Review
White-coat hypertension, as defined by ambulatory
blood pressure monitoring, and subclinical cardiac
organ damage: a meta-analysis
Cesare Cuspidi a,b, Marta Rescaldani c, Marijana Tadic d, Carla Sala c, Guido Grassi a,e, and
Giuseppe Mancia a,b
Aim: The clinical and prognostic relevance of white-coat
hypertension (WCH) has not been fully elucidated; in
particular, the association of this blood pressure phenotype
with suclinical organ damage remains unclear. We
performed a systematic meta-analysis in order to provide a
comprehensive information on cardiac structural and
functional changes in WCH, as defined by ambulatory
blood pressure monitoring.
Design: Studies were identified by the following search
terms: ‘white-coat hypertension’, ‘isolated clinic
hypertension’, ‘cardiac organ damage’, ‘target organ
damage’, ‘left ventricle’, ‘left ventricular hypertrophy’,
‘cardiac hypertrophy’, ‘ventricular dysfunction’, and
‘echocardiography’.
Results: A total of 7382 untreated adult patients (2493
normotensive, 1705 WCH, and 3184 hypertensive
individuals) included in 25 studies were considered. Left
ventricular mass index was higher in WCH than in
normotensive patients [standardized difference in mean
(SDM) 0.50, P < 0.01]; mitral E/A ratio was lower (SDM

0.27, P < 0.01) and left atrium larger (SDM 0.29,
P < 0.05) in WCH than in the normotensive counterparts.
Hypertensive patients showed a greater left ventricular
mass index (SDM 0.42, P < 0.01), reduced E/A (SDM

0.15, P < 0.01), and larger left atrium diameter (SDM
0.27, P < 0.01) than WCH patients.
Conclusions: Our meta-analysis shows that alterations in
cardiac structure and function in WCH patients, as defined
by ambulatory blood pressure monitoring, are intermediate
between sustained hypertensive patients and normotensive
controls. The study supports the view that WCH should
not be further considered a fully benign entity.
Keywords: ambulatory blood pressure monitoring, cardiac
damage, white-coat hypertension
Abbreviations: ABPM, ambulatory blood pressure
monitoring; BP, blood pressure; BSA, body surface area;
LVH, left ventricular hypertrophy; SDM, standardized
difference in means; E/A ratio, ratio of early (E) to late (A)
peak of mitral inflow velocity; WCH, white-coat
hypertension
24 www.jhypertension.com
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INTRODUCTION
W
hite-coat or isolated clinic hypertension currently
defines individuals whose blood pressure (BP) is
elevated in the medical setting, but normal when
assessed away from the medical environment, such as by
24-h ambulatory BP recording and/or home BP measure-
ment [1–3]. Since the pioneering publication by Pickering
et al. [1] in which ‘white-coat hypertension’ (WCH) was
used for the first time to define untreated hypertensive
patients, the vast majority of studies agree that this con-
dition accounts for a noticeable fraction of the hypertensive
population [4,5]. No agreement, however, exists on the
prognostic significance of WCH: whether it is an innocent
clinical entity or is associated with an adverse/increased
cardiovascular risk is still unsettled [6]. Despite numerous
investigations, the presence and extent of increased car-
diovascular risk in WCH patients as compared to their true
normotensive counterparts remain controversial. This is
because the extent of subclinical organ damage [that is left
ventricular hypertrophy (LVH), carotid atherosclerosis,
microalbuminuria, and retinopathy] in WCH patients has
been reported to be similar as in normotensive patients by
some investigators, but as severe as in sustained hyper-
tensive patients by others [7–10]. Likewise, the incidence of
cardiovascular morbid or fatal events in patients with WCH
has been reported to be similar either as in normotensive
patients, as in hypertensive patients, or intermediate
between these groups [11–13]. The relationship between
cardiovascular outcomes and WCH has been also inves-
tigated by some recent meta-analyses.
Journal of Hypertension 2015, 33:24–32
a
Department of Health Science, University of Milano-Bicocca, bIstituto Auxologico
Italiano, cDepartment of Clinical Sciences and Community Health, University of Milan,
Milan, Italy, dFondazione, Policlinico di Milano University Clinical Hspital Centre
‘Dragisa Misovic’, Belgrade, Serbia and eIstituto di Ricerche a Carattere Scientifico
Multimedica, Sesto San Giovanni, Milan, Italy
Correspondence to Professor Cesare Cuspidi, Istituto Auxologico Italiano, Clinical
Research Unit, Viale della Resistenza 23, 20036 Meda, Italy. Tel: +39 0362/772433;
fax: +39 0362/772416; e-mail: cesare.cuspidi@unimib.it
Received 4 May 2014 Revised 9 September 2014 Accepted 9 September 2014
J Hypertens 33:24– 32 ß 2014 Wolters Kluwer Health | Lippincott Williams &
Wilkins.
DOI:10.1097/HJH.0000000000000416
Volume 33  Number 1  January 2015

