Download Short- and Long-Term Blood Pressure Variability

Short- and Long-Term Blood Pressure Variability
Present and Future
Giuseppe Mancia
I
experimental animals, that is, the disappearance of some
variability components with the persistence or even the
increase of others.6 The factors possibly responsible for
24-hour BP variability are illustrated in Figure 1.
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
t has long been known that blood pressure (BP) is
characterized by an array of spontaneous variations.1 That
is, BP values vary markedly within the 24 hours because of
day-night changes but also because of differences among
hours, minutes, and even adjacent beats. They also show
variations over more prolonged periods because of differences among days, months, and seasons,2 also with a trend for
systolic BP to increase over the years and for diastolic BP to
display an age-related biphasic change.3
This article summarizes current knowledge on short-term
(within the 24 hours) and long-term BP variability. Mention
will be made of the following: (1) factors responsible for BP
variations and mechanisms through which they occur; (2) the
relationship of BP variability with BP mean values in absence
and during antihypertensive treatment; and (3) the prognostic
significance of BP variability. Current limitations of the
studies on BP variability will be also discussed to emphasize
what future studies should address.
Relationship With 24-Hour BP Mean
Early studies with intra-arterial ambulatory BP monitoring
have shown that 24-hour, daytime, and nighttime BP variabilities (quantified as the SD of the 24-hour, day, and night
mean values) increase from normotensives to patients with a
progressively more severe hypertension7 (Figure 2, top left).
They have further shown that an increase of BP variability
when BP mean increases also occurs within individuals,
because the BP SD becomes progressively greater from the
half hours in which mean BP is lowest to the half hours in
which it is maximal (Figure 2, top right). They have also
shown that, from normotensive to hypertensive subjects, the
increase in BP SD is proportional to the increase in mean BP,
with, thus, no change in the coefficient of variation (Figure 2,
bottom left). However, this is not the case within individuals
in whom the increase in BP variability associated with an
increase in BP mean is more pronounced and accompanied by
an increase in its normalized value (Figure 2, bottom right). It
is possible that the resetting of the baroreflex that is known to
occur during prolonged BP elevations, such as hypertension,8
allows its antioscillatory influence to remain fully operative,
thereby attenuating the increase in BP variability that accompanies more transient increases of BP mean.
Twenty-Four Hour BP Variability
Factors and Mechanisms
A large body of evidence shows that, over the 24 hours, BP
undergoes marked variations in response to physical activity,
sleep, and emotional stimuli of various nature and duration,
thereby documenting the profound involvement of behavioral
influences on BP variability. However, spontaneous BP
variations also occur independently on behavior. For example, throughout the day and night, BP oscillates regularly at
different frequencies, presumably because of influences originating within the brain.4 Furthermore, BP varies more or less
regularly in response to the mechanical forces generated by
ventilation and also shows irregular nonbehaviorally and
nonmechanically related changes with a possible origin from
humoral influences and even local vasomotor phenomena.
Finally, BP variations are opposed throughout the 24 hours by
the baroreflex, which makes the magnitude of 24-hour BP
variability in a given individual the net effect of prooscillatory and antioscillatory influences.1 Some of these
influences operate via the sympathetic nervous system,5 but
nonneural mediators are also importantly involved, as shown
by the complex effects of sympathectomy on BP variability in
Effect of Antihypertensive Treatment
Both intra-arterial and noninvasive ambulatory BP monitoring have shown that 24-hour, daytime, and, to a lesser extent,
nighttime BP SDs all decrease as the corresponding BP mean
is reduced by antihypertensive drugs.1 This occurs with a
variety of antihypertensive treatments, that is, angiotensinconverting enzyme inhibitors, calcium channel blockers,
central agents, and ␤-blockers without or with vasodilator
properties given alone or in combination with a diuretic,9–17
suggesting that this is the consequence of BP lowering, per
se. Interestingly, in most instances the reduction of the SD
has been found to be proportional to the reduction of the mean
Received March 5, 2012; first decision April 12, 2012; revision accepted April 12, 2012.
