzoni, D.,
Agabiti‑Rosei, E. & Mancia, G. The smoothness
index: a new, reproducible and clinically relevant
measure of the homogeneity of the blood
pressure reduction with treatment for
hypertension. J. Hypertens. 16, 1685–1691
(1998).
40. Mancia, G., Di Rienzo, M. & Parati, G. Ambulatory
blood pressure monitoring use in hypertension
research and clinical practice. Hypertension 21,
510–524 (1993).
41. Bilo, G. et al. A new method for assessing 24‑h
blood pressure variability after excluding the
contribution of nocturnal blood pressure fall.
J. Hypertens. 25, 2058–2066 (2007).
42. Mancia, G. et al. Long-term prognostic value of
blood pressure variability in the general
population: results of the Pressioni Arteriose
Monitorate e Loro Associazioni Study.
Hypertension 49, 1265–1270 (2007).
43. Mena, L. et al. A reliable index for the prognostic
significance of blood pressure variability.
J. Hypertens. 23, 505–511 (2005).
44. Stolarz-Skrzypek, K. et al. Blood pressure
variability in relation to outcome in the
International Database of Ambulatory blood
pressure in relation to Cardiovascular Outcome.
Hypertens. Res. 33, 757–766 (2010).
45. Boggia, J. et al. Prognostic accuracy of day
versus night ambulatory blood pressure: a
cohort study. Lancet 370, 1219–1229 (2007).
46. Hansen, T. W. et al. Predictive role of the
nighttime blood pressure. Hypertension 57,
3–10 (2011).
47. Lurbe, E. et al. Increase in nocturnal blood
pressure and progression to microalbuminuria in
type 1 diabetes. N. Engl. J. Med. 347, 797–805
(2002).
48. Verdecchia, P. et al. Day-night dip and earlymorning surge in blood pressure in
hypertension: prognostic implications.
Hypertension 60, 34–42 (2012).
49. Parati, G. et al. European Society of
Hypertension guidelines for blood pressure
NATURE REVIEWS | CARDIOLOGY 50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
monitoring at home: a summary report of the
Second International Consensus Conference on
Home Blood Pressure Monitoring. J. Hypertens.
26, 1505–1526 (2008).
McManus, R. J. et al. Targets and self monitoring
in hypertension: randomised controlled trial and
cost effectiveness analysis. BMJ 331, 493
(2005).
Mancia, G., Facchetti, R., Parati, G. &
Zanchetti, A. Visit‑to‑visit blood pressure
variability in the European Lacidipine Study on
Atherosclerosis: methodological aspects and
effects of antihypertensive treatment.
J. Hypertens. 30, 1241–1251 (2012).
Stergiou, G. S. & Nasothimiou, E. G. Home
monitoring is the optimal method for assessing
blood pressure variability. Hypertens. Res. 34,
1246–1248 (2011).
Cappuccio, F. P., Kerry, S. M., Forbes, L. &
Donald, A. Blood pressure control by home
monitoring: meta-analysis of randomised trials.
BMJ 329, 145 (2004).
Rogers, M. A. et al. Home monitoring service
improves mean arterial pressure in patients with
essential hypertension. A randomized, controlled
trial. Ann. Intern. Med. 134, 1024–1032 (2001).
Mancia, G. et al. 2007 Guidelines for the
Management of Arterial Hypertension: The Task
Force for the Management of Arterial
Hypertension of the European Society of
Hypertension (ESH) and of the European Society
of Cardiology (ESC). J. Hypertens. 25,
1105–1187 (2007).
Whitworth, J. A. for the World Health
Organization, International Society of
Hypertension Writing Group. 2003 World Health
Organization (WHO)/International Society of
Hypertension (ISH) statement on management
of hypertension. J. Hypertens. 21, 1983–1992
(2003).
Imai, Y. et al. Japanese society of hypertension
(JSH) guidelines for self-monitoring of blood
pressure at home. Hypertens. Res. 26, 771–782
(2003).
Parati, G. et al. Home blood pressure
telemonitoring improves hypertension control
in general practice. The TeleBPCare study.
J. Hypertens. 27, 198–203 (2009).
Mancia, G. et al. Relation between blood
pressure variability and carotid artery damage in
hypertension: baseline data from the European
Lacidipine Study on Atherosclerosis (ELSA).
J. Hypertens. 19, 1981–1989 (2001).
Mancia, G. & Parati, G. The role of blood
pressure variability in end-organ damage.
J. Hypertens. 21, S17–S23 (2003).
Sega, R. et al. Blood pressure variability and
organ damage in a general population: results
from the PAMELA study (Pressioni Arteriose
Monitorate E Loro Associazioni). Hypertension
39, 710–714 (2002).
