Journal of Human Hypertension (1997) 11, 515–521
 1997 Stockton Press. All rights reserved 0950-9240/97 $12.00
ORIGINAL ARTICLE
Parallel increase in carotid, brachial and
left ventricular cross-sectional areas in
arterial hypertension
F Fantini, G Barletta, R Del Bene, C Lazzeri, G La Villa and F Franchi
Cardiology and Internal Medicine, University of Florence, Italy
Few data have been published about the relation
between the vessels geometry and development of left
ventricular (LV) hypertrophy in patients with arterial
hypertension. The aim of this study is to describe
arterial and LV geometry changes due to mild-to-moderate arterial hypertension in an untreated hypertensive
population.
In 95 untreated patients with mild-to-moderate hypertension and 23 age- and sex-matched healthy normotensives, we measured the end-diastolic diameter and wall
thickness of the left ventricle and the internal diameter
and intimal-medial thickness (IMT) of carotid and brachial arteries. From these data, the cross-sectional areas
(CSAs) of arterial and myocardial walls were calculated.
Hypertensive patients were further subdivided on the
basis of the presence of LV hypertrophy defined according to Devereux et al as anatomical LV mass .125 g/m.
In hypertensive patients with hypertrophy, carotid and
brachial CSAs increased, without significant changes in
thickness/diameter ratio (arterial ‘enlargement’), while
the left ventricle developed ‘concentric’ hypertrophy.
Arterial and LV CSAs showed a significant direct correlation with systolic blood pressure (BP). However, when
data were corrected for BP, the correlation between the
increase in arterial and LV CSAs became much
improved than for the raw data.
In conclusion patients with untreated mild-to-moderate hypertension, both carotid and brachial arterial walls
showed an enlargement that was proportional to the
development of LV hypertrophy. These results suggest
that the effects of arterial hypertension on carotid,
brachial and LV wall geometry have a common modulation.
Keywords: left ventricular hypertrophy; intimal-medial thickness; carotid artery; brachial artery
Introduction
Recent progress in ultrasound imaging allows direct
examination of the wall of the large arteries, with
a high degree of spatial resolution. A characteristic
image made of two parallel echo-reflecting lines at
the far wall of the vessel (the double line pattern)
has been described.1 The distance between the two
lines corresponds to that between the internal elastica lamina and intimal layer and does not differ significantly from the intimal + medial thickness (IMT)
directly measured in anatomic specimens.2
Many studies have examined the relationship
among IMT of the carotid artery, blood pressure (BP)
levels3–10 and the development of atherosclerotic
carotid8,11,12 or coronary alterations.13–18 Few data
have been published about the relation between the
carotid IMT and the development of left ventricular
(LV) hypertrophy in patients with arterial hypertension.19 To our knowledge, no data are known about
brachial IMT and LV hypertrophy in hypertensive
patients. Therefore, this study was aimed at
investigating the geometry of the carotid and brachCorrespondence: Dr Giuseppe Barletta, Via Medaglie d’Oro 43,
59100 Prato, Italy
Received 11 February 1997; revised 22 April 1997; accepted 13
May 1997
ial arteries and of the left ventricle in patients with
mild hypertension who had never been on antihypertensive drug therapy.
In this work, we correlated the internal diameter,
thickness and cross-sectional area (CSA) of the
carotid and brachial arteries with the mass and CSA
of the left ventricle and with arterial BP in a group
of patients with untreated and uncomplicated mildto-moderate hypertension.
Subjects and methods
The study population consisted of 118 subjects: 95
hypertensive patients and 23 normotensive control
subjects who gave their informed consent to participate in the study. The hypertensive group (40 men,
55 women, mean age ± s.d. 54.6 ± 11, 20–79 years)
was recruited from a large out-patient population
who attended the arterial hypertension clinic. The
selection criteria were the presence of untreated
mild-to-moderate essential arterial hypertension
(supine systolic and diastolic BP, average of three
out-patient visits, ranging from 140–179 and from
90–109 mm Hg, respectively20 and the absence of
any clinical and laboratory evidence of carotid and
peripheral atherosclerotic complications. Twentytwo per cent of the hypertensive patients consistently had arterial BP above 160/90 mm Hg. Other
Vascular and cardiac changes in hypertension
F Fantini et al
516
selection criteria were: absence of signs and symptoms of heart disease (ischaemic or valvular heart
disease, cardiomyopathy), renal or connective tissue
diseases, presence of severe obesity and hypercholesterolaemia (serum total cholesterol .7.8 mmol/l).