From the University of Milano-Bicocca, Milan, Italy.
This paper was sent to John E. Hall, Consulting editor, for review by expert referees, editorial decision, and final disposition.
Correspondence to Giuseppe Mancia, Department of Medicine, University of Milano-Bicocca, St Gerardo Hospital, via Pergolesi 33, 20900 Monza
(MB), Italy. E-mail [email protected]
(Hypertension. 2012;60:512-517.)
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.112.194340
512
Mancia
+
+
Mechanical
factors
+
+
+
BP
variabi lity
Ventilation
Figure 1. Factors involved in 24 hour blood
pressure (BP) variability. The sign “⫹” refers to
factors favoring and the sign “⫺” to factors
opposing BP variations. The query indicates
absence of conclusive evidence.
Arterial stiffness ?
-/+
Other reflexes ?
Genetic factors ?
Rhythmic influences
(probably largely centra l)
+
+
Baroreflexes
Environmental
stimuli
Prognostic Relevance
Intra-arterial and noninvasive BP monitoring studies have
shown that, for a given 24-hour BP mean value, cardiac and
vascular damage are greater and lower in subjects with,
24h SD
*
8
*
6
*
Half hour mean (mmHg)
*
10
24h SD (mmHg)
Half hour mean and SD
n = 176
*
*
4
2
n=10
n=31
n=69
n=66
N
BH
MH
SH
0
n = 89
130
Mean
12
120
10
110
SD
100
8
90
6
19
3
23
7
19
15
11
Half hour SD (mmHg)
Time of the 24 hours
Half hour mean SD and CV
24h CV
n = 176
10
6
4
2
n=10
n=31
n=69
n=66
N
BH
MH
SH
0
12
n = 89
12
∆
10
10
∆
8
∆
6
∆
6
4
4
2
8
Half hour CV (%)
8
Half hour mean (mmHg)
12
24h CV (%)
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
respectively, a greater and lower 24-hour BP SD.19,20 Furthermore, evidence has been obtained that, over a follow-up
of several years, an initially greater BP variability leads to a
greater progression of the left ventricular mass index or
carotid-intima media thickness value.21,22 Finally, and most
importantly, in several studies, BP variability within the 24
hours has been found to be an independent predictor of the
incidence of cardiovascular events.22–27 For example, Sander
et al22 have shown a greater 24-hour BP SD of systolic BP to
be accompanied by a greater 3-year incidence of cardiovascular morbid and fatal events. Kikuya et al23 have found that,
BP value with, thus, little or no change in the BP coefficient
of variation.18 The change of BP variability associated with
antihypertensive treatment thus reflects the difference in BP
variability between normotensive and hypertensive individuals, making it possible that a baroreflex resetting (this time
toward lower BP values) is again involved.
12
513
Vasomotiion ?
Humoral ?
(endothelial etc)
factors
Behavioral
factors
Short and Long-Term BP Variability
2
Lowest
Inter- Highest
mediate
Lowest
Inter- Highest
mediate
Half hour MAP values
Figure 2. Top left panel, SD of the 24-hour average value for mean arterial pressure in normotensive subjects (N) and borderline (B),
moderate (M), and severe (S) hypertensive (H) patients. Top right panel, Half-hour average values for mean arterial pressure and the
corresponding SD for the 24-hour blood pressure (BP) monitoring in normotensive and hypertensive subjects pooled. Bottom left
panel, Coefficient of variation (CV) of the 24-hour average value for mean arterial pressure in the subjects of top left panel. Bottom
right panel, SD and CV for the half hours with the lowest, intermediate, and highest average values for mean arterial pressure in the
subjects of top right panel. Data were collected by intra-arterial ambulatory BP monitoring. Bars refer to the SD of the mean. *P⬍0.05;
⌬P⬍0.01. Adapted from Mancia et al7 with permission of the publisher. Copyright © 1983, the American Heart Association, Inc.
