Full research paper

European Journal of Preventive

Cardiology

The impact of systolic and diastolic 0(00) 1–10

! The European Society of
Cardiology 2019
blood pressure variability on mortality Article reuse guidelines:
sagepub.com/journals-permissions
is age dependent: Data from the DOI: 10.1177/2047487319872572
journals.sagepub.com/home/cpr
Dublin Outcome Study

Grzegorz Bilo1,2, Eamon Dolan3, Eoin O’Brien4, Rita Facchetti2,

Davide Soranna1,2, Antonella Zambon1,2, Giuseppe Mancia5,6
and Gianfranco Parati1,2

Abstract
Background: Twenty-four-hour blood pressure variability (BPV) is independently related to cardiovascular outcomes,
but limited and conflicting evidence is available on the relative prognostic importance of systolic and diastolic BPV.
The aim of this study was to verify the hypothesis that the association of systolic and diastolic blood pressure variability
over 24 h with cardiovascular mortality in untreated subjects is affected by age.
Design and methods: The study included 9154 untreated individuals assessed for hypertension between 1982 and
2002 in the frame of the Dublin Outcome Study, in which 24 h ambulatory blood pressure monitoring was obtained
(age 54.1  14.3 years, 47% males). The association of short-term systolic and diastolic blood pressure variability with
cardiovascular and all-cause mortality in the entire sample and separately in younger and older age subgroups was
assessed over a median follow-up period of 6.3 years.
Results: Diastolic BPV was directly and independently related to cardiovascular mortality (adjusted hazard ratio (adjHR)
for daytime standard deviation 1.16 (95% confidence interval 1.08–1.26)) with no significant differences among
age groups. Conversely, systolic BPV was independently associated with cardiovascular mortality only in younger
(<50 years) subjects (adjHR for daytime standard deviation 1.72 (95% confidence interval 1.33–2.23)), superseding
the predictive value of diastolic BPV in this group.
Conclusions: Diastolic short-term BPV independently predicts cardiovascular mortality in hypertensive subjects at all
ages, while systolic BPV seems a particularly strong predictor in young adults. If confirmed, these findings might improve
the understanding of the prognostic value of BPV, with new perspectives for its possible clinical application.

Keywords
Hypertension, aging, mortality, blood pressure variability, ambulatory blood pressure monitoring
Received 28 March 2019; accepted 6 August 2019