In a pooled population of 7961 untreated patients (16%
with WCH), Pierdomenico and Cuccurullo [14] showed that
cardiovascular risk was not different in WCH compared to
true normotensive patients. The International Database on
Ambulatory Blood Pressure Monitoring in Relation to Car-
diovascular Outcomes (IDACO) study [15], assessing the
significance of WCH in older persons with isolated systolic
hypertension, free of cardiovascular disease at baseline and
stratified according to the presence or absence of antihy-
pertensive treatment, reported that untreated WCH and
normotensive patients were at a similar risk. This was
not true for treated WCH patients, who had a higher
cardiovascular risk as compared with the untreated
normotensive patients.
The association between subclinical organ damage and
WCH remains controversial; in particular, meta-analysis-
based findings on this important topic are lacking. There-
fore, the primary aim of this systematic review and meta-
analysis was to provide a comprehensive and updated
information on the presence and extent of subclinical
structural and functional cardiac damage, as assessed by
echocardiography in untreated patients with WCH.
METHODS
Search strategy and study selection
Medical literature was reviewed in order to identify all
articles evaluating the impact of WCH on cardiac structure
and function as assessed by echocardiography.
A computerized search was performed using PubMed,
OVID, EMBASE, and Cochrane library databases from 1
December 1990 up to 31 January 2014. The studies were
identified by the following search terms: ‘white-coat hyper-
tension’, ‘isolated clinic hypertension’, ‘cardiac organ dam-
age’, ‘target organ damage’, ‘left ventricle’, ‘left ventricular
Studies identified and
screened for retrieval
(n = 392)
Appropriate studies to
be included in the
review
(n = 94)
Studies included in
the final review
(n = 25)
FIGURE 1 Schematic flowchart for the selection of studies. BP, blood pressure; WCH, white-coat hypertension.
Journal of Hypertension
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
White-coat hypertension and cardiac damage
hypertrophy’, ‘cardiac hypertrophy’, ‘ventricular dysfunc-
tion’ and ‘echocardiography’. Checks of the reference lists
of selected papers and pertinent reviews complemented
the electronic search. Data have been extracted by three
independent investigators (C.C., M.R., and C.S.); additional
data have been obtained by personal contact with authors
of the selected papers.
Inclusion criteria were: full articles published in English
in peer-reviewed journals; studies reporting quantitative
data on left ventricular structure, as defined by left ven-
tricular mass indexed to body size measures in at least 15
untreated adult patients with WCH; normal out-of-office BP
defined by ambulatory BP monitoring (ABPM) (that is mean
24-h or mean daytime levels).
Only updated or largest reports were considered when
multiple publications by the same research group were
found in order to avoid double counting patients. The first
literature search identified 392 papers. After the initial
screening of titles and abstracts, 298 studies were excluded
and 94 were reviewed; of these, 25 studies fulfilled the
inclusion criteria and contained sufficient details to be
included in the final review [16–40] (Fig. 1).
Statistical analysis
The primary aim of the meta-analysis was to compare sub-
clinical alterations in left ventricular structure, expressed as a
continuous variable (i.e. left ventricular mass index) and/or
as a categorical variable (i.e. prevalence of LVH), as assessed
by echocardiography, in WCH compared to sustained hyper-
tensive and/or normotensive controls. To this purpose,
pooled analysis of echocardiographic parameters was per-
formed using fixed or random-effects meta-analysis by Com-
prehensive Meta-Analysis Version 2 (Biostat, Englewood,
New Jersey, USA). In order to calculate the average preva-
lence of LVH in the pooled population, we considered the
Studies excluded based on
title and abstract review
(n = 298)
- No echocardiographic data on left
ventricular mass index (n = 16)
- WCH not defined by ambulatory BP
criteria (n = 6)
- Review or editorial articles (n = 21)
- Lack of clinical data (n = 8)
- Antihypertensive treatment (n = 6)
- Study population <15 patients (n = 5)
- Double or serial publications (n = 4)
- Miscellaneous reasons (n = 3)
www.jhypertension.com 25
Cuspidi et al.