514
Hypertension
August 2012
CV Mortality
DBP variability
HR
R
P value
SD 24h
1.13 ((0.98-1.31)
0.098
SD day
1.24 (1.07-1.44)
0.004
SD night
1.13 ((0.97-1.31)
0.11
Day-night ∆
0.90 (0.78-1.04)
0.16
Residual (erratic) variability
1.24 (1.07-1.43)
(
0.005
0.5
1.0
Figure 3. Risk of cardiovascular mortality for
a 1-SD increase in various measures of
24-hours diastolic blood pressure (BP) variability. Data were adjusted for the covariates
indicated at the bottom. Numbers in parenthesis refer to 95% CIs. Adapted from Mancia et al.24
2.0
models adjusted for age / gender / smoking / previous CV events / LVMI / serum cholesterol and
* Cox
glucose / 24h mean DBP
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
in subjects with a daytime SD of systolic BP lower than ⬇16
mm Hg, the rate of cardiovascular mortality as assessed over
a multiyear follow-up was significantly less than in subjects
with an SD of systolic BP equal or above this value.
Verdecchia et al27 have seen that, in initially untreated
hypertensive patients followed for 16 years, an enhanced BP
variability during the night was an independent predictor of
cardiac events. Mancia et al24 have observed that, in the
general population of the Pressioni Arteriose Monitorate e
Loro Associazioni Study, the 12-year cardiovascular mortality exhibited a positive relationship with the magnitude of the
day and night erratic diastolic BP changes that could be
detected by eliminating the cyclic components (nocturnal and
postprandial BP falls) by Fourier analysis of the 24-hour BP
tracing, independent of other potentially confounding demographic and clinical cardiovascular risk factors (Figure 3).
Indeed, as shown in Table 1, these erratic BP variations were
found to be a predictor of cardiovascular fatal events more
important than the mean 24-hour BP value and the difference
in day-night BP, for which the relationship with cardiovascular mortality was of a protective nature. They were also
found to exceed the prognostic importance of 24-hour BP
mean, suggesting a nonmarginal contribution to cardiovascular risk.
Current Limitations and the Future
Current knowledge on 24-hour BP variability has important
limitations (Table 2), which makes future studies in this area
important. First, more studies are needed on the factors and
mechanisms involved in this phenomenon and, in particular,
on the role played by arterial stiffness and genetic factors on
Table 1.
Multivariate Analysis Showing Diastolic BP Values
Independently Predicting CV and All-Cause Death
CV Death
All-Cause Death
the magnitude and patterns of short-term BP variations.
Second, some studies have shown short-term BP variability
not to predict events after adjustment for potential confounders or have concluded that its prognostic importance is minor
vis-à-vis that of mean BP values.28 Thus, additional longitudinal evidence based on an accurate quantification of the
variability phenomena (see below) would be desirable. Third,
more evidence is needed on whether some drugs or treatment
strategies have greater effects on within 24-hour BP variations than others. Furthermore, because 24-hour ambulatory
BP has not been used in large-scale trials on antihypertensive
treatment (except for small substudies on nonrandomized
patients), the protective effect of treatment-induced changes
in BP variability with respect to the concomitant changes in
BP mean awaits proper documentation. Finally, when using
noninvasive ambulatory BP monitoring (the only approach
suitable for large, long-term studies) it will be important to
more precisely quantify the magnitude of the 24-hour BP
variations. This means to space BP readings by ⱕ15 or 20
minutes, because, beyond these intervals, quantification of
the 24-hour BP SD can be grossly inaccurate.29 It also means
the use of indices other than the SD, because the same SD
(or the coefficient of variation) value may be associated with
completely different patterns of BP variability. Complementary measures, such as the weighted SD, the frequency
distribution, or the BP ranges over the day and night and the
average differences between consecutive systolic or diastolic
values may offer some advantages.30,31 It should be emphasized, however, that no matter which measure is used, this
goal can hardly be obtained via noninvasive automatic
Table 2.