Background
Arterial hypertension is a universally acknowledged
risk factor for cardiovascular morbidity and mortality,1
characterized by a linear relationship of both office2
and out of office1,3–5 blood pressure (BP) average
levels with adverse outcomes. However, BP values are
characterized by marked fluctuations occurring over
time, a phenomenon referred to as BP variability
(BPV). BPV differs between individuals and is more
pronounced at higher BP levels.6 A large number of
observational studies and their meta-analyses7,8 have
1
Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular
Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy
2
Department of Medicine and Surgery, University of Milano-Bicocca,
Milan, Italy
3
Connolly Hospital, Dublin, Ireland
4
Conway Institute, University College, Dublin, Ireland
5
University of Milano-Bicocca, Milan, Italy
6
Policlinico di Monza, Monza, Italy
Corresponding author:
Gianfranco Parati, Department of Cardiovascular Neural and Metabolic
Sciences, San Luca Hospital, IRCCS, Istituto Auxologico Italiano, Piazzale
Brescia 20, 20149-Milan, Italy.
Email: gianfranco.parati@unimib.it
2 European Journal of Preventive Cardiology 0(00)
suggested that BPV might independently contribute to
prognosis in hypertension, but the clinical importance
of this contribution is still a matter of debate.9–11
In particular, increased 24-h BPV was reported to be
independently associated with organ damage and car-
diovascular events in many studies,7,12–18 although the
actual ability of currently used BPV indices to signifi-
cantly improve risk stratification is controversial.11,18 It
is also not clear whether systolic and diastolic BPV play
different roles in this regard. Indeed, while associations
with more advanced organ damage were usually
reported for systolic BPV,15,19–22 most large studies
focusing on cardiovascular events or mortality indi-
cated that diastolic BPV might be at least as relevant
as, if not superior to, systolic BPV.9,11,14–18
Short-term BPV is an extremely complex phe-
nomenon involving physiological factors (e.g. cardiac
contractility, large artery distensibility, humoral,
central and reflex modulation of vasomotor tone),
behavioural factors (e.g. daily activities) and haemo-
dynamic responses to environmental challenges.7
However, the role of these factors is modified by
aging, along with age-related changes in arterial stiff-
ness, function of cardiovascular control mechanisms
(e.g. arterial baroreflexes), responses to vasoactive sub-
stances and cardiovascular reactivity to environmental
stimuli. The above changes may therefore make the
overall clinical significance of BPV different in the eld-
erly as compared with a younger population.23
To our knowledge no study has addressed specific-
ally the question whether the prognostic value of
systolic and diastolic BPV is different in old and
young individuals. Therefore, in the present study we
evaluated whether age may influence the association
of different systolic and diastolic BPV estimates with
cardiovascular and all-cause mortality in untreated
individuals.
Methods
Participants
This paper is based on a retrospective analysis of
Dublin Outcome Study data. The detailed methodology
of this study has been reported previously.24,25 The
study included consecutive subjects referred between
1982 and 2002 to Beaumont Hospital in Dublin because
of an elevated clinic BP, followed-up for at least 12
months. The original dataset included 14,414 untreated
participants (treatment naı̈ve or with antihypertensive
treatment discontinued over the previous week for
clinical purposes). Of those, 3123 participants were
excluded because: their 24-h ambulatory BP monitoring
(ABPM) at registration included less than 10 daytime
or five night-time blood pressure readings (n ¼ 2612);
at baseline, not all of the cardiovascular risk factors
had been recorded (n ¼ 433); vital status could not be
ascertained (n ¼ 78). Of the remaining 11,291 partici-
pants, a further 791 were excluded because they did
not meet the more stringent ABPM quality criteria
applied specifically for BPV analysis (see below),
because of incomplete pulse rate data (n ¼ 28) and
because of follow-up duration less than one year
(n ¼ 1318). Thus, the final dataset included 9154 par-
ticipants. The study protocol was approved by the local
Ethics Committee and data handling was in accordance
with Irish national regulations. Informed consent
requirement was waived due to the historical nature
of the dataset and the anonymization of personal data.
Twenty-four-hour ABPM was performed by vali-
dated oscillometric SpaceLabs 90202 and 90207 devices
(SpaceLabs Inc., USA)26,27 set to measure BP every
half-hour throughout the 24-h period. Only recordings
with at least 40 valid measurements were considered.
Since the individual bedtime and awakening hours
were not available, narrow fixed criteria were adopted
to define the day and night periods: 10:00 to 21:59 h
was considered the daytime and midnight to 05:59 h
the night-time.28 In each subject the following ambula-
tory systolic (S) and diastolic (D)BP variables were cal-
culated: 1) mean 24-h, daytime and night-time
values; 2) nocturnal fall (as percentage of mean daytime
values); 3) standard deviation (SD) of daytime and
night-time mean BP; 4) 24-h weighted SD (wSD;
time-weighted average of daytime and night-time
SD);19 5) average real variability (ARV; average of
absolute differences between consecutive BP readings
over 24 h);29 6) residual BPV (power of 24-h BP spec-
trum remaining after removing the two main cyclic
components).9 Coefficients of variation were also com-
puted to normalize the corresponding SDs for mean BP
values on an individual level (for specific formulas see
Supplementary Material Table S1 online).
For the purposes of this analysis participants were
stratified in four age categories (<50, 50–65, 65–75 and
75 years), termed young, middle aged, old and very
old, respectively. The covariates available in this histor-