occurrence of LVH as an event rate. Demographic and
clinical data provided by the selected studies are expressed
as absolute numbers, percentage, mean  SD, mean 
standard error (SE), or median and interquartile range.
Meta-regression analysis was used to determine the impact
of office and ambulatory BP upon left ventricular mass index.
The limit of statistical significance was set at P value less
than 0.05.
Heterogeneity was estimated using the I-square test;
random-effect models were applied when the heterogen-
eity across studies was high (I2 >75). Publication bias was
assessed using the funnel plot method.
RESULTS
Characteristics of the studies
Table 1 shows the main characteristics of the analyzed
studies, including the year of publication, sample size,
mean age, sex distribution, mean BMI, office BP, mean
24-h and/or daytime ABPM values, and criteria defining
normal ABPM values.
Overall, 7382 untreated patients (2493 normotensive,
1705 WCH, and 3184 hypertensive individuals) of both
sexes were included in the 25 studies performed in different
geographical areas (Europe 18; Asia 6; North America 1).
The assessment of left ventricular structural and/or func-
tional changes associated to WCH was the primary aim of all
studies but two [33,40]. Most of these studies examined
patients recruited in out-patient hypertension clinics, three
in population-based samples [27,29,39], and one in a
primary care setting [26].
Characteristics of white-coat hypertension
patients
Mean age range was 33–70 years [24,29]; 50.9% of the
participants were men (n ¼ 846, data provided by 24 stud-
ies including 1663 patients). Average office SBP ranged
from 141  13 [35] to 176  12 mmHg [18], and DBP from
86  9 [39] to 105  10 mmHg [23]. Average daytime SBP
varied from 115  12 [34] to 137  8 mmHg [18], and DBP
from 73  6 [36] to 88  6 mmHg [16] (24 studies, 1527
patients). Average BMI ranged from 24.9  2.5 [19] to
28.7  5.2 kg/m2 [37] (18 studies, 1384 patients). All
examined patients were free from previous or overt
cardiovascular disease.
Normal ABPM thresholds were defined according to 11
different criteria (five based on average 24-h BP and six
on average daytime values). The most frequently used
criterion for defining normal out-of office BP was average
daytime SBP/DBP lower than 135/85 mmHg [24–26,29,
31–35,38–40].
Echocardiographic findings in white-coat
hypertension, true normotensive and
hypertensive patients
In all selected studies, left ventricular mass was normalized
to body surface area (BSA). In the pooled study population,
mean left ventricular mass index ranged from 70 [38] to