Tatasciore, A. et al. Awake systolic blood
pressure variability correlates with target-organ
damage in hypertensive subjects. Hypertension
50, 325–332 (2007).
Manios, E. et al. Time rate of blood pressure
variation is associated with impaired renal
function in hypertensive patients. J. Hypertens.
27, 2244–2248 (2009).
Frattola, A., Parati, G., Cuspidi, C., Albini, F. &
Mancia, G. Prognostic value of 24-hour blood
pressure variability. J. Hypertens. 11,
1133–1137 (1993).
Sander, D., Kukla, C., Klingelhofer, J., Winbeck, K.
& Conrad, B. Relationship between circadian
blood pressure patterns and progression of early
carotid atherosclerosis: a 3‑year follow-up study.
Circulation 102, 1536–1541 (2000).
VOLUME 10 | MARCH 2013 | 153
© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
66. Dawson, S. L., Manktelow, B. N., Robinson, T. G.,
Panerai, R. B. & Potter, J. F. Which parameters of
beat‑to‑beat blood pressure and variability best
predict early outcome after acute ischemic
stroke? Stroke 31, 463–468 (2000).
67. Pringle, E. et al. Systolic blood pressure
variability as a risk factor for stroke and
cardiovascular mortality in the elderly
hypertensive population. J. Hypertens. 21,
2251–2257 (2003).
68. Kario, K. et al. Morning surge in blood pressure
as a predictor of silent and clinical
cerebrovascular disease in elderly
hypertensives: a prospective study. Circulation
107, 1401–1406 (2003).
69. Kario, K. et al. Morning hypertension: the
strongest independent risk factor for stroke in
elderly hypertensive patients. Hypertens. Res.
29, 581–587 (2006).
70. Verdecchia, P., Angeli, F., Gattobigio, R.,
Rapicetta, C. & Reboldi, G. Impact of blood
pressure variability on cardiac and
cerebrovascular complications in hypertension.
Am. J. Hypertens. 20, 154–161 (2007).
71. Hansen, T. W. et al. Prognostic value of
reading‑to‑reading blood pressure variability
over 24 hours in 8,938 subjects from 11
populations. Hypertension 55, 1049–1057
(2010).
72. Kikuya, M. et al. Prognostic significance of
blood pressure and heart rate variabilities: the
Ohasama study. Hypertension 36, 901–906
(2000).
73. Stolarz-Skrzypek, K. et al. Short-term blood
pressure variability in relation to outcome in the
International Database of Ambulatory blood
pressure in relation to Cardiovascular Outcome
(IDACO). Acta Cardiol. 66, 701–706 (2011).
74. Staessen, J. A. et al. Predicting cardiovascular
risk using conventional vs ambulatory blood
pressure in older patients with systolic
hypertension. JAMA 282, 539–546 (1999).
75. Sega, R. et al. Prognostic value of ambulatory
and home blood pressures compared with
office blood pressure in the general population:
follow-up results from the Pressioni Arteriose
Monitorate e Loro Associazioni (PAMELA) study.
Circulation 111, 1777–1783 (2005).
76. Clement, D. L. et al. Prognostic value of
ambulatory blood-pressure recordings in
patients with treated hypertension. N. Engl.
J. Med. 348, 2407–2415 (2003).
77. Fagard, R. H., Van Den Broeke, C. & De Cort, P.
Prognostic significance of blood pressure
measured in the office, at home and during
ambulatory monitoring in older patients in
general practice. J. Hum. Hypertens. 19,
801–807 (2005).
78. Redon, J. et al. Prognostic value of ambulatory
blood pressure monitoring in refractory
hypertension: a prospective study.
Hypertension 31, 712–718 (1998).
79. Kikuya, M. et al. Ambulatory blood pressure and
10-year risk of cardiovascular and
noncardiovascular mortality: the Ohasama
study. Hypertension 45, 240–245 (2005).
80. Fagard, R. H. et al. Daytime and nighttime blood
pressure as predictors of death and causespecific cardiovascular events in hypertension.
Hypertension 51, 55–61 (2008).
81. Dolan, E. et al. Superiority of ambulatory over
clinic blood pressure measurement in
predicting mortality: the Dublin outcome study.
Hypertension 46, 156–161 (2005).
82. Hansen, T. W., Jeppesen, J., Rasmussen, S.,
Ibsen, H. & Torp-Pedersen, C. Ambulatory blood
pressure and mortality: a population-based
study. Hypertension 45, 499–504 (2005).
154 | MARCH 2013 | VOLUME 10
83. Kawai, T. et al. Differences between daytime and
nighttime blood pressure variability regarding
systemic atherosclerotic change and renal
function. Hypertens. Res. http://dx.doi.org/
10.1038/hr.2012.162.