Twenty-Four h BP Variability: Limitations and Future
● More information on factors/mechanisms involved (eg, arterial stiffness,
genetic factors)
● Data from observational studies with larger No. of events/statistical power
␹
P Value
␹2
P Value
Variability
30.80
⬍0.0001
31.69
0.0001
● Data from randomized trials (protective effect of treatment-induced
reduction of BP variability?)
2Day/night (inverse)
21.34
0.001
19.87
0.001
● Head-to-head comparisons of different drugs/drug combinations
24-h mean
16.11
0.003
16.40
0.002
● More precise assessment of 24-h SD/CV
Diastolic BP Value
2
BP indicates blood pressure; CV, cardiovascular. Data show adjustment of
age, sex, cholesterol, glucose, smoking, previous CV events, and left ventricular
hypertrophy. Data are from a 12-y follow-up of the general population recruited
in the Pressione Arteriose Monitorate e Loro Associazioni Study.
● Need of beat-to-beat BP measuring devices (not interfering with subjects
activity/sleep) for mechanistic/prognostic studies of variability components
including speed of BP changes
BP indicates blood pressure; CV, cardiovascular.
Mancia
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
ambulatory BP monitoring, which provides ⬍0.1% of the BP
values that occur over the 24 hours. Furthermore, because
noninvasive automatic BP measurements require the patient
to stop any activity at the time of measurement, this approach
does not capture BP variability in truly real-life conditions.
Finally, although in a previous study intra-arterially measured
nighttime BP fall was found to be superimposable with and
without concomitant noninvasive ambulatory BP monitoring,32 the possibility that cuff inflations (and the accompanying noise) alter sleep pattern and its cardiovascular effects, at
least in some patients, cannot be excluded. The most important progress for BP variability will, therefore, be to develop
devices that measure beat-to-beat ambulatory BP noninvasively without restriction at a cost that could make their use
in large and long-term studies feasible. Beat-to-beat BP
monitoring would also allow us to apply methods such as
restricted or broad-band spectral analysis to the recorded
tracing, thereby detecting even subtle differences in the
magnitude and type of BP variations.33 It would even permit
us to assess on a large scale the speed of the BP changes
during the frequent pressor and depressor episodes that occur
spontaneously over the 24 hours. BP has been shown to
change faster in hypertensive than in normotensive subjects
throughout the day and night,34 but no data are available on
whether the potentially greater traumatic effect of faster BP
changes on the heart and the vessel wall favors organ damage
and increases the risk of cardiovascular events.
Long-Term BP Variability
Evidence
Information on the factors involved in long-term BP variations are scattered and incomplete. Behavioral changes are
regarded to play a major role on day-to-day BP variations,
particularly those making the ambulatory BP values of the
working days, and of Monday in particular, different from
those of the weekend.35 Changes in temperature are thought
to be the main reason for the lower BP that characterizes
summer as compared with winter months.36 Large artery
stiffening is known to be majorly responsible for the progressive BP changes that occur with aging.37 Little is known, on
the other hand, about the factors responsible for the BP
difference that has been observed between visits spaced by
months or years in observational studies and antihypertensive
drug trials.38–40 These differences, however, have been shown
to have a prognostic value. For example, in the hypertensive
patients with a history of coronary disease of the International
Verapamil-Trandolapril Study,40 the incidence of cardiovascular morbid and fatal events increased progressively as the
number of on-treatment visits in which BP was controlled to
⬍140/90 mm Hg increased from ⬍25% to ⱖ75%, irrespective of the mean BP value throughout the treatment period.
Even more impressively, in the high-risk hypertensive patients of the Anglo-Scandinavian Cardiac Outcome Trial, the
incidence of cardiovascular events, and of stroke in particular, increased progressively as the SD or the coefficient of
variation of the on-treatment BP mean increased from the
lowest to the highest decile value.38 This implies that physicians should pay attention to consistency of BP control over
Short and Long-Term BP Variability
515
Table 3.