TABLE 1. Summary of 25 studies reporting data on left ventricular structure and function in white-coat hypertensive patients
Mean Mean Normal
Year Sample Office 24-h daytime ambulatory
Author of size Age Men BMI SBP/DBP SBP/DBP SBP/DBP BP values
(reference) publication (n) (years) (%) (kg/m2) (mmHg) (mmHg) (mmHg) (mmHg)
Cardillo et al. [16] 1993 18 43  5 55 NA 148  13/98 6 121  5/82  5 126  7/88  6 Day SBP/DBP <134/90
Hoegholm et al.[17] 1993 53 46  13 36 25.1 þ 3.4 158 þ 16/102 þ 7 NA 133  13/84  5 Day DBP <90
Kuwajiama et al. [18] 1993 17 74  6 18 NA 176 þ 12/91 þ 8 133  6/74  6 137  8/78  7 24-h SBP <140
Cavallini et al. [19] 1995 24 61  9 33 24.9  2.5 158 þ 10/92 þ 4 128  5/77  5 130  5/79  6 Day SBP/DBP <134/90
Cuspidi et al. [20] 1995 31 35  12 65 NA 144  18/97  4 127  6/79  4 132  7/83  5 24-h SBP/DBP <132/85
Pierdomenico 1995 25 46  11 52 26.3 þ 2.8 149 þ 5/96 þ 2 123  7/75  5 129  6/78  6 24-h SBP/DBP <135/85
et al. [21]
Rizzo et al. [22] 1996 22 69  3 55 NA 159  15/102 þ 7 NA 133  13/84  5 Day SBP/DBP <142/90
Glen et al. [23] 1996 22 58  8 64 NA 160  19/105  10 NA 135  10/83  6 Day DBP <95
Palatini et al. [24] 1998 260 33  8 69 25.1  3.7 143  10/93  5 121  7/76  6 124  8/88  6 Day SBP/DBP <135/85
Owens et al. [25] 1999 33 40 27 NA 162/102 8 NA 125/78 Day SBP/DBP <135/85
Martinez et al. [26] 1999 71 54  11 35 28.0 þ 4.0 146 þ 15/95 þ 6 NA 124  8/80  7 Day SBP/DBP <135/85
Sega et al. [27] 2001 178 58  11 50 NA 149 þ 9/93 þ 4 119  6/74  4 NA 24-h SBP/DBP <125/80
Grandi et al. [28] 2001 42 42  7 NA 25.3  2.7 154  16/93  14 120  5/70  5 126  5/74  6 Day SBP/DBP <130/80
Bjorklund et al. [29] 2002 49 70 100 25.3  3.0 150  17/85  5 NA 128  6/75  5 Day SBP/DBP <135/85
Silveira et al. [30] 2002 57 46  2a 47 26.0  1.0a 148  3/89  2a NA 124  2/79  1a Day SBP/DBP <130/84
Pose-Reino et al. [31] 2002 27 46  12 44 27.5  3.2 148  11/96  5 120  8/71  6 125  9/75  7 Day SBP/DBP <135/85
Karter et al. [32] 2003 24 50  11 46 29.0  4.0 156  21/98  11 NA 121  6/74  5 Day SBP/DBP <135/85
Curgunlu et al. [33] 2005 33 49  2 48 25.0  0.9 152  7/88  3 122  5/75  3 131  3/82  6 Day SBP/DBP <135/85
Erdogan et al. [34] 2006 35 47  6 46 28.1  1.9 147  8/93  4 113  10/73  11 115  12/75  11 Day SBP/DBP <135/85
Cuspidi et al. [35] 2007 43 46  12 53 25.7  3.6 141  13/95  7 121  5/77  4 125  4/81  3 Day SBP/DBP <135/85
Mulè et al. [36] 2007 145 43 þ 12 48 27.5  4.0 150  17/92  10 117  7/70  6 121  7/7  6 Day SBP/DBP <130/80
Kotsis et al. [37] 2008 274 52  14 37 28.7  5.2 154  13/95  10 120  7/77  6 121  6/73  6 24-h SBP/DBP <125/80
Ihm et al. [38] 2009 30 48  9 33 24.0  3.0 145  16/95  12 NA 124  7/76  6 Day SBP/DBP <135/85
Sung et al. [39] 2013 153 58  13 51 25.0  3.0 145  13/86  9 122  7/76  5 126  8/77  8 Day SBP/DBP <135/85
Caliskan et al. [40] 2013 40 45  7 45 28.1  2.2 146  7/93  4 116  11/74  10 123  7/78  5 Day SBP/DBP <135/85

NA, not available.

a
Standard error; confidence intervals.

26 www.jhypertension.com Volume 33  Number 1  January 2015

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 White-coat hypertension and cardiac damage

124 g/m2 [29] in the normotensive controls, from 70 [30] to
132 g/m2 [31] in the WCH patients, and from 84 [30]
to 142 g/m2 [31] in the sustained hypertensive patients.
As shown in Fig. 2a, mean left ventricular mass index
was lowest in normotensive (88.05  2.5 g/m2), inter-
mediate in WCH (95.72  1.8 g/m2) and highest
(109.2  2.5 g/m2) in the sustained hypertensive patients.
Figure 3a reports the results of the meta-analysis from
20 studies providing data on average left ventricular
mass indexed to BSA and SD in 1355 WCH patients
and 2493 normotensive controls. The standardized differ-
ence in means (SDM) was positive in favor of the WCH
individuals [0.50  0.10, 95% confidence interval (CI)
0.31–0.70, P < 0.01]. As shown in Fig. 3b, reporting the
(a)
120
110
100
LVMI (g/m2)
findings of the meta-analysis from 22 studies, left ven-
tricular mass index was significantly higher in sustained
hypertensive (n ¼ 3184) as compared to WCH patients
(n ¼ 1505), with a SDM of 0.42  0.03 (95% CI 0.35–0.48,
P < 0.01).
Data on LVH prevalence in normotensive, WCH, and
sustained hypertensive patients were provided by a limited
fraction of the reports included in the meta-analysis, namely
by two [27,31], eight [17,19–22,27,31,35], and seven [17,19–
21,27,31,35] studies, respectively. Overall, 58 out of the 408
WCH patients (15%) and 209 out of the 1028 sustained
hypertensive patients (21%) were found to have LVH
according to the different criteria provided by the authors.
LVH prevalence consistently varied among studies, ranging
from 4 to 59% in WCH and from 13 to 75% in sustained
hypertensive patients.
As for left ventricular diastolic function, as assessed by
the ratio of early (E) to late (A) peak of mitral inflow velocity
(E/A ratio), the average value from pooled data of eight
studies [16,18,23,24,29,34,38,40] was 1.17  0.07 in normo-
tensive (n ¼ 337), 1.07  0.07 in WCH (n ¼ 471), and
0.99  0.11 in sustained hypertensive patients (n ¼ 852)