ical dataset were recorded at the time of the assessment
and included sex, body mass index (BMI), current
smoking, history of diabetes and history of previous
cardiovascular events.
Follow-up and outcomes
All patients of the final cohort were followed until the
earliest date between death and study end (30 September
2002, when outcomes were censored). Mortality out-
come was ascertained through access to the Irish
national computerized register of deaths.30 The causes
of death were coded according to the World Health
Bilo et al.
Organization’s International Classification of Diseases,
9th Revision (ICD-9) as cardiac mortality (including
myocardial infarction, heart failure, sudden death and
chronic coronary heart disease) and cerebrovascular
mortality (including stroke). Cardiovascular mortality
was a composite of cardiac mortality, stroke and other
vascular deaths. All-cause and non-cardiovascular mor-
tality were also assessed as secondary outcomes.
Statistical analysis
All continuous variables are reported as mean  SD
and categorical variables as numbers and proportions.
BPV estimates were standardized (one unit of BPV
standardized estimate corresponds to one SD of the
same BPV estimate) in order to account for the differ-
ent variance of these measures. Separate unadjusted
and adjusted Cox proportional hazards regression
models were fitted for each standardized BPV estimate
to determine the corresponding hazard ratios (and their
95% confidence intervals) for total mortality, cardio-
vascular and non-cardiovascular mortality. The model
included three dummy variables for age categories
(participants younger than 50 years were considered
the reference category), BPV continuous index and
three interaction terms (obtained by multiplying BPV
by dummy variables). The hazard ratio of BPV index
for each age category on total/cardiovascular mortality
was obtained as function of the sum of the main effect of
BPV (bBPV) and the effect of interaction between BPV
index and the relative age category (bint(i)). Specifically,
for the reference age category the hazard ratio was
obtained as exp(bBPV), while for the other age categories
the hazard ratio was obtained as exp(bBPV þ bint(i)).
This model was labelled as Model 1 (unadjusted).
A second model, labelled as Model 2 (adjusted), was
obtained adding into Model 1 the following covariates:
sex, diabetes, smoking, previous cardiovascular disease,
BMI, mean SBP, mean DBP, the corresponding BP noc-
turnal fall and 24-h mean pulse rate. The covariates were
selected a priori based on their clinical significance and
availability. For each adjusted Cox model, we assessed
the proportional hazard assumption with the scaled
Schoenfeld residuals. In the adjusted models for the
main outcome we controlled the statistical significance
of interaction coefficients accounting for multiple testing
with false discovery rate (FDR) approach.31 Finally, for
the cardiovascular mortality and the group <50 years,
we compared the goodness of fit of different adjusted
models including additionally systolic BPV estimate, dia-
stolic BPV estimate, or both, by means of the Akaike
Information Criterion (AIC) (lower values are better).
A p-value less than 0.05 was considered statistically sig-
nificant. Data were analysed with the SAS 9.4 software
(SAS Institute, Cary, North Carolina, USA).
3
Results
Data of 9154 subjects were analysed (47% males, age
range 18–94 years, median follow-up 6.3 years). There
were 725 deaths, of which 429 were cardiovascular, includ-
ing 272 cardiac and 113 cerebrovascular. Subjects’ clinical
characteristics and BP variables at baseline are shown in
Table 1 for the entire population and by age category.
Older strata were characterized by larger proportion of
females, greater prevalence of diabetes (except the oldest
group) and previous cardiovascular disease, lower rate of
smoking, lower BMI and higher all-cause and specific-
cause mortality. Except for night-time DBP SD, aging
was also associated with higher values of ambulatory
SBP and DBP variability indices, with lower mean ambu-
latory DBP levels and lower 24-h pulse rate.
Cardiovascular mortality
Figures 1 and 2 summarize the unadjusted and adjusted
associations of cardiovascular mortality with 1 SD
increase in different systolic and diastolic BPV indices
in the entire cohort and in each age group. In unad-
justed analysis (Model 1) systolic and diastolic BPV
estimates (except night-time systolic SD) predicted car-
diovascular mortality in the overall cohort. The
adjusted model confirmed the associations observed in
Model 1 for DBP (except night-time SD) while for SBP
a significant association was confirmed only for day-
time SD. Unadjusted hazard ratios were lower for coef-
ficient of variation than for SD in the case of systolic
BPV and similar in the case of diastolic BPV, while
adjusted hazard ratios were similar for coefficient of
variation and SD (Supplementary Figure S1).
Considering the results relative to age groups, some
systolic BPV indices showed significantly different effect
for the youngest with respect to the remaining age groups
(day SD, 24-h wSD – except for subjects aged 75 years –
and residual BPV). This different effect was also observed
for ARV but only in participants aged 65–75 years
(Table 2). The age-specific hazard ratios were significant
only for the youngest age group (ranging from 1.44 to
1.72) for all BPV indices except for night SD (Figure 1).
Conversely, no significant interactions were observed for
diastolic BPV with age-specific hazard ratios being similar
in different age groups (Figure 2).
In the youngest group of patients, the comparison of
AIC for adjusted model including systolic BPV, diastolic
BPV or both revealed that a better fit was obtained in
models which included only systolic BPV (and not dia-
stolic BPV) index (Supplementary Table S2).
Other outcomes
The effect of BPV on all-cause mortality followed a
similar pattern to that of cardiovascular mortality
4 European Journal of Preventive Cardiology 0(00)