Visit-to-Visit Intra-Individual BP Variability:
Limitations and Future
● Derived from post hoc analysis of data/comparisons of nonrandomized
groups
● Several visits needed/patients with early events excluded
● Limited information on factors involved/could reflect different timing of BP
measurement and/or adherence to treatment
● Low correlation with visit-to-visit variability of 24-h mean BP
● Use of interindividual variability as a surrogate for intraindividual
variability questionable
BP indicates blood pressure.
time, because lack of control at any given visit may have
adverse prognostic consequences, a conclusion recently
reached also by the Ongoing Telmisartan Alone and in
Combination With Ramipril Global Endpoint Trial in which
the risk of a cardiovascular event showed a relationship with
the BP status in the immediately preceding visit.41 This may
not be an easy goal to achieve, however, because an unstable
BP control is a common phenomenon not only in clinical
practice but also in trials. In the European Lacidipine Study
on Atherosclerosis, for example, ⬇40% to 50% of the treated
hypertensive patients achieved a BP ⬍140/90 mm Hg at each
yearly visit, whereas in only approximately one third of them
was BP control achieved for the entire 4-year duration of
treatment.42
Limitations
Before concluding that consistency of BP control represents
an additional important goal of antihypertensive treatment,
important limitations of current evidence on visit-to-visit BP
variability should be mentioned (Table 3). Fourth, visit-tovisit BP variability has been studied by a post hoc approach,
which means that comparisons have involved nonrandomized
groups, a condition that does not guarantee that factors other
than those under study play a role. Second, because a number
of values is needed to quantify BP variability, patients
experiencing an early event have been excluded, limiting the
analysis to the later part of a trial. Third, the variability of
visit-to-visit on-treatment clinic BP has shown a very limited
relationship (correlation coefficients between 0.10 and 0.20)
with the concomitant visit-to-visit variability of on-treatment
24-hour mean BP,43 which means that consistency of clinic
BP control may not reflect that of 24-hour BP control, that is,
a measure of recognized prognostic importance.44–46 Fourth,
no conclusive data exist on the effect of different drugs or
treatment regimens on visit-to-visit BP variability, because,
in absence of data from individual subjects, this has been
quantified by the more or less wide range of the BP-lowering
effect of treatment in the whole group of patients.47 Although
this “interindividual” variability has been claimed to be
significantly related to the “intraindividual” one, it is not easy
to understand why the more or less uniform BP effect of an
antihypertensive drug in a large group of patients should
measure the tendency of the BP-lowering effect of treatment
in a given individual to be more or less sustained with time.
Finally, much more will have to be learned regarding the
factors responsible for between-visit BP variations during
516
Hypertension
August 2012
antihypertensive treatment. Although it cannot be excluded
that neurohumoral and structural characteristics of the cardiovascular system are involved, it will be important to know
the contribution of more practical factors, such as the different timing of BP measurements at different visits, that is, the
fact that at one visit BP measurements may be closer to drug
administration that at another visit, and the role played by
patient adherence to the prescribed treatment regimen, because adherence to treatment has been shown to be prognostically important.48,49 Progress on all of above points will be
possible, if at variance from what has been done in the past,50
future trials will collect precise information on intraindividual
BP variability during the treatment.
Disclosures
15.
16.
17.
18.
19.
None.
20.
References
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
1. Parati G, Di Rienzo M, Mancia G, Zanchetti A. Blood pressure variability. In: Handbook of Hypertension, Zanchetti A, eds. Amsterdam, the
Netherlands: Elsevier; 1997:117–169.
2. Sega R, Cesana G, Bombelli M, Grassi G, Stella ML, Zanchetti A,
Mancia G. Seasonal variations in home and ambulatory blood pressure in
the PAMELA population: Pressione Arteriose Monitorate E Loro Associazioni. J Hypertens. 1998;16:1585–1592.
3. Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres
M, Kastarinen M, Poulter N, Primatesta P, Rodríguez-Artalejo F,
Stegmayr B, Thamm M, Tuomilehto J, Vanuzzo D, Vescio F. Hypertension prevalence and blood pressure levels in 6 European countries,
Canada, and the United States. JAMA. 2003;289:2363–2369.