(Fig. 2b). The ratio was higher in normotensive than in

90 WCH patients (SDM 0.27  0.07, 95% CI 0.12–0.41,
P < 0.01) (Fig. 4a) and in WCH compared to sustained
80 hypertensive patients (SDM 0.20  0.06, 95% CI 0.09–
0.31, P ¼ 0.01) (Fig. 4b).
70 Finally, pooled data from five studies [17,18,31,34,40]
2493 1705 3184 documented that left atrium diameter was 3.26  0.03 cm in
60
normotensive (n ¼ 161), 3.31  0.11 cm in WCH (n ¼ 193),
(b) and 3.44  0.13 cm in sustained hypertensive patients
1.40 (n ¼ 261) (Fig. 2c). Left atrium diameter was greater in
WCH than in 141 normotensive patients (SDM
0.29  0.13, 95% CI 0.04–0.54, P < 0.05) (Fig. 5a) and in
1.20 sustained hypertensive than in WCH patients (SDM
0.27  010, 95% CI 0.07–0.46, P < 0.01) (Fig. 5b).
E/A ratio

1.00 Correlation analyses

A meta-regression analysis performed on data from all WCH
(Fig. 6a) and sustained hypertensive patients (Fig. 6b)
0.80
included in the 25 studies showed a direct correlation
337 471 852
between left ventricular mass index and office SBP
(r ¼ 0.42, P < 0.01; and r ¼ 0.64, P < 0.05, respectively).
0.60
The relation between left ventricular mass index and
daytime SBP in WCH patients (meta-regression data from 24
(c)
3.75 studies, 1527 WCH individuals) was not significant
(r ¼ 0.18, P ¼ 0.17). This was also the case for sustained
3.50 hypertensive patients (meta-analysis from 21 studies, 3163
individuals), as left ventricular mass index showed a weak
correlation with daytime BP (P ¼ 0.26, P ¼ 0.44). Further-
LA (cm)

3.25
more, we failed to demonstrate in WCH patients a signifi-
3.00 cant relation between left ventricular mass index and 24-h
SBP (P ¼ 0.32) in the 16 studies providing this kind of
2.75 information. Similar findings were observed in sustained
161 196 261 hypertensive patients.
2.50 A funnel plot excluded the presence of publication bias
NT WCH SH of studies comparing left ventricular mass index in WCH
FIGURE 2 (a) Left ventricular mass index (LVMI), (b) E/A ratio, and (c) left atrium and sustained hypertensive patients (23 studies), as well in
diameter in normotensive (NT), white-coat hypertensive (WCH), and sustained WCH and normotensive controls (20 studies). A sensitivity
hypertensive (SH) patients. Meta-analysis from 25 echocardiographic studies.
Means  SE; number of patients in each group are reported in the histograms. SE, analysis showed that the final result was not substantially
standard error. affected by a single study effect.

Journal of Hypertension www.jhypertension.com 27

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Cuspidi et al.

(a)
Left ventricular mass index
SDM and 95% CI
StudyRef. % weight
Cardillo16 3.53
Owens25 4.18
Mule36 5.06
Kuwajiama18 3.69
Pose-Reino31 4.92
Karter32 4.43
Curgunlu33 4.84
Grandi25 5.20
Sega27 6.61
Ihm38 4.74
Palatini24 6.30
Sung39 6.45
Pierdomenico21 4.51
Cavallini19 4.46
Rizzo22 4.26
Caliskan40 5.19
Bjorklund29 5.69
Erdogan34 5.03
Kotsis37 6.66
Glen23 4.26
Total 100
–2.0 –1.0 0.0 1.0 2.0
Favours Favours
NT WCH

(b) Left ventricular mass index

SDM and 95% CI
StudyRef. % weight
Pierdomenico21 1.45
Glen23 0.99
Ihm38 1.44
Cavallini19 1.23
Cuspidi20 2.00
Silveira30 2.83
Grandi25 2.25
Cardillo16 1.30
Palatini24 I8.05
Sung39 13.00
Caliskan40 2.65
Karter32 1.22
Curgunlu33 1.86
Kuwajiama18 1.24
Bjorklund29 4.12
Martinez26 1.94
Hoelgholm17 3.67
Kotsis37 19.70
Erdogan34 2.28
Pose-Reino31 1.41
Cuspidi35 4.45
Sega27 10.91
Total 100
–2.0 –1.0 0.0 1.0 2.0
Favours Favours
WCH SH
FIGURE 3 Forest plots for standardized difference in mean (SDM) of left ventricular mass index (LVMI, g/m2) in: (a) white-coat hypertensive (WCH, n ¼ 1335) and
normotensive (NT, n ¼ 2493) patients; (b) WCH (n ¼ 1505) and sustained hypertensive (SH, n ¼ 3184) patients. CI, confidence interval.

