Progressive arterial wall stiffening in patients with

Journal of Human Hypertension (2001) 15, 685–691
 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00
www.nature.com/jhh
ORIGINAL ARTICLE
Progressive arterial wall stiffening in
patients with increasing diastolic blood
pressure
FWPJ van den Berkmortel1, M van der Steen1, H Hoogenboom, H Wollersheim1,
H van Langen2, and Th Thien1
1
Department of Medicine, Division of General Internal Medicine, 2Clinical Vascular Laboratory of the
University Hospital Nijmegen, The Netherlands
Background: Hypertension is an established risk factor
for cardiovascular disease. Risk factor patterns for various cardiovascular complications are different. We
studied the relationship between increasing diastolic
blood pressure and arterial wall dynamics of various
peripheral arteries in hypertensives to increase insight
in the variability of properties within the arterial tree.
Methods: Eighty-six untreated hypertensives participated in this cross-sectional study. The study-population was divided into quartiles with increasing diastolic office blood pressure. Cross-sectional compliance
and distensibility coefficients of the carotid and femoral
arteries were determined, using a vessel wall movement
detector system (Wall Track System).
Results: Diameters of both common carotid arteries
enlarged (right: from 7.4 ⴞ 0.2 to 7.9 ⴞ 0.2 mm) while
cross-sectional compliance (right: from 0.61 ⴞ 0.04 to
0.42 ⴞ 0.04 mm2/kPa) and distensibility coefficients
(right: from 14.2 ⴞ 1.0 to 9.0 ⴞ 1.0 10−3/kPa) gradually
dropped with increasing diastolic blood pressure.
Cross-sectional compliance and diameter of the right
common femoral artery remained unchanged while distensibility coefficient decreased although less gradually
when compared with the carotid arteries.
Conclusions: In untreated hypertensives gradual
arterial wall stiffening of the carotid arteries occurred
with increasing diastolic blood pressure. Gradual
changes were less clear in the common femoral artery
which points to the heterogeneity of the arterial tree.
Journal of Human Hypertension (2001) 15, 685–691
Keywords: cross-sectional compliance coefficient; distensibility coefficient; arterial wall stiffening; carotid artery; femoral
artery
Introduction
Hypertension is one of the most important cardiovascular risk factors. Risk factor patterns for various
cardiovascular complications are different. For
stroke, hypertension is the most important risk factor whereas, for intermittent claudication, smoking
appears to be the number one risk.1 These differences in risk patterns suggest heterogeneity of the
arterial tree. Ultrasonographic determinations of
arterial wall stiffness are used to estimate the cardiovascular risk in groups of subjects. Recently, Blacher
et al2–4 provided evidence for the use of dynamic
vessel wall properties to estimate cardiovascular
risk in patients with end-stage renal disease and
hypertension.
Correspondence: FWPJ van den Berkmortel, MD; Department of
Medicine, Division of General Internal Medicine 541, University
Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: F.Vandenberkmortel얀aig.azn.nl
Received 10 September 2000; revised 19 April 2001; accepted 30
April 2001
Cross-sectional compliance (CC) and distensibility coefficient (DC) are two parameters which
describe arterial wall dynamics and can be calculated from ultrasonographically measured (changes
in) diameters of peripheral arteries.5,6 Results of
studies which compared CC and DC of the common
carotid (elastic arteries) and common femoral
arteries (muscular arteries) between normotensive
and hypertensive patients revealed decreased CC
and DC in hypertensives.7–9 The elastic properties of
muscular arteries are variable in the short-term
which is partly due to influences of both vasoactive
substances and the central nervous system.10
Whether CC and DC gradually decline with increasing blood pressure and whether the relationship
between blood pressure and arterial wall dynamics
is different at the various sites of the arterial tree
(which is possibly reflected in differences in risk
factor patterns of cardiovascular complications) was
the subject of this study. Therefore, we determined
CC and DC of both the right (rCCA) and left (lCCA)
common carotid artery and of the right common
femoral artery (rCFA) in untreated middle-aged
Arterial wall stiffening in hypertension
FWPJ van den Berkmortel et al
686
hypertensive subjects who were divided into quartiles on the basis of their increasing diastolic office
blood pressures (OBP).
automated oscillometric device (Dinamap, Critikon
Inc, Tampa, FL, USA). CC and DC were calculated
from D, ⌬D and pulse pressure (⌬P), according to the
following equations:
Materials and methods
CC = ␲D(⌬D/2⌬P) expressed in mm2/kPa
Subjects
DC = (2⌬D/D)/⌬P expressed in 10−3/kPa
A total of 101 hypertensive subjects who visited the
outpatient clinic of our university hospital in the
period between November 1995 and October 1998
for the first time because of hypertension, were
asked to participate in this study. Subjects only
joined the study if, in their own physicians opinion,
it was safe to stop all antihypertensive drugs or if
they did not use antihypertensive medication at all.
After informed consent, current antihypertensive
drugs were stopped or tapered off in case of betaadrenoceptor blocking drugs. Two weeks after stopping the medication the patients were seen at least
twice for OBP measurements with a mercury sphygmomanometer. These were performed according to
protocol: at least two times after a 10 min rest, in a
supine position and with an appropriate cuff
attached to the right upper arm. Patients were
defined hypertensive when the average of the two
office sessions systolic OBP exceeded 160 mm Hg or
if the diastolic OBP amounted to over 90 mm Hg.
Fifteen subjects were excluded because they did not
fulfill the inclusion criteria. The remaining 86
patients were divided into quartiles (Q) according
to their mean diastolic OBP. The first (QI) and last
quartile (QIV) consisted of 22 subjects; in the other
two quartiles 21 patients were assigned to each.