4. Parati G, Castiglioni P, Di Rienzo M, Omboni S, Pedotti A, Mancia G.
Sequential spectral analysis of 24-hour blood pressure and pulse interval
in humans. Hypertension. 1990;16:414–421.
5. Narkiewicz K, Winnicki M, Schroeder K, Philips BG, Kato M, Cwalina
E, Somers VK. Relationship between muscle sympathetic nerve activity
and diurnal blood pressure profile. Hypertension. 2002;39:168–172.
6. Daffonchio A, Franzelli C, Radaelli A, Castiglioni P, Di Rienzo M,
Mancia G, Ferrari AU. Sympathectomy and cardiovascular spectral components in conscious normotensive rats. Hypertension. 1995;25:
1287–1293.
7. Mancia G, Ferrari A, Gregorini L, Parati G, Pomidossi G, Bertinieri G,
Grassi G, di Rienzo M, Pedotti A, Zanchetti A. Blood pressure and heart
rate variabilities in normotensive and hypertensive human beings. Circ
Res. 1983;53:96–104.
8. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex
control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31:68–72.
9. Ferrari AU, Buccino N, Pedotti A, Mancia G, Zanchetti A. Labetalol and
24 hour monitoring of arterial blood pressure in hypertensive patients.
J Cardiovasc Pharmacol. 1981;3:S42–S52.
10. Mancia G, Ferrari AU, Gregorini L, Parati G, Pomidossi G, Bertinieri G,
Zanchetti A. Evaluation of a slow release clonidine preparation by direct
continuous blood pressure recording in essential hypertensive patients.
J Cardiovasc Pharmacol. 1981;3:1193–1202.
11. Mancia G, Ferrari AU, Pomidossi G, Parati G, Bertinieri G, Grassi G,
Gregorini L, Di Rienzo M, Zanchetti A. Twenty-four hour blood pressure
profile and blood pressure variability in untreated hypertension and
during antihypertensive treatment with once-a-day nadolol. Am Heart J.
1984;108:1078–1083.
12. Pomidossi G, Parati G, Motolese M, Mancia G, Zanchetti A. Hemodynamic effects of once a day administration of combined clorthalidone
and metoprolol retard in essential hypertension. Int J Clin Pharmacol
Ther Toxicol. 1984;12:665–671.
13. Pomidossi G, Parati G, Malaspina D, Camesasca C, Motolese M,
Zanchetti A, Mancia G. Antihypertensive effect of a new formulation of
a slow release oxeprenolol in essential hypertension. J Cardiovasc
Pharmacol. 1987;10:593–598.
14. Parati G, Pomidossi G, Casadei R, Ravogli A, Trazzi S, Mutti E, Mancia
G. 24 h ambulatory non-invasive blood pressure monitoring in the
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
assessment of the antihypertensive action of celiprolol. J Internat Med
Res. 1988;16:52A–61A.
Mancia G, De Cesaris R, Fogari R, Lattuada S, Montemurro G, Palombo
C, Porcellati C, Ranieri G, Tettamanti F, Verdecchia P, Marelli C,
Omboni S, Ravogli A, Zanchetti A. Evaluation of the antihypertensive
effect of once-a-day trandolapril by 24 hour ambulatory blood pressure
monitoring. Am J Cardiol. 1992;70:60D–66D.
The Italian Verapamil Study Group. 4 hour antihypertensive effect of
verapamil sustained release 240 mg vs nitrandipine and enalapril in
essential hypertension. High Blood Press. 1993;2:241–248.
Omboni S, Ravogli A, Fogari R, Riva D, Mancia G. Effect of once-a-day
fosinopril on 24h ambulatory blood pressure in mild to moderate essential
hypertension. High Blood Press. 1994;3:103–107.
Mancia G, Omboni S, Ravogli A, Parati G, Zanchetti A. Ambulatory
blood pressure monitoring in the evaluation of antihypertensive treatment: additional information from a large data-base. Blood Press. 1995;
4:148–156.