84. Metoki, H. et al. Prognostic significance for
stroke of a morning pressor surge and a
nocturnal blood pressure decline: the Ohasama
study. Hypertension 47, 149–154 (2006).
85. Ohkubo, T. et al. Relation between nocturnal
decline in blood pressure and mortality. The
Ohasama Study. Am. J. Hypertens. 10,
1201–1207 (1997).
86. Willich, S. N., Goldberg, R. J., Maclure, M.,
Perriello, L. & Muller, J. E. Increased onset of
sudden cardiac death in the first three hours
after awakening. Am. J. Cardiol. 70, 65–68
(1992).
87. Rocco, M. B. et al. Circadian variation of
transient myocardial ischemia in patients with
coronary artery disease. Circulation 75,
395–400 (1987).
88. Muller, J. E. et al. Circadian variation in the
frequency of onset of acute myocardial
infarction. N. Engl. J. Med. 313, 1315–1322
(1985).
89. Elliott, W. J. Circadian variation in the timing of
stroke onset: a meta-analysis. Stroke 29,
992–996 (1998).
90. Amici, A. et al. Exaggerated morning blood
pressure surge and cardiovascular events.
A 5‑year longitudinal study in normotensive
and well-controlled hypertensive elderly.
Arch. Gerontol. Geriatr. 49, e105–e109
(2009).
91. Matsui, Y. et al. Maximum value of home blood
pressure: a novel indicator of target organ
damage in hypertension. Hypertension 57,
1087–1093 (2011).
92. Kikuya, M. et al. Day‑by‑day variability of blood
pressure and heart rate at home as a novel
predictor of prognosis: the Ohasama study.
Hypertension 52, 1045–1050 (2008).
93. Johansson, J. K., Niiranen, T. J., Puukka, P. J.
& Jula, A. M. Prognostic value of the variability
in home-measured blood pressure and heart
rate: the Finn-Home Study. Hypertension 59,
212–218 (2012).
94. Masugata, H. et al. Visit‑to‑visit variability in
blood pressure over a 1‑year period is a marker
of left ventricular diastolic dysfunction in
treated hypertensive patients. Hypertens. Res.
34, 846–850 (2011).
95. Kilpatrick, E. S., Rigby, A. S. & Atkin, S. L.
The role of blood pressure variability in the
development of nephropathy in type 1
diabetes. Diabetes Care 33, 2442–2247
(2010).
96. Kawai, T. et al. The impact of visit‑to‑visit
variability in blood pressure on renal function.
Hypertens. Res. 35, 239–243 (2012).
97. Yokota, K. et al. Impact of visit‑to‑visit variability
of blood pressure on deterioration of renal
function in patients with non-diabetic chronic
kidney disease. Hypertens. Res. http://
dx.doi.org/10.1038/hr.2012.145.
98. Brickman, A. M. et al. Long-term blood pressure
fluctuation and cerebrovascular disease in an
elderly cohort. Arch. Neurol. 67, 564–569
(2010).
99. Diaz, K. M. et al. Relationship of visit‑to‑visit
and ambulatory blood pressure variability to
vascular function in African Americans.
Hypertens. Res. 35, 55–61 (2012).
100.Nagai, M., Hoshide, S., Ishikawa, J., Shimada,
K. & Kario, K. Visit‑to‑visit blood pressure
variations: new independent determinants for
cognitive function in the elderly at high risk of
cardiovascular disease. J. Hypertens. 30,
1556–1563 (2012).
101.Hata, Y. et al. Office blood pressure variability as
a predictor of brain infarction in elderly
hypertensive patients. Hypertens. Res. 23,
553–560 (2000).
102.Rothwell, P. M. et al. Effects of beta blockers and
calcium-channel blockers on within-individual
variability in blood pressure and risk of stroke.
Lancet Neurol. 9, 469–480 (2010).
103.Eguchi, K., Hoshide, S., Schwartz, J. E.,
Shimada, K. & Kario, K. Visit‑to‑visit and
ambulatory blood pressure variability as
predictors of incident cardiovascular events in
patients with hypertension. Am. J. Hypertens. 25,
962–968 (2012).
104.Hata, Y. et al. Office blood pressure variability as
a predictor of acute myocardial infarction in
elderly patients receiving antihypertensive
therapy. J. Hum. Hypertens. 16, 141–146
(2002).
105.Schutte, R. et al. Within-subject blood pressure
level—not variability—predicts fatal and nonfatal
outcomes in a general population. Hypertension
60, 1138–1147 (2012).
106.Muntner, P. et al. Within-visit variability of blood
pressure and all-cause and cardiovascular
mortality among US adults. J. Clin. Hypertens.
(Greenwich) 14, 165–171 (2012).
107.Liu, J. G., Xu, L. P., Chu, Z. X., Miao, C. Y.