No patient had clinical diabetes; five showed carbohydrate intolerance; patients who smoked cigarettes
were excluded. The history of hypertension in the
group had a mean duration of 6 years (median = 4
years).
Control subjects, matched for age and sex (11 men,
12 women, mean age ± s.d.: 54.1 ± 8 years, range 23–
75) were selected from the hospital staff and their
relatives, having been found normotensive and free
from any clinical evidence of cardiac and cerebrovascular disease. They were non-smokers, with normal
ECG. Echocardiographic and Doppler examination
of the heart and large vessels did not demonstrate
any significant abnormalities in these subjects.
Echocardiography
All subjects underwent M-mode, two-dimensional
and Doppler echocardiography performed using a
commercially available machine (Toshiba SSH-270
HG, Tokyo, Japan) equipped with 2.5 and 3.75 MHz
transducers. LV dimensions were obtained from
two-dimensionally guided M-mode tracings, according to the commonly accepted criteria.21 Measurements were performed on four to six cycles by
means of a computer-aided method and averaged.
LV wall thickness was calculated as the mean
between septal and posterior wall values. LV mass
index (g/m) was calculated using the formula
0.7 × ([LV diameter + septal thickness + posterior
wall thickness]3 − [LV diameter] 3) + 2.4.22 LV
hypertrophy was considered to be present if the LV
anatomical mass corrected for height was >125 g/m.
A similar partition value has been used in some prospective studies on the independent prognostic
value
of
echocardiographic-determined
LV
hypertrophy that were carried out on a mixed population of men and women.23–25 The CSA of the left
ventricle was calculated from end-diastolic radius
and wall thickness (mean of interventricular septum
and posterior wall end-diastolic thickness), according to the formula:
LV CSA (mm2) = (LV radius + LV thickness)2
× 3.14 − LV radius2 × 3.14
Arterial ultrasonography
Imaging of both carotid and brachial arteries was
performed using the same machine used for the
echocardiographic examination equipped with a
high-resolution
linear
imaging
transducer
(7.5 MHz). The presence of discrete atherosclerotic
lesions was excluded by direct ultrasound examination, in order to avoid the focal dilation of the vessel that has been described in segments corresponding to atherosclerotic plaques.26 No patient with
significant atherosclerotic lesions involving the
carotid artery was included in the study group. Twodimensionally guided M-mode tracings of the distal
left common carotid artery were obtained with the
subject in the supine position with slight hyperextension of the neck. End-diastolic and end-systolic
diameters (minimum and maximal internal diameters, respectively) were measured on several cardiac cycles from repeated non-continuous recordings (at least three) and averaged.
End-diastolic wall thickness (defined as the
intimal−medial thickness of the far wall) was also
measured. The same measurements were collected
by imaging the brachial artery at the elbow of the
non-dominant arm. All measurements of wall
geometry (diameter and IMT) were taken by one
observer (DBR), who was completely blinded to the
clinical diagnosis of the patients. Interobserver
measurement error, in fact, has been reported to be
greater than when the same observer looks at the
same images.27
The reproducibility of vessel diameter and thickness measurements in this series of patients was
tested in 33 consecutive subjects (Table 1). The
results are similar to those reported for brachial
measurements by Celermajer et al28 and recently by
Corretti et al.29 The Pearson’s correlation coefficient
for brachial IMT of 0.507 was statistically significant
(P = 0.003) and the low value of Bland and Altman
coefficient of 0.16 (P = 0.38) confirms its clinical
applicability.
IMT can be affected not only by a change in tissue
mass in the inner layer, but also by a simultaneous
widening of the vessel. To overcome this potential
source of error,12 an estimation of circumferential
IMT was made by calculating the CSA of the arterial
wall from IMT and end-diastolic radius, assuming a
circular contour and a uniform wall thickness,
according to the formula:
arterial wall CSA (mm2) = (IMT + radius mm)2
× 3.14 − (radius mm)2 × 3.14
The ratio between diastolic radius and wall thickness of both carotid and brachial arteries was calculated from the end-diastolic radius and the end-diastolic IMT of the vessels.