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. 1987;5:93–98.
Mancia G, Parati G, Hennig M, Flatau B, Omboni S, Glavina F, Costa B,
Scherz R, Bond G, Zanchetti A, for the ELSA Investigators. Relation
between blood pressure variability and carotid artery damage in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens. 2001;19:1981–1989.
Frattola A, Parati G, Cuspidi C, Albini F, Mancia G. Prognostic value of
24-hour blood pressure variability. J Hypertens. 1993;11:1133–1137.
Sander D, Kukla C, Klingelhöfer J, Winbeck K, Conrad B. Relationship
between circadian blood pressure patterns and progression of early
carotid atherosclerosis: a 3-year follow-up study. Circulation. 2000;102:
1536–1541.
Kikuya M, Ohkubo T, Metoki H, Asayama K, Hara A, Obara T, Inoue R,
Hoshi H, Hashimoto J, Totsune K, Satoh H, Imai Y. Day-by-day variability of blood pressure and heart rate at home as a novel predictor of
prognosis: the Ohasama Study. Hypertension. 2008;52:1045–1050.
Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, Trevano QF,
Grassi G, Sega R. Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study. Hypertension. 2007;49:1265–1270.
Dawson SL, Manktelow BN, Robinson TG, Panerai RB, Potter JF. Which
parameters of beat-to-beat blood pressure and variability best predict
early outcome after acute ischemic stroke? Stroke. 2000;31:463–468.
Pringle E, Phillips C, Thijs L, Davidson C, Staessen JA, de Leeuw PW,
Jaaskivi M, Nachev C, Parati G, O’Brien ET, Tuomilehto J, Webster J,
Bulpitt CJ, Fagard RH, for the Syst-Eur investigators. Systolic blood
pressure variability as a risk factor for stroke and cardiovascular mortality
in the elderly hypertensive population. J Hypertens. 2003;21:2251–2257.
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. 2007;20:154–161.
Hansen TW, Thijs L, Li Y, Boggia J, Kikuya M, Björklund-Bodegård K,
Richart T, Ohkubo T, Jeppesen J, Torp-Pedersen C, Dolan E, Kuznetsova
T, Stolarz-Skrzypek K, Tikhonoff V, Malyutina S, Casiglia E, Nikitin Y,
Lind L, Sandoya E, Kawecka-Jaszcz K, Imai Y, Wang J, Ibsen H,
O’Brien E, Staessen JA, for the International Database on Ambulatory
Blood Pressure in Relation to Cardiovascular Outcomes Investigators.
Prognostic value of reading-to-reading blood pressure variability over 24
hours in 8938 subjects from 11 populations. Hypertension. 2010;55:
1049–1057.
Di Rienzo M, Grassi G, Pedotti A, Mancia G. Continuous vs intermittent
blood pressure measurements in estimating 24-hour average blood
pressure. Hypertension. 1983;5:264–269.
Bilo G, Giglio A, Styczkiewicz K, Caldara G, Maronati A, KaweckaJaszcz K, Mancia G, Parati G. A new method for assessing 24h blood
pressure variability after excluding the contribution of nocturnal blood
pressure fall. J Hypertens. 2007;25:2058–2066.
Castiglioni P, Parati G. Present trends and future directions in the analysis
of cardiovascular variability. J Hypertens. 2011;29:1285–1288.
Villani A, Parati G, Groppelli A, Omboni S, Di Rienzo M, Mancia G.
Noninvasive automatic blood pressure monitoring does not attenuate
nighttime hypertension: evidence from 24 h intraarterial blood pressure
monitoring. Am J Hypertens. 1992;5:744–747.
Castiglioni P, Daffonchio A, Ferrari AU, Mancia G, Pedotti A, Di Rienzo
M. Blood pressure and heart rate variability in conscious rats before and
Mancia
34.
35.
36.
37.
38.
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
39.
40.
41.
after autonomic blockade: evaluation by broad band spectral analysis.