Table 1. Baseline characteristics of study population considered as a whole and by age categories.

Age category

All <50 years 50–65 years 65–75 years 75 years

N ¼ 9154 n ¼ 3391 n ¼ 3649 n ¼ 1512 n ¼ 602

Age, years 54.08  14.28 39.16  8.18 57.31  4.29 69.48  2.81 79.85  3.99
Male 4278 (46.73%) 1686 (49.72%) 1724 (47.25%) 656 (43.39%) 212 (35.22%)
BMI, kg/m2 27.34  4.66 27.69  4.96 27.78  4.49 26.53  4.35 25.14  3.97
Smokers 1874 (20.47%) 840 (24.77%) 731 (20.03%) 247 (16.34%) 56 (9.30%)
Diabetes 642 (7.01%) 135 (3.98%) 296 (8.11%) 166 (10.98%) 45 (7.48%)
Previous cardiovascular disease 1090 (11.91%) 116 (3.42%) 436 (11.95%) 378 (25.00%) 160 (26.58%)
24 h PR, beats/min 72.31  10.63 74.74  10.33 71.68  10.43 69.61  10.52 69.29  10.73
Mortality during follow-up:
Any cause 725 (7.92%) 85 (2.51%) 217 (5.95%) 261 (17.26%) 162 (26.91%)
Cardiovascular including: 429 (4.69%) 41 (1.21%) 126 (3.45%) 159 (10.52%) 103 (17.11%)
Cardiac 272 (2.97%) 24 (0.71%) 78 (2.14%) 102 (6.75%) 68 (11.30%)
Cerebrovascular 113 (1.23%) 15 (0.44%) 30 (0.82%) 42 (2.78%) 26 (4.32%)
Other 44 (0.48%) 2 (0.06%) 18 (0.49%) 15 (0.99%) 9 (1.50%)
Non-cardiovascular 296 (3.23%) 44 (1.30%) 91 (2.49%) 102 (6.75%) 59 (9.80%)
SBP, mmHg
24 h 139.69  17.20 135.03  15.37 141.18  16.76 143.72  18.51 146.89  19.48
Daytime 145.69  17.99 142.02  16.34 147.37  17.91 148.26  19.42 149.73  20.09
Night-time 128.47  18.61 123.15  16.11 129.34  17.96 133.89  20.14 139.50  21.74
Nocturnal fall 11.66  8.40 13.15  7.15 12.02  8.43 9.47  9.03 6.59  9.98
DBP, mmHg
24 h 82.23  11.17 84.62  11.02 84.23  10.87 79.90  10.97 77.69  10.97
Daytime 87.89  12.01 90.35  11.55 88.74  11.60 83.39  11.76 80.25  11.55
Night-time 74.52  11.93 74.55  12.04 75.69  11.66 72.69  11.79 71.84  12.30
Nocturnal fall 14.95  9.60 17.39  8.86 14.48  9.19 12.53  9.87 10.16  11.39
Blood pressure variability:
Systolic, mmHg
Daytime SD 12.40  4.21 10.78  3.43 12.77  4.03 13.98  4.43 15.35  4.93
Night-time SD 10.58  4.30 9.77  4.03 10.78  4.25 11.42  4.57 11.89  4.56
24 h wSD 11.80  3.49 10.44  2.92 12.11  3.32 13.13  3.65 14.20  3.97
ARV 10.27  2.57 9.23  2.09 10.47  2.41 11.35  2.72 12.18  3.01
Residual BPV 8.11  2.14 7.20  1.73 8.29  1.97 9.06  2.27 9.77  2.57
Diastolic, mmHg
Daytime SD 9.39  3.20 9.11  2.86 9.33  3.16 9.78  3.51 10.30  4.05
Night-time SD 8.43  3.38 8.51  3.40 8.39  3.27 8.33  3.39 8.51  3.89
24 h wSD 9.07  2.60 8.91  2.38 9.02  2.56 9.30  2.78 9.70  3.29
ARV 8.29  2.14 8.21  1.91 8.20  2.08 8.45  2.33 8.93  2.94
Residual BPV 6.35  1.59 6.27  1.42 6.28  1.55 6.52  1.73 6.86  2.16
Values are shown as counts (percentages) for categorical variables and as means  standard deviations for age, BMI, 24 h PR, mean blood pressure
values and BPV estimates.
BMI: body mass index; PR: pulse rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; SD: standard deviation; wSD: weighted standard
deviation; ARV: average real variability; BPV: blood pressure variability

(Figures 3 and 4). It is noteworthy that systolic BPV with non-cardiovascular mortality in the entire cohort,
indices (except night SD) remained significant predictors either in unadjusted or in adjusted models
of all-cause mortality also in fully adjusted models in the (Supplementary Figures S2 and S3). No statistically sig-
entire cohort. Most BPV estimates were also associated nificant differences among age strata were found in this
Bilo et al. 5

Unadjusted model Adjusted model

Age classes Hazard ratio [95% CI] Hazard ratio [95% CI]

Day SD
<50 yrs 1.90 [1.47, 2.47] 1.72 [1.33, 2.23]
50–65 yrs 1.18 [1.01, 1.39] 1.06 [0.91, 1.23]
65–75 yrs 1.04 [0.90, 1.20] 1.00 [0.86, 1.16]
75+ yrs 1.17 [1.00, 1.37] 1.15 [0.98, 1.36]
Overall 1.17 [1.08, 1.27] 1.10 [1.01, 1.21]
Night SD
<50 yrs 1.38 [1.09, 1.75] 1.21 [0.94, 1.54]
50–65 yrs 1.11 [0.95, 1.31] 1.00 [0.85, 1.18]
65–75 yrs 1.00 [0.87, 1.15] 0.92 [0.79, 1.06]
75+ yrs 1.03 [0.87, 1.22] 0.94 [0.79, 1.12]
Overall 1.07 [0.99, 1.17] 0.97 [0.89, 1.07]
24-h wSD
<50 yrs 1.87 [1.48, 2.36] 1.62 [1.28, 2.06]
50–65 yrs 1.20 [1.03, 1.41] 1.05 [0.90, 1.23]
65–75 yrs 1.03 [0.89, 1.19] 0.97 [0.83, 1.13]
75+ yrs 1.16 [0.99, 1.36] 1.10 [0.92, 1.31]
Overall 1.17 [1.08, 1.27] 1.08 [0.98, 1.18]
ARV
<50 yrs 1.64 [1.25, 2.15] 1.44 [1.09, 1.90]
50–65 yrs 1.21 [1.03, 1.42] 1.07 [0.91, 1.27]
65–75 yrs 1.04 [0.90, 1.20] 0.94 [0.81, 1.10]
75+ yrs 1.12 [0.96, 1.32] 1.06 [0.90, 1.25]
Overall 1.15 [1.05, 1.25] 1.04 [0.95, 1.15]
Residual BPV
<50 yrs 1.83 [1.41, 2.36] 1.56 [1.21, 2.02]
50–65 yrs 1.10 [0.92, 1.31] 0.97 [0.81, 1.16]
65–75 yrs 1.08 [0.93, 1.25] 1.01 [0.87, 1.17]
75+ yrs 1.08 [0.93, 1.26] 1.02 [0.87, 1.21]
Overall 1.13 [1.04, 1.23] 1.04 [0.95, 1.14]