28 www.jhypertension.com Volume 33  Number 1  January 2015

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 White-coat hypertension and cardiac damage

(a) (a) Left atrium diameter

E/A ratio SDM and 95%CI
StudyRef. SDM and 95% CI %Weight Study Ref.
%Weight
Cardillo16 4.67
Kuwajiama18 12.64
Glen23 5.99
8.07 Pose-Reino31 27.34
Ihm38
Kuwajiama18 4.57 Erdogan34 27.99
Palatini24 38.79 Caliskan40 32.02
Bjorklund29 17.01 Total 100
Caliskan40 11.08
Erdogan34 9.81 –2.0 –1.0 0.0 1.0 2.0
Favours Favours
Total 100
NT WCH
–2.0 –1.0 0.0 1.0 2.0
Favours Favours (b) StudyRef. %Weight
WCH NT
(b) StudyRef. Hoelghom17 32.47
%Weight
Caliskan40 7.79 Kuwajiama18 10.90
Ihm38 4.84
Pose-Reino31 12.45
Glen23 3.48
Bjorklund29 12.57 Erdogan34 20.24
Erdogan34 6.92 Caliskan40 23.93
Kuwajiama18 3.84
Palatini24 56.51 Total 100
Cardillo16 4.07 –2.0 –1.0 0.0 1.0 2.0

Total 100 Favours Favours

–2.0 –1.0 0.0 1.0 2.0
Favours Favours
SH WCH
FIGURE 4 Forest plot for standardized difference in mean (SDM) of E/A ratio in: (a)
white-coat hypertensive (WCH, n ¼ 471) and normotensive patients (NT, n ¼ 337);
(b) WCH (n ¼ 471) and sustained hypertensive patients (SH, n ¼ 852).
Study quality evaluation
Two reviewers graded each study independently evaluat-
ing four items: office BP measurements taken in two or
more sessions versus a single session; use of validated
ABPM devices; blind assessment of echocardiographic
examinations; and sample size including at least 35 cases
and controls, allowing to detect a 10% or greater difference
among groups in echocardiographic variables. The score of
each article can range from 0 (lowest quality) to 4 (highest
quality). Nine studies showed a score of 4 points (excellent
quality), seven a score of 3 points (good quality), and nine a
score of 2 points (fair quality).
DISCUSSION
The present meta-analysis of 25 studies published in the
past two decades provides an updated information on
subclinical markers of cardiac damage, as assessed by
echocardiographic left ventricular mass index, E/A ratio,
and left atrial diameter in a pooled population of 1705 WCH
patients from different clinical settings characterized by
various degrees of office BP levels as compared to true
normotensive and hypertensive counterparts.
The principal findings of our analysis are the following:
left ventricular mass index showed a graded, signifi-
cant increase from normotensive, WCH to sustained
hypertensive patients; the E/A ratio was significantly
WCH SH
FIGURE 5 Forest plot for standardized difference in mean (SDM) of left atrial
diameter in: (a) white-coat hypertensive (WCH, n ¼ 118) and normotensive patients
(NT, n ¼ 141); (b) WCH (n ¼ 171) and sustained hypertensive patients (SH, n ¼ 261).
reduced in WCH as compared to the normotensive patients
and in sustained hypertensive as compared to the WCH
patients; left atrial diameter was greater in WCH as com-
pared to the normotensive controls, and in sustained hyper-
tensive as compared to the WCH patients; office but not
ambulatory BP showed a direct, significant correlation with
left ventricular mass index in both WCH and sustained
hypertensive patients. Several aspects of our results deserve
to be further commented.
Our meta-analysis clearly shows that WCH is a risk factor
for LVH development. Patients with WCH, indeed, exhib-
ited an average left ventricular mass index intermediate
between true normotensive and sustained hypertensive
patients. This finding supports the view that transient BP
rises, such as those triggered by stress-related sympathetic
activation during clinical visit, may modulate cardiac
growth. This hypothesis is also supported by the meta-
regression including all selected studies that shows a sig-
nificant, direct association between office BP and left ven-
tricular mass index. Thus, transient BP elevations in the
office setting tend to increase the left ventricular mass,
although this parameter remains below the conventional
cut-off values for hypertrophy, as in our pooled population,
only a limited fraction of the WCH patients (15%) fulfilled
the diagnostic criteria for LVH.
The relation between left ventricular mass and risk of
cardiovascular events has been shown to be extended over
a wide range of left ventricular mass values, and to persist
below upper normal limits currently accepted by the
authoritative international guidelines [3].