Arterial pressure
BP was measured by sphygmomanometry using a
semiautomatic oscillometric method (Sirecust 888,
Siemens-Elema, Solna, Sweden). Three to five
measurements were obtained, at intervals of 2–
3 min, from the non-dominant arm, while the
patient was quietly resting supine. The BP average
values did not significantly differ (paired t-test) from
the mean of the values taken during the last three
outpatient visits, so they were considered representative of the subjects’ BP.
Statistics
Group data were expressed as mean values ± s.d.
The correlation of different echographic measures of
carotid and brachial arteries was expressed by Pearson’s correlation coefficient and by Bland and Altman correlation coefficient between difference and
Vascular and cardiac changes in hypertension
F Fantini et al
517
Table 1 Intra-observer variability of vessel echographic measurements
Mean ± s.d.
1st set
Diastolic carotid diameter
Systolic carotid diameter
Diastolic brachial diameter
Systolic brachial diameter
Carotid IMT
Brachial IMT
57.76 ± 7.80
64.27 ± 7.56
36.03 ± 6.04
40.64 ± 6.60
7.15 ± 1.72
5.27 ± 1.04
2nd set
58.48 ± 7.82
64.45 ± 7.38
35.73 ± 6.02
41.00 ± 6.63
7.24 ± 1.71
5.21 ± 1.19
Paired difference
Mean
−0.73
−0.18
0.30
−0.36
−0.09
0.06
Pearson Bland-Altman
95% CI
Lower
Upper
−1.46
−0.95
−0.41
−0.84
−0.22
−0.33
0.01
0.58
1.02
0.11
0.04
0.46
r
r
0.965
0.959
0.944
0.979
0.975
0.507
0.01
0.08
0.01
0.03
0.01
0.16
Paired correlations among two different sets of measures (reported in tenths of mm). The correlation of different sets of measures of
carotid and brachial arteries was expressed by Pearson’s correlation coefficient r and by Bland and Altman correlation coefficient
(between difference and average). Intra-observer variability is described by the absolute values of paired differences (mean and confidence interval = CI). IMT = intimal + medial thickness.
average of each couple of values.30 The comparison
of variables was accomplished by analysis of variance and then t-test or Bonferroni correction as indicated. The relation between continuous variables
was evaluated as first step by correlation matrix.
Independence of association was assessed by stepwise multiple regression, using backward elimination. Normal probability (P–P) plots of standardised residuals were used to assess robustness of
adjusted predicted values. Data were analysed by
SPSS statistical package for Windows 6.0 (SPSS Inc,
Chicago, IL, USA).
Results
The results obtained from the normotensive healthy
subjects and the hypertensive population are shown
in Table 2.
Patients with arterial hypertension showed a statistically significant increase in carotid artery IMT
and CSA, in brachial artery IMT and IMT/radius
ratio and in LV thickness, CSA and thickness/
radius ratio.
An increased LV mass index (>125 g/m) was
found in 33 patients with hypertension (35%). They
had the same age and sex distribution as the group
without LV hypertrophy (t-test and x2 respectively
not significant).
The healthy subjects and patients with and without LV hypertrophy were statistically different as far
as BP values were concerned, with the highest systolic, diastolic and mean arterial BP values in hypertensive patients with a LV mass index (LVMI)
.125 g/m. The three groups were also statistically
different in LV thickness, the hypertensive patients
with LVMI .125 g/m showing the greatest values of
LV thickness.
Patients with LV hypertrophy differed from healthy subjects and from patients without LV hypertrophy in carotid artery diameter, IMT and CSA and in
brachial artery IMT and CSA.
The CSAs of brachial and carotid arteries
appeared to be closely related to each other
(r = 0.558; P , 0.0001) and directly and significantly
correlated to the LV CSA (r = 0.371; P , 0.001 for
brachial CSA vs LV CSA; r = 0.367; P , 0.001 for
carotid CSA vs left ventricle CSA). Similar relationships were found considering anatomical LVMI
(brachial CSA, r = 0.393, P , 0.001; carotid CSA,
r = 0.340, P , 0.001). As shown in Figure 1, the
relationship is steeper for the carotid artery.