0.6 1 2.5 0.6 1 2.5

Hazard ratio Hazard ratio

Figure 1. Association of systolic blood pressure variability estimates with cardiovascular mortality overall and by age category.
Standardized (per 1 SD) hazard ratios with 95% confidence interval are shown for Models 1 (unadjusted) and 2 (adjusted).
CI: confidence interval; SD: standard deviation; yrs: years; wSD: weighted standard deviation; BPV: blood pressure variability;
ARV: average real variability

regard. Of note, the associations were consistently non-
significant in the oldest age group (over 75 years).
Discussion
Our study, performed in a large sample of untreated
subjects evaluated for hypertension, not only confirms
that 24-h BPV is an independent predictor of cardio-
vascular mortality,9,11,16–18 but also provides additional
new evidence that may help clarifying the clinical rele-
vance of BPV. In particular, our findings offer new
insights into the respective predictive role of systolic
and diastolic BPV indices as well as on their changing
importance at different ages. A first key novel informa-
tion is that, in the overall sample, diastolic but not sys-
tolic BPV independently predicted cardiovascular
mortality. When focusing on subjects aged less than
50 years, however, systolic BPV was independently
associated with cardiovascular mortality and was
superior to diastolic BPV in this regard.
The novelty of our study derives from the fact that
current evidence regarding differences in the prognostic
significance of systolic and diastolic BPV is limited and
none of the available studies focused specifically on this
aspect. Hansen et al. in the analysis of the IDACO
database found significant associations with outcomes
for both systolic and diastolic BPV estimates, although
for some variables and outcomes (e.g. 24-h wSD and
cardiovascular mortality) the associations appeared
stronger for diastolic BPV.11 In the Ambulatory
Blood Pressure-International Study hazard ratio point
estimates were higher for diastolic than for systolic
BPV, although direct comparisons are difficult because
the reported hazard ratios were not standardized.18
Also in the study by Hsu et al. diastolic BPV seemed
a somewhat better predictor of all cause and cardiovas-
cular mortality, but the results were not able to defin-
itely clarify this issue.32 Also in the PAMELA general
population study diastolic but not systolic BPV pre-
dicted outcome,9 while in the Syst-Eur trial and in the
study by Pierdomenico et al. significant associations
between systolic BPV and outcome were reported.17,33
Such significant heterogeneity among previous stu-
dies may derive from differences in data origin
6 European Journal of Preventive Cardiology 0(00)

Unadjusted model Adjusted model

Age classes Hazard ratio [95% CI] Hazard ratio [95% CI]

Day SD
<50 yrs 1.38 [1.06, 1.81] 1.28 [0.98, 1.68]
50–65 yrs 1.13 [0.98, 1.32] 1.09 [0.94, 1.27]
65–75 yrs 1.18 [1.04, 1.33] 1.18 [1.04, 1.34]
75+ yrs 1.11 [0.97, 1.26] 1.18 [1.03, 1.35]
Overall 1.16 [1.07, 1.24] 1.16 [1.08, 1.26]
Night SD
<50 yrs 1.26 [1.00, 1.59] 1.13 [0.89, 1.43]
50–65 yrs 1.13 [0.97, 1.31] 1.05 [0.90, 1.23]
65–75 yrs 1.11 [0.96, 1.27] 1.01 [0.88, 1.17]
75+ yrs 1.17 [1.03, 1.33] 1.08 [0.95, 1.23]
Overall 1.15 [1.06, 1.24] 1.06 [0.98, 1.14]
24-h wSD
<50 yrs 1.45 [1.12, 1.87] 1.28 [0.99, 1.66]
50–65 yrs 1.16 [1.00, 1.35] 1.10 [0.95, 1.28]
65–75 yrs 1.20 [1.06, 1.36] 1.16 [1.02, 1.33]
75+ yrs 1.16 [1.02, 1.32] 1.18 [1.03, 1.35]
Overall 1.19 [1.11, 1.28] 1.16 [1.07, 1.26]
ARV
<50 yrs 1.28 [0.96, 1.70] 1.16 [0.87, 1.55]
50–65 yrs 1.20 [1.03, 1.39] 1.14 [0.98, 1.32]
65–75 yrs 1.21 [1.07, 1.38] 1.13 [0.99, 1.29]
75+ yrs 1.11 [0.99, 1.25] 1.14 [1.00, 1.28]
Overall 1.17 [1.09, 1.26] 1.14 [1.05, 1.23]
Residual BPV
<50 yrs 1.40 [1.06, 1.85] 1.24 [0.94, 1.64]
50–65 yrs 1.17 [1.00, 1.36] 1.11 [0.96, 1.29]
65–75 yrs 1.25 [1.10, 1.43] 1.18 [1.04, 1.35]
75+ yrs 1.11 [0.99, 1.26] 1.14 [1.00, 1.29]
Overall 1.19 [1.10, 1.28] 1.15 [1.07, 1.25]