Journal of Hypertension www.jhypertension.com 29

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Cuspidi et al.

(a) adjustment for traditional risk factors, as well as new ones,

160 such as carotid–femoral pulse wave velocity.
r = 0.42
P < 0.01 The increased left ventricular mass is the major mani-
140 festation of hypertensive heart disease, and reflects the
response of the heart to chronic BP elevation aimed to
LVMI (g/m2)

120 counterbalance the left ventricular wall stress [43,44].

Additional alterations of cardiac structure and function
100 may also occur in the hypertensive patients, including left
atrial enlargement and left ventricular systolic/diastolic
80 dysfunction [45,46].
Most of the attention has been focused on left ventricular
60 diastolic dysfunction because of the high prevalence of this
130 140 150 160 170 180 alteration and, more importantly, for its association with an
Office systolic BP (mmHg)
increased risk of heart failure and cardiovascular mortality.
A large body of evidence points to LVH as a key factor in the
(b) pathogenesis of diastolic dysfunction, although other
160
r = 0.64 observations indicate that an impairment of left ventricular
P < 0.01 compliance may precede LVH development [46]. Among
140
conventional Doppler indexes assessing diastolic function,
LVMI (g/m2)

120
100
80
60
130 140 150 160 170 180
Office systolic BP (mmHg)
FIGURE 6 Meta-regression of left ventricular mass index (LVMI) with office SBP in:
(a) white-coat hypertensive (n ¼ 1431) and (b) sustained hypertensive patients
(n ¼ 3164).
An observational study by Schillaci et al. [41], including a
total of 1925 uncomplicated essential hypertensive patients,
showed that the relative risk of developing cardiovascular
events progressively increased from the first to the fifth
quintile of the left ventricular mass index, after adjusting
for several risk factors and 24-h ambulatory BP values. Similar
results have been recently reported in the Pressioni Moni-
torate E Loro Associazioni (PAMELA) study, a population-
based study comprising 1716 patients [42]. After adjusting for
age, sex, office or ambulatory BP, blood glucose, total
cholesterol, and use of antihypertensive drugs, the patients
stratified in the two highest quintiles of the left ventricular
mass indexed to BSA or height2.7 exhibited a greater like-
lihood of incident cardiovascular disease, the relative risk
being 2.69 (95% CI1.05–6.96, P ¼ 0.04) and 4.62 (95% CI
1.42–15.02, P ¼ 0.01), respectively, as compared to the first
reference quintile. These results support the view that
patients with left ventricular mass index in the high-normal
range are at a higher risk than their counterparts in the
lower range.
In a prospective study, Sung et al. [39]. showed that
WCH patients with intermediate values of left ventricular
mass index (98  25 g/m2) between true normotensive
(89  21 g/m2) and sustained hypertensive patients
(111  28 g/m2) displayed a higher risk for cardiovascular
mortality than their normotensive counterparts. The greater
hazard ratio in the WCH patients remained significant after
the E/A ratio has been widely used in clinical research and
current practice [47]. The relation of this index with the
cardiovascular outcomes has a U-shaped form, the lowest
and highest values being associated with poor cardiovas-
cular prognosis in different clinical settings [48]. In our
meta-analysis, the E/A ratio progressively decreased from
normotensive, WCH, and sustained hypertensive patients:
this finding indicates that a subtle impairment of left ven-
tricular diastolic function, as expressed by a reduction in the
E/A ratio, may be detected not only in sustained hyper-
tensive but also in WCH patients.
Left atrial enlargement is also regarded as an independ-
ent marker of increased cardiovascular risk in the general
population, as well as in patients with hypertension and
chronic heart disease [49]. Cross-sectional studies have
shown that left atrial enlargement is associated with a
variety of pathogical entities such as hypertensive heart
disease, diabetes, obesity, metabolic syndrome, and sleep
apnea. Longitudinal investigations have consistently dem-
onstrated that left atrial enlargement, as documented by a
single left atrial diameter or the more accurate left atrial
volume measurement, is a strong predictor of cardiovascular
outcomes [50,51]. In spite of the clinical and prognostic
relevance of this issue, only a few studies included in the
present meta-analysis provided data on left atrial size, in
particular, less than 10% of the total population of WCH and
less than 5% of normotensive controls. In spite of this
limitation, the significant difference in left atrial diameter
between the normotensive and WCH patients indicates
that left atrial morphology is also not preserved in
WCH patients.
Some other points of our study, including the strengths
and limitations, deserve to be briefly discussed. First, the
meta-regression analyses demonstrated a direct, significant
relation between office SBP and left ventricular mass index
in both WCH and sustained hypertensive patients. This
finding is in keeping with the general notion that elevated
SBP values measured in the office are associated with
increased risk of subclinical cardiac damage. Our meta-
analysis adds a new piece of information on this topic by
showing that transient elevation in BP in the setting of WCH
may impact on the cardiac structure.