The matrix of correlation coefficients of linear
regression between the geometric parameters and
some potential determinants such as age, systolic,
diastolic and mean BP is shown in Table 3. At stepwise multiple regression analysis, brachial, carotid
and LV CSA appeared to be significantly related to
systolic BP; carotid CSA appeared to be also related
to age (Table 4). Using carotid artery CSA values
adjusted for age and body surface area and brachial
artery and LV CSA values adjusted for body surface
area, better correlations with a reduced scattering of
individual data were found, as shown in Figure 2a,
where arterial CSA and LV CSA were plotted. As
shown in Figure 2b, the correlation between the
CSA of carotid and brachial arteries and that of the
left ventricle was much improved using the adjusted
data for systolic BP (for brachial CSA, r = 0.909,
P , 0.001, standard error of estimate (s.e.e.) = 0.241;
for carotid CSA, r = 0.767, P , 0.001, s.e.e. = 1.01).
Discussion
In this study we report on the changes occurring in
the geometry of both left ventricle and carotid and
brachial arteries in a group of patients with
untreated and uncomplicated mild-to-moderate
essential hypertension. Our hypertensive population consisted of relatively young, non-smoking
subjects (mean age 54.6 years), who were carefully
selected from our out-patient clinic, excluding subjects with clinical and laboratory data indicating
carotid, peripheral and coronary atherosclerotic
involvement. More importantly, none of the patients
had ever been on drug therapy, thus allowing the
study of the natural history of the early stages of
arterial hypertension.
LV hypertrophy was present in 35% of the hypertensive patients we studied and it was characterised
by an increase in wall thickness and in
thickness/radius ratio (‘concentric’ hypertrophy).
The group of patients without increased LV mass
Vascular and cardiac changes in hypertension
F Fantini et al
518
Table 2 Comparisons between the hypertensive patients (with and without left ventricular hypertrophy) and healthy subjects
Healthy
subjects
Hypertensive
patients
Healthy vs
hypertensive
P
Hypertensive patients
LVMI
,125 g/m
LVMI
>125 g/m
55.9 ± 11.2
6.7 ± 6.3
(median 7)
160 ± 29
NS
54.1 ± 7.1
54.5 ± 11.0
NS
92 ± 12
121 ± 35
,0.001
53.7 ± 10.8
5.8 ± 3
(median 3)
102 ± 16
131 ± 9
78 ± 6
96 ± 7
155 ± 18
90 ± 9
111 ± 12
,0.001
,0.001
,0.001
152 ± 17
88 ± 8
109 ± 11
164 ± 20
94 ± 10
117 ± 13
*†‡
*†‡
*†‡
Carotid Artery
Diameter (mm)
IMT (mm)
IMT-radius ratio
CSA (mm2)
5.8 ± 0.7
0.67 ± 0.11
0.23 ± 0.04
13.93 ± 3.42
6.3 ± 1.0
0.73 ± 0.13
0.24 ± 0.05
16.29 ± 4.54
NS
0.04
NS
0.03
6.1 ± 1.0
0.72 ± 0.15
0.24 ± 0.06
15.59 ± 5.01
6.7 ± 1.0
0.80 ± 0.13
0.24 ± 0.05
18.19 ± 4.09
*†
*†
NS
*†
Brachial Artery
Diameter (mm)
IMT (mm)
IMT-radius ratio
CSA (mm2)
3.6 ± 0.5
0.50 ± 0.05
0.28 ± 0.03
6.43 ± 1.25
3.6 ± 0.6
0.53 ± 0.07
0.30 ± 0.05
6.95 ± 1.91
NS
0.03
0.02
NS
3.5 ± 0.6
0.52 ± 0.08
0.30 ± 0.05
6.55 ± 1.92
3.8 ± 0.5
0.56 ± 0.08
0.30 ± 0.05
7.56 ± 1.57
†
*†
NS
*†
25.3 ± 2.0
10.0 ± 0.08
0.40 ± 0.04
1906 ± 198
25.9 ± 2.4
11.6 ± 1.7
0.45 ± 0.07
2297 ± 489
NS
,0.001
,0.001
,0.001
25.0 ± 1.8
10.7 ± 1.0
0.43 ± 0.05
2045 ± 253
27.7 ± 2.5
13.4 ± 1.4
0.49 ± 0.07
2895 ± 392
*†
*†‡
*†
*†
Age
Estimated duration of hypertension
(years)
LVMI (g/m)
Brachial BP (mm Hg)
Systolic
Diastolic
Mean
Left Ventricle
Radius (mm)
Thickness (mm)
Thickness-radius ratio
CSA (mm2)
*†
Data are expressed as mean value ± s.d.