0.6 1 2.5 0.6 1 2.5

Hazard ratio Hazard ratio

Figure 2. Association of diastolic blood pressure variability estimates with cardiovascular mortality overall and by age category.
Standardized (per 1 SD) hazard ratios with 95% confidence interval are shown for Models 1 (unadjusted) and 2 (adjusted).
CI: confidence interval; SD: standard deviation; yrs: years; wSD: weighted standard deviation; BPV: blood pressure variability;
ARV: average real variability

(trials, population studies, convenience sampling),
sample characteristics (proportion of hypertensive par-
ticipants, age distribution), methodology (e.g. BP sam-
pling frequency, quality of ambulatory BP recordings,
standardization of subjects’ behaviour) and analytic
approach (choice of variables for multiple adjust-
ments). Our study has the advantage of having included
a homogeneous sample, representative of subjects
typically seen for a clinical evaluation of suspected
hypertension, at variance from data from clinical
trials such as Syst-Eur or from general population stu-
dies such as the PAMELA or Ohasama.9,16,17
Moreover, we tried to carefully address several poten-
tially relevant analytic aspects: 1) we avoided using
uncorrected 24-h SD, known to be heavily affected by
day–night BP fluctuation;19 2) we calculated standar-
dized hazard ratios for different estimates of systolic
and diastolic BPV, which allows their direct compari-
son; 3) the adjusted Cox regression models included
both mean SBP and DBP levels for any BPV variable
(either systolic or diastolic). This is important
considering that SBP is a much stronger predictor of
outcome and adjusting diastolic BPV only for the cor-
responding (i.e. diastolic) BP levels11 may disregard the
potential confounding effect of SBP levels.
An important and novel contribution of our study is
the finding of age-related differences in the predictive
significance of systolic and diastolic BPV. Previously
only the IDACO database provided age-specific results:
no significant interactions were found in terms of BPV
association with outcome between participants aged
above or below 60 years, although diastolic BPV was
significantly associated with cardiovascular events only
in older participants.11 Also in our data there was
no significant heterogeneity among age groups in the
association between diastolic BPV and cardiovascular
mortality. Conversely, systolic BPV was closely asso-
ciated with cardiovascular mortality only in youngest
(<50 years old) participants, where it superseded both
diastolic BPV and mean SBP level. Although the pres-
ence of multiple comparisons and the limited number
of events do not allow us to exclude the possibility of
Bilo et al. 7

Table 2. p-values related to differences among age classes may speculate that in elderly subjects systolic BPV may
(considering group <50 years as reference) in the effect of be driven by increased stiffness of large arteries,
systolic blood pressure variability indices on cardiovascular whereby small variations in stroke volume translate
mortality and all-cause mortality. into pronounced SBP fluctuations.23 In this group, age
Cardiovascular All-cause and mean SBP, both factors closely associated with
mortality mortality arterial stiffness, were strongly related to outcome and
p-value p-value their impact may have overridden that of SBP variability
per se. In fact, after removing age from the adjusted
Day SD: models, the association of systolic BPV with cardiovas-
<50 years (reference) – – cular mortality became significant. On the other hand, in
50–65 years 0.011 0.046 younger subjects arterial stiffness is less related to age
65–75 years 0.005 0.043 and in this group systolic BPV may emerge as an inde-
75 years 0.021 0.093 pendent indicator of early arterial damage.23 This
Night SD hypothesis is supported by numerous studies showing
<50 years (reference) – – association of systolic BPV with vascular (and also car-
50–65 years 0.237 0.413 diac) organ damage in middle-aged individuals.15,19–22
65–75 years 0.089 0.117 Another possibility is that systolic BPV identifies
75 years 0.130 0.144
young hypertensives with excessive pressor reactivity to
external stressors, driven by sympathetic activation.
24-h wSD
Such a phenomenon might be related to excessive BP
<50 years (reference) – –
increase with exercise, also reported to predict adverse
50–65 years 0.013 0.058 outcomes.35 In young subjects, increased systolic BPV
65–75 years 0.005 0.043 might thus reflect an impaired autonomic control of
75 years 0.1403 0.080 circulation (reduced sensitivity of arterial baroreflex
ARV may contribute to mortality by increasing the risk of
<50 years (reference) – – sudden cardiac death).36,37
50–65 years 0.097 0.147 In our study several BPV indices independently
65–75 years 0.021 0.043 predicted non-cardiovascular mortality. This finding
75 years 0.089 0.138 may appear surprising but is not quite in contrast
Residual BPV with previous reports.8,9,11,18 One possible explanation
<50 years (reference) – –
is that enhanced BPV may indicate a generally poor
health condition (reverse causality). Another possibility
50–65 years 0.013 0.117
is that some non-cardiovascular deaths occurred as a
65–75 years 0.014 0.043
complication of non-fatal cardiovascular disease (e.g.
75 years 0.021 0.046 infections or other respiratory problems in heart failure
p-values adjusted for multiple comparisons with the false discovery rate patients).
approach. p-values <0.05 are highlighted in bold character. No significant Our data add further evidence regarding the prognos-
differences were found for diastolic blood pressure variability (BPV) and tic information carried by different estimates of short-
for non-cardiovascular mortality.
term BPV. Among the investigated BPV indices, daytime
SD: standard deviation; wSD: weighted standard deviation; ARV: average
real variability; BPV: blood pressure variability SD, 24-h wSD, ARV and residual BPV were all inde-
pendently related to the risk of cardiovascular mortality
chance findings, our data are corroborated by a recent (none of these being clearly superior), while the SD of
publication from the HARVEST study, where a signifi- night-time DBP was not. The lack of independent pre-
cant association of high systolic BPV with cardiovascu- dictive value of night-time BPV is in contrast with the
lar events was found even in younger subjects results of Syst-Eur17 and of the Ambulatory Blood
(although, at variance from our report, that study Pressure-International Study,18 where night-time BPV
did not include older subjects for a direct comparison was superior to daytime BPV in predicting outcome.
and mainly focused on non-fatal events).34 Thus, we Different population characteristics may account for
hypothesize that systolic and diastolic 24-h BPV are this difference: Syst-Eur included elderly patients with
fundamentally different entities, a hypothesis further isolated systolic hypertension,17 while the Ambulatory
supported by the fact that, contrary to systolic BPV, Blood Pressure-International Study included a mixture
the association of diastolic BPV with outcome was lar- of population samples and patients referred for hyper-
gely unaffected by adjustment for covariates. tension, among which there was a large cohort of young,
Our data do not allow clarifying the pathophysio- low risk subjects with mild hypertension.18 Moreover, at
logical reasons underlying these intriguing findings. We variance from our analysis, the authors did not include
8 European Journal of Preventive Cardiology 0(00)