& Su, D. F. Contribution of blood pressure
variability to the effect of nitrendipine on endorgan damage in spontaneously hypertensive
rats. J. Hypertens. 21, 1961–1967 (2003).
108.Xie, H. H., Miao, C. Y., Jiang, Y. Y. & Su, D. F.
Synergism of atenolol and nitrendipine on
hemodynamic amelioration and organ protection
in hypertensive rats. J. Hypertens. 23, 193–201
(2005).
109.Xie, H. H. et al. Reduction of blood pressure
variability by combination therapy in
spontaneously hypertensive rats. J. Hypertens.
25, 2334–2344 (2007).
110.Ferrari, A. et al. Labetalol and 24-hour monitoring
of arterial blood pressure in hypertensive
patients. J. Cardiovasc. Pharmacol. 3 (Suppl. 1),
S42–S52 (1981).
111.Mancia, G. et al. Evaluation of a slow-release
clonidine preparation by direct continuous blood
pressure recording in essential hypertensive
patients. J. Cardiovasc. Pharmacol. 3,
1193–1202 (1981).
112.Mancia, G. et al. Twenty-four-hour blood pressure
profile and blood pressure variability in
untreated hypertension and during
antihypertensive treatment by once-a-day
nadolol. Am. Heart J. 108, 1078–1083 (1984).
113.Pomidossi, G., Parati, G., Motolese, M.,
Mancia, G. & Zanchetti, A. Hemodynamic effects
of once a day administration of combined
chlorthalidone and metoprolol slow-release in
essential hypertension. Int. J. Clin. Pharmacol.
Ther. Toxicol. 22, 665–671 (1984).
114.Pomidossi, G. et al. Antihypertensive effect of a
new formulation of slow release oxprenolol in
essential hypertension. J. Cardiovasc. Pharmacol.
10, 593–598 (1987).
115.Parati, G. et al. 24‑h ambulatory non-invasive
blood pressure monitoring in the assessment of
the antihypertensive action of celiprolol. J. Int.
Med. Res. 16 (Suppl. 1), 52A–61A (1988).
116.Mancia, G. et al. Evaluation of the
antihypertensive effect of once‑a‑day trandolapril
by 24-hour ambulatory blood pressure
monitoring. The Italian Trandolapril Study Group.
Am. J. Cardiol. 70, 60D–66D (1992).
117.Mancia, G., Omboni, S., Ravogli, A., Parati, G.
& Zanchetti, A. Ambulatory blood pressure
www.nature.com/nrcardio
© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
monitoring in the evaluation of antihypertensive
treatment: additional information from a large
data base. Blood Press. 4, 148–156 (1995).
118.Rizzoni, D. et al. The smoothness index, but not
the trough‑to‑peak ratio predicts changes in
carotid artery wall thickness during
antihypertensive treatment. J. Hypertens. 19,
703–711 (2001).
119.Collins, R. et al. Blood pressure, stroke, and
coronary heart disease. Part 2, Short-term
reductions in blood pressure: overview of
randomised drug trials in their epidemiological
context. Lancet 335, 827–838 (1990).
120.Turnbull, F. for the Blood Pressure Lowering
Treatment Trialists’ Collaboration. Effects of
different blood‑pressure‑lowering regimens on
major cardiovascular events: results of
prospectively-designed overviews of
randomised trials. Lancet 362, 1527–1535
(2003).
121.Mancia, G., Facchetti, R., Parati, G. &
Zanchetti, A. Visit‑to‑visit blood pressure
variability, carotid atherosclerosis, and
cardiovascular events in the European
Lacidipine Study on Atherosclerosis. Circulation
126, 569–578 (2012).
122.Matsui, Y. et al. Combined effect of angiotensin
II receptor blocker and either a calcium channel
blocker or diuretic on day‑by‑day variability of
home blood pressure: the Japan Combined
Treatment With Olmesartan and a CalciumChannel Blocker Versus Olmesartan and
Diuretics Randomized Efficacy Study.
Hypertension 59, 1132–1138 (2012).
NATURE REVIEWS | CARDIOLOGY 123.Webb, A. J. & Rothwell, P. M. Effect of dose and
combination of antihypertensives on
interindividual blood pressure variability: a
systematic review. Stroke 42, 2860–2865 (2011).
124.Webb, A. J., Fischer, U., Mehta, Z. &
Rothwell, P. M. Effects of antihypertensive-drug
class on interindividual variation in blood
pressure and risk of stroke: a systematic review
and meta-analysis. Lancet 375, 906–915 (2010).
125.Zanchetti, A. Wars, war games, and dead bodies
on the battlefield: variations on the theme of
blood pressure variability. Stroke 42, 2722–2724
(2011).
Author contributions
All the authors substantially contributed to the
research, writing, and reviewing of the manuscript.
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