Abbreviations: BP = blood pressure; IMT = intima + media thickness; CSA = cross-sectional area; LVMI = anatomical left ventricular
mass index.
Statistical analysis (ANOVA followed by Bonferroni test) is reported in the last column on the right as follows: * = significant difference
(P , 0.05) between hypertensive subjects with left ventricular hypertrophy and healthy subjects; † = significant difference (P , 0.05)
between hypertensive patients without left ventricular hypertrophy and hypertensive subjects with left ventricular hypertrophy; ‡ =
significant difference (P , 0.05) between hypertensive patients without left ventricular hypertrophy and healthy subjects.
Figure 1 Scatterplots of cross-sectional areas (CSA) of the left
ventricle, carotid artery and of the brachial artery. Each line represents the regression line obtained from raw values as indicated
in the legend.
showed a significant increase in wall thickness with
a trend towards an increased thickness/radius ratio.
Therefore, they closely resembled the patients’
group described by Ganau et al 31 as having ‘concentric remodelling’.
Previous studies on carotid artery wall geometry
in hypertension made with various methods including echography, pulsed Doppler and echo-tracking
techniques gave conflicting results, probably due to
the heterogeneity of the hypertensive population in
respect to various factors such as age, BP, sex, therapy and probably others not yet identified10 and to
the different reliability of the used techniques. No
significant difference in carotid internal dimension
between patients with hypertension and agematched control subjects was found by some
authors,3–5 while an increased carotid diameter was
described by others.6,10 The carotid luminal CSA
was reported to be positively correlated to the
LVMI,32 while others did not find any relation
between carotid artery IMT and LV thickness.33 A
significant increase in brachial internal diameter has
been observed in hypertensive patients by means of
pulsed Doppler, a non-imaging technique that does
not allow the measurement of wall thickness.34–36
Up to now brachial artery direct measurements have
not been reported in hypertensive population.28,29
This may depend on the difficulties in correctly
measuring diameters and thickness of brachial
artery. In our study lower values of repeatability
show the limits of echographic measures of brachial
artery. The IMT of the carotid artery results were
related to BP values in some studies,7 but not in
others.8–10,33
The structural changes of the arteries were characterised by an almost proportional increase in the
internal diameter and wall thickness (intima +
media), without any significant changes of
Vascular and cardiac changes in hypertension
F Fantini et al
519
Table 3 Matrix of correlation coefficient R among geometric indexes and age, systolic, diastolic and mean BP
Brachial artery
Age
BSA
SBP
DBP
MBP
Carotid artery
Left ventricle
Dd
IMT
CSA
Dd
IMT
CSA
Dd
Th
0.145
0.231†
0.050
0.114
0.085
0.180
0.092
0.309†
0.262†
0.294†
0.203†
0.236†
0.229†
0.224†
0.234†
0.129
0.180
0.232†
0.140
0.193†
0.344†
0.085
0.344†
0.265†
0.314†
0.308†
0.167
0.365†
0.277†
0.331†
−0.036
0.130
0.094
0.081
0.090
0.096
0.271†
0.435†
0.388†
0.424†
CSA
0.071
0.286†
0.415†
0.379†
0.409†
Matrix of correlation coefficient R among geometric indexes and age, systolic, diastolic and mean BP.
Abbreviations: CSA = cross sectional area; DBP = diastolic blood pressure; Dd = diastolic diameter; IMT = intimal + medial thickness;
MBP = mean blood pressure; SBP = systolic blood pressure; Th = mean left ventricular thickness.
† indicates a significant correlation: P , 0.05.