Unadjusted model Adjusted model

Age classes Hazard ratio [95% CI] Hazard ratio [95% CI]

Day SD
<50 yrs 1.60 [1.31, 1.96] 1.47 [1.20, 1.79]
50–65 yrs 1.18 [1.05, 1.34] 1.09 [0.97, 1.22]
65–75 yrs 1.09 [0.98, 1.22] 1.07 [0.95, 1.20]
75+ yrs 1.16 [1.02, 1.31] 1.15 [1.01, 1.31]
Overall 1.17 [1.10, 1.25] 1.12 [1.05, 1.20]
Night SD
<50 yrs 1.35 [1.14, 1.59] 1.19 [1.00, 1.42]
50–65 yrs 1.18 [1.05, 1.32] 1.09 [0.97, 1.22]
65–75 yrs 1.06 [0.95, 1.17] 0.99 [0.89, 1.11]
75+ yrs 1.07 [0.94, 1.22] 1.00 [0.87, 1.15]
Overall 1.12 [1.06, 1.20] 1.04 [0.98, 1.12]
24-h wSD
<50 yrs 1.65 [1.37, 1.98] 1.45 [1.20, 1.74]
50–65 yrs 1.24 [1.10, 1.39] 1.11 [0.99, 1.25]
65–75 yrs 1.10 [0.98, 1.22] 1.06 [0.94, 1.18]
75+ yrs 1.16 [1.02, 1.32] 1.13 [0.98, 1.30]
Overall 1.20 [1.12, 1.28] 1.13 [1.05, 1.21]
ARV
<50 yrs 1.51 [1.24, 1.84] 1.35 [1.11, 1.65]
50–65 yrs 1.23 [1.09, 1.39] 1.12 [0.99, 1.28]
65–75 yrs 1.06 [0.95, 1.18] 0.99 [0.88, 1.11]
75+ yrs 1.16 [1.02, 1.31] 1.11 [0.97, 1.26]
Overall 1.17 [1.09, 1.25] 1.09 [1.01, 1.17]
Residual BPV
<50 yrs 1.65 [1.36, 2.00] 1.44 [1.19, 1.74]
50–65 yrs 1.16 [1.02, 1.33] 1.06 [0.93, 1.21]
65–75 yrs 1.06 [0.95, 1.19] 1.02 [0.90, 1.14]
75+ yrs 1.11 [0.98, 1.25] 1.07 [0.94, 1.22]
Overall 1.15 [1.07, 1.23] 1.08 [1.00, 1.16]