Comput Cardiol. 1993:487–490.
Mancia G, Parati G, Castiglioni P, Tordi R, Tortorici E, Glavina F, Di
Rienzo M. Daily life blood pressure changes are steeper in hypertensive
than in normotensive subjects. Hypertension. 2003;42:277–282.
Murakami S, Otsuka K, Kubo Y, Shinagawa M, Matsuoka O, Yamanaka
T, Nunoda S, Ohkawa S, Kitaura Y. Weekly variation of home and
ambulatory blood pressure and relation between arterial stiffness and
blood pressure measurements in community-dwelling hypertensives. Clin
Exp Hypertens. 2005;27:231–239.
Modesti PA, Morabito M, Bertolozzi I, Massetti L, Panci G, Lumachi C,
Giglio A, Bilo G, Caldara G, Lonati L, Orlandini S, Maracchi G, Mancia
G, Gensini GF, Parati G. Weather-related changes in 24-hour blood
pressure profile: effects of age and implications for hypertension management. Hypertension. 2006;47:155–161.
Reference Values for Arterial Stiffness’ Collaborators. Determinants of
pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: establishing normal reference values. Eur Heart J.
2010;31:2338–2350.
Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B,
Sever PS, Poulter NR. Prognostic significance of visit-to-visit variability,
maximum systolic blood pressure, and episodic hypertension. Lancet.
2010;375:895–905.
Muntner P, Shimbo D, Tonelli M, Reynolds K, Arnett DK, Oparil S. The
relationship between visit-to-visit variability in systolic blood pressure
and all-cause mortality in the general population: findings from NAHNES
III, 1988 to 1994. Hypertension. 2011;57:160–166.
Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood
pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension. 2007;50:
299–305.
Mancia G, Schumacher H, Redon J, Verdecchia P, Schmieder R, Jennings
G, Yusoff K, Ryden L, Liu GL, Teo K, Sleight P, Yusuf S. Blood pressure
targets recommended by guidelines and incidence of cardiovascular and
renal events in the Ongoing Telmisartan Alone and in Combination With
Ramipril Global Endpoint Trial (ONTARGET). Circulation. 2011;124:
1727–1736.
Short and Long-Term BP Variability
517
42. Mancia G, Parati G, Bilo G, Maronati A, Omboni S, Baurecht H, Hennig
M, Zanchetti A. Assessment of long-term antihypertensive treatment by
clinic and ambulatory blood pressure: data from the European Lacidipine
Study on Atherosclerosis. J Hypertens. 2007;25:1087–1094.
43. 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. 2012;30:1241–1251.
44. Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw
PW, Mancia G, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster
J. Predicting cardiovascular risk using conventional vs ambulatory
blood pressure in older patients with systolic hypertension: Systolic
Hypertension in Europe Trial Investigators. JAMA. 1999;282:
539–546.
45. Dolan E. Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond
E, McCormack P, Staessen JA, O’Brien E. Superiority of ambulatory
over clinic blood pressure measurements in predicting mortality: the
Dublin Outcome Study. Hypertension. 2005;46:156–161.
46. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia
G. 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. 2005;111:1777–1783.
47. Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensivedrug class on interindividual variation in blood pressure and risk of stroke: a
systematic review and meta-analysis. Lancet. 2010;375:906–915.
48. Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, Varney
J, Johnson JA. A meta-analysis of the association between adherence to
drug therapy and mortality. BMJ. 2006;333:315.
49. Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, Mancia
G. Better compliance to antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011;29:610–618.
50. Fischer U, Webb AJS, Howard SC, Rothwell PM. Reporting of consistency of blood pressure control in randomised controlled trials of
antihypertensive drugs: a systematic review of 1372 trial reports.
J Hypertens. In press.
Short- and Long-Term Blood Pressure Variability: Present and Future
Giuseppe Mancia
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
Hypertension. 2012;60:512-517; originally published online June 25, 2012;
doi: 10.1161/HYPERTENSIONAHA.112.194340
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/60/2/512
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/