30 www.jhypertension.com Volume 33  Number 1  January 2015

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

In contrast, we found no significant relation between
ambulatory daytime systolic or 24-h SBP and left ventricular
mass index in either group. The closer association between
left ventricular mass index and office as compared to
ambulatory BP observed in this study, not only in WCH
but also in sustained hypertensive patients, appears in
contrast with the view that multiple measurements of BP
during routine life reflect BP load more accurately than a
single BP measurement in the doctor’s office.
This may be related to the previous observations that in
sustained hypertensive patients, nocturnal BP load is of
major relevance in the development of LVH, as suggested
by a recent study of our group [52]; unfortunately, nocturnal
BP values were not available in all studies of the present
analysis. In WCH, on the contrary, diurnal BP values were,
by definition, in the normal range.
Second, as reported in the ‘Methods’ section, we selected
only studies in which normal BP outside the medical
environment was based on ABPM. This is because we
included only studies conducted with comparable BP
measurement tools, and this methodological approach
for the diagnosis of WCH phenotype has been used by
the vast majority of reports published in the literature.
The left ventricular mass was indexed to BSA in all
selected studies: this allowed us to compare the echocar-
diographic data concerning the left ventricular structure of
all cases and controls examined across the 25 studies,
without potential confounders related to heterogeous
methods of left ventricular mass indexation. It should be,
however, noted that left ventricular mass normalized to
different body size measures such as height or height to
allometric power of 2.7 was not an exclusion criterion in
our study selection.
In early studies, upper normal limits of ambulatory BP
were higher [16–19,22,23] than those recommended by
contemporary guidelines. Thus, a fraction of the patients
classified as having WCH in the previous studies nowadays
would be classified as sustained hypertensive patients;
however, a meta-analysis restricted to studies based on
ambulatory BP updated normal thresholds and confirmed
the differences in left ventricular mass index across the
three groups (data not shown). Finally, as WCH patients
were classified in all studies according to the normal day-
time or 24-h ambulatory BP levels, without taking in to
account the night-time BP, it was possible that individuals
with nocturnal hypertension were misclassified as
having WCH.
In conclusion, our meta-analysis shows that echo-
graphic alterations in cardiac structure and function in
WCH patients, as defined by ABPM, are intermediate
between sustained hypertensive patients and normoten-
sive controls; this finding supports the view that WCH
should be no longer considered an entirely benign entity.
In a practical perspective, patients with WCH should be
carefully evaluated in order to provide appropriate
prevention strategies.
ACKNOWLEDGEMENTS
Conflicts of interest
The authors report no conflicts of interest.
Journal of Hypertension
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
White-coat hypertension and cardiac damage
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Reviewers’ Summary Evaluations
Reviewer 1
The authors performed a meta-analysis to provide a quan-
titative estimation of cardiac structure and function in
normotensive subjects, patients with white-coat hyperten-
sion (WCH) and hypertensive patients. Alterations found in
patients with WCH were intermediary between those found
in sustained hypertensive patients and normotensive sub-
jects. This meta-analysis sheds new light on a controversial
and clinically relevant topic, i.e. target organ damage
associated with WCH. It suggests that WCH is not an
innocuous condition, and that patients with WCH may
benefit from preventive measures and a strict follow-up.
32 www.jhypertension.com
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Reviewer 2
A valuable meta-analysis suggesting that white coat hyper-
tension (WCH) is not benign, but an intermediate pheno-
type between normotension and hypertension. There are
no data for subjects aged <30 years or for WCH detected by
home blood pressure (BP) monitoring, both of which might
give different findings. The significant association of office
BP, but not of daytime or 24-h ambulatory BP, with left
ventricular mass index in WCH and sustained hypertensives
is problematic. Finally, it might be argued that studies
reporting only daytime ambulatory BP might be misleading
because the most important component of the BP profile
(nocturnal BP) is ignored.
Volume 33  Number 1  January 2015