0.6 1 2.5 0.6 1 2.5

Hazard ratio Hazard ratio

Figure 3. Association of systolic blood pressure variability estimates with all-cause mortality overall and by age category.
Standardized (per 1 SD) hazard ratios with 95% confidence interval are shown for Models 1 (unadjusted) and 2 (adjusted).
CI: confidence interval; SD: standard deviation; yrs: years; wSD: weighted standard deviation; BPV: blood pressure variability;
ARV: average real variability

cardiovascular disease history or nocturnal BP fall in the
multivariable models.
A few limitations of our study need to be acknowl-
edged. One, the interval between ambulatory BP read-
ings was 30 min, which in some subjects might have
reduced the accuracy in estimating BPV.38 However,
if anything, this might have led to an underestimation
of BPV impact on mortality. Two, ambulatory BP
recordings were obtained off-treatment: while this
allowed to avoid the potential effects of treatment on
basal BPV, we cannot exclude a confounding effect of
treatment during follow-up. Nonetheless, given the fact
that the currently used treatments have limited impact
on BPV, it is plausible that individuals with initially
high BPV retained this characteristic during the
follow-up period and thus the prognostic impact of ini-
tial BPV was maintained over time. Three, the strong
contribution of age to mortality could have masked the
possible association of systolic BPV with outcome in
older subjects. Four, in non-drug-naı̈ve participants
washout period was relatively short and some residual
effect of previous treatment cannot be fully ruled
out. Five, the generalizability of our findings would
need to be tested in more contemporary cohorts.
Six, our study involved multiple comparisons and
applying FDR with a conventional statistical signifi-
cance level of 0.05 may be considered not conservative
enough. Also, the rather low number of events in the
youngest age group may have affected the stability and
reproducibility of risk estimates. However, the consist-
ency of the observed patterns indicates, in our view,
that the observed associations reflect true phenomena
rather than chance findings.
To conclude, while confirming that BPV is a signifi-
cant and independent predictor of cardiovascular risk,
the present study offers new information by indicating
that systolic and diastolic BPV may have different
pathophysiological background and prognostic mean-
ing at different ages. Based on our findings, studies on
the prognostic value of BPV should always consider
systolic and diastolic BPV as distinct entities and con-
sider their relationship with age. Further research is
Bilo et al. 9

Unadjusted model Adjusted model

Age classes Hazard ratio [95% CI] Hazard ratio [95% CI]

Day SD
<50 yrs 1.33 [1.10, 1.61] 1.25 [1.03, 1.51]
50–65 yrs 1.18 [1.06, 1.32] 1.15 [1.03, 1.29]
65–75 yrs 1.19 [1.08, 1.30] 1.19 [1.08, 1.31]
75+ yrs 1.08 [0.97, 1.20] 1.13 [1.01, 1.26]
Overall 1.16 [1.10, 1.23] 1.17 [1.10, 1.24]
Night SD
<50 yrs 1.22 [1.03, 1.44] 1.09 [0.92, 1.30]
50–65 yrs 1.16 [1.04, 1.30] 1.09 [0.97, 1.22]
65–75 yrs 1.12 [1.00, 1.24] 1.02 [0.92, 1.14]
75+ yrs 1.16 [1.04, 1.28] 1.07 [0.96, 1.19]
Overall 1.15 [1.09, 1.22] 1.06 [1.00, 1.13]
24-h wSD
<50 yrs 1.38 [1.15, 1.66] 1.24 [1.03, 1.49]
50–65 yrs 1.22 [1.09, 1.35] 1.16 [1.04, 1.30]
65–75 yrs 1.21 [1.10, 1.34] 1.18 [1.07, 1.31]
75+ yrs 1.13 [1.02, 1.25] 1.14 [1.02, 1.27]
Overall 1.20 [1.13, 1.27] 1.17 [1.10, 1.24]
ARV
<50 yrs 1.26 [1.03, 1.54] 1.17 [0.96, 1.42]
50–65 yrs 1.21 [1.08, 1.36] 1.16 [1.04, 1.30]
65–75 yrs 1.21 [1.10, 1.34] 1.14 [1.03, 1.26]
75+ yrs 1.07 [0.97, 1.17] 1.08 [0.98, 1.20]
Overall 1.16 [1.10, 1.22] 1.13 [1.06, 1.20]
Residual BPV
<50 yrs 1.41 [1.17, 1.71] 1.27 [1.06, 1.54]
50–65 yrs 1.21 [1.08, 1.36] 1.16 [1.03, 1.30]
65–75 yrs 1.24 [1.12, 1.37] 1.18 [1.07, 1.31]
75+ yrs 1.07 [0.97, 1.19] 1.09 [0.98, 1.21]
Overall 1.18 [1.12, 1.25] 1.15 [1.08, 1.23]

0.6 1 2.5 0.6 1 2.5

Hazard ratio Hazard ratio

Figure 4. Association of diastolic blood pressure variability estimates with all-cause mortality overall and by age category.
Standardized (per 1 SD) hazard ratios with 95% confidence interval are shown for Models 1 (unadjusted) and 2 (adjusted).
CI: confidence interval; SD: standard deviation; yrs: years; wSD: weighted standard deviation; BPV: blood pressure variability;
ARV: average real variability

clearly needed, aimed at a more profound understand-

ing of pathophysiological and clinical aspects of BPV
and on the therapeutic approaches which might specif-
ically target increased BPV.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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