Table 4 Multiple regression between arterial and ventricular CSA
and arterial pressure and age
Brachial CSA
Independent
r = 0.395
SBP
BSA
Age
F = 4.87
t = 2.20
t = 2.27
t = 1.75
P = 0.004
P , 0.05
P , 0.05
P = 0.08
Carotid CSA
Independent
r = 0.466
SBP
BSA
Age
F = 7.23
t = 3.394
t = 1.76
t = 2.107
P = 0.0002
P = 0.002
P = 0.08
P , 0.05
Left ventricular CSA
Independent
r = 0.512
F = 10.53
P , 0.0001
SBP
BSA
Age
t = 4.543
t = 3.472
t = 0.851
P , 0.0001
P , 0.001
P = 0.40
Abbreviations: CSA = cross-sectional area; SBP = systolic blood
pressure; BSA = body surface area.
thickness/radius ratio (wall ‘enlargement’) for the
carotid artery and by a small increase in wall thickness, with respect to the internal radius, for the
brachial artery. The CSAs of both vessels were
consequently significantly increased. These changes
in wall geometry were not present in the hypertensive patients without LV hypertrophy, who showed
a remodelling of LV geometry, described as ‘concentric remodelling’.31
Systolic BP (SBP) was directly correlated with
both LV thickness and CSA and with arterial diameters, IMTs and CSAs. The close relationship
between LV hypertrophy and SBP seems to corroborate the results of many epidemiological studies
indicating that office SBP is a strong predictor of cardiovascular risk in a hypertensive population.37
We found a significant correlation between the
CSAs of brachial and carotid arteries and the LV
CSA. This correlation became better when data
Figure 2 Scatterplots of cross-sectional areas (CSA) of the left ventricle, carotid artery and of the brachial artery. Each line represents,
as indicated in the legend, the regression line as follows: (A) the comparison performed using the adjusted corrected values of arterial
CSA (using the regression values for age and body surface area); (B) the comparison performed using the adjusted corrected values for
systolic blood pressure; (C) normal P-P plot of regression standardised residuals of brachial artery (vs systolic blood pressure using as
dependent variable the left ventricular CSA); (D) Normal P-P plot of regression standardised residuals of carotid artery (vs systolic
blood pressure using as dependent variable the left ventricular CSA). Abbreviations: Cum Prob = cumulative probability.
Vascular and cardiac changes in hypertension
F Fantini et al
520
adjusted for SBP were used, a procedure adopted in
order to minimise the statistical variability likely
related to a single systolic arterial pressure value
(even if the latter was not significantly different from
the mean of three out-patient BP measurements).
The correlation between LV hypertrophy and vascular remodelling was previously reported by Roman
et al 19 for the carotid artery and this could be a
patho-physiological correlate of the well documented clinical association between the presence of
LV hypertrophy and the incidence of cerebrovascular events.38
Altogether our data seem to indicate that patients
with arterial hypertension show parallel changes in
LV hypertrophy and arterial wall geometry, and that
the development of both arterial IMT and LV
hypertrophy, mainly triggered by SBP, may be
modulated by common factors on an individual
basis. Several agents are produced by both arterial
smooth muscle cells and cardiac myocytes,29 that
have been demonstrated to stimulate cell growth
both in vivo and in vitro. They are paracrine and
autocrine peptide growth factors (including plateletderived growth factor AA, insulin-like growth factor
and transforming growth factor b) and vasoconstrictor hormones (angiotensin II, noradrenaline).40,41 It
is still debated whether alterations in the interplay
of these factors lead to systemic hypertension and/or
directly stimulate hypertrophic or hyperplastic
responses at vascular and cardiac levels.42–44
Several data indicate that LV mass is also under
hereditary control, as it has been clearly shown in
studies on twins45 in which echocardiographic LV
mass was nearly identical in monozygotic than in
dizygotic twins. Similarly, in family studies, normotensive offspring of hypertensive parents had
increased LV mass that was only partially explained
by subtle increases in BP detected by ambulatory
monitoring. 46 Finally, in longitudinal studies,
increased LV mass at baseline was found to predict
the development of subsequent hypertension.47,48
Duration of hypertension is a subtle parameter to
be evaluated, as it depends on several environmental and individual factors. We were not able to demonstrate a relationship between the degree of LV
hypertrophy and the anamnestical duration of
hypertension. However, the hypertensive patients
without LV hypertrophy had a median duration of
hypertension of only 3 years, that is certainly less
than the 7 years of median duration observed in the
group with LV hypertrophy.
In conclusion, in untreated mild-to-moderate
essential hypertension, concomitant and proportional changes in carotid and brachial arteries
and LV geometry develop. They appear correlated
mainly to SBP, even though our data suggest the
presence of a various individual tendency towards
the development of both IMT of the vessels and
LV hypertrophy.
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