Materials
Compliance and distensibility are vessel wall
properties which describe arterial wall stiffness.
Compliance and distensibility are defined as
respectively the absolute and relative change in volume for a given change in pressure. Arterial volume
cannot be measured directly.
Therefore it is assumed that arteries have a circular shape and that the arterial length does not change
during the cardiac cycle. With this assumption it is
possible to estimate compliance and distensibility
by calculating the cross-sectional compliance (CC)
and distensibility coefficient (DC). CC and DC can be
assessed by measuring diameters (D) and diameter
changes (⌬D) ultrasonographically. The vessel wall
movement detector (Wall Track System, Maastricht, The Netherlands) has extensively been
described by the group of Hoeks and Reneman.5,6
Briefly, with this system arterial D and ⌬D were
measured during the cardiac cycle for about 4 s. The
system used in this study consisted of an ultrasound
device with a 7.5 MHz transducer (Scanner 200, Pie
Medical) and a data acquisition system, coupled to
a personal computer. Blood pressures were measured at the left upper arm every 3 min with a semiJournal of Human Hypertension
Pulse pressures (⌬P = systolic − diastolic blood
pressure) were calculated out of all blood pressure
recordings which were registered during the
measurements of the particular artery. In our laboratory reproducibility figures for CC and DC varied
between 10 and 15–20% respectively for the common carotid and common femoral artery.11
Study design
The study design was approved by the Medical Ethics Committee of the University Hospital of
Nijmegen. All participants gave informed consent
before entering the study.
Preparation
Participants were not allowed to drink caffeinecontaining beverages for at least 10 h before
measurement. They were also requested to stop
smoking 1 h before dynamic vessel wall properties
were assessed.
Measurement conditions
Measurements were started after 10 min of supine
rest. Special attention was given to perform the tracings at the end of a normal expiration to avoid movement artefacts. All measurements were performed
by the same investigator (FvdB) to aim at maximal
accuracy. The CCA was measured after turning the
head of the subject 45 degrees contralateral from
midline position. The rCFA was measured in supine
position with the legs parallel to each other.
Measurement sites
Both CCA and the rCFA were measured. The CCA
were measured 2 cm proximal of the bulb. The rCFA
was measured at least 1 cm proximal of the bifurcation into the deep and superficial femoral artery.
We only measured the CFA at one side as this
measurement is time consuming and measurements
only reach high quality if subjects lie down motionless.
Data analysis
At least three recordings were obtained to gather
information over about 12–15 cardiac cycles. A tracing was rejected if a standard deviation of more than
10% of ⌬D was present in one recording of 4 s which
mostly contains three to five consecutive heart-
Arterial wall stiffening in hypertension
FWPJ van den Berkmortel et al
beats.11 For each heart cycle, and therefore each
determination of D and ⌬D of the artery under investigation, CC and DC were calculated. The average of
all 12–15 single calculated CC’s and DC’s was used
as the final result.
Initially Kruskal–Wallis tests were used for overall testing over the four groups. In case of statistical
significant differences a Mann–Whitney U test was
used for between group analysis. P values less than
0.05 (two-sided) were considered significant.
We also calculated moving averages of CC and DC
of both CCA according to Chau.12 Therefore, the 86
hypertensive subjects were classified by increasing
diastolic OBP and designated by an index. Overlapping subgroups of 20 subjects each were formed by
grouping subjects one up to 20, then subjects two
up to 21, and so on, until subgroup 67 comprising
patients 67 up to 86. In each subgroup the mean DC
was calculated and plotted against the mean diastolic OBP.
In addition, stepwise regression analysis was performed (SPSS Inc, Chicago, IL, USA) with D, CC and
DC of rCCA, lCCA and rCFA as dependent variables
and age, gender, systolic OBP, diastolic OBP, smoking habit, previous antihypertensive treatment, heart
rate, length, weight, plasma cholesterol and glucose
as independent variables.
Results
In Table 1 the baseline characteristics of the studypopulation divided in quartiles (Q) are shown. Less
than three patients were not included because in
their own physicians opinion it was not safe to stop
antihypertensive medication (mainly due to recent
cerebrovascular events). Each Q consisted of 21–22
subjects with mean diastolic OBP increasing from
95 ⫾ 0.7 mm Hg in QI to 118 ⫾ 1.7 mm Hg in QIV.
There were no significant differences in main baseline characteristics (age, weight and plasma cholesterol levels). Pulse pressures were not significantly
different in all quartiles. The number of males in QII
(7 (33%)) was smaller compared with values in the
other quartiles (QI: 11 (50%), QIII: 10 (48%) and
QIV: 12 (55%)). The number of smokers was not different between the quartiles. Subjects with higher
diastolic OBP more often used antihypertensive
drugs and combinations of antihypertensives at the
first visit to our hospital. Moreover, symptomatic
atherosclerotic disease was present more frequently
in the higher quartiles.
Overall testing over the four quartiles was statistically significant for all measured vessel wall parameters except for the diameter (P = 0.06) and crosssectional compliance of the rCFA. In Figure 1 diameters (D; Figure 1a), cross-sectional compliance (CC;
Figure 1b) and distensibility coefficients (DC; Figure
1c) of the rCFA and of both CCA are shown for the
whole group divided into quartiles with increasing
diastolic OBP. Results of comparisons between the
quartiles (Mann–Whitney U test) are shown if
Kruskal–Wallis tests were statistically significant.
Figure 1a shows that D of both CCA were significantly enlarged in subjects with more severe hyper-
687
Table 1 Baseline characteristics of quartiles (Q) with increasing mean diastolic office blood pressure (OBP)
Group/Parameter
QI
(n = 22)
QII
(n = 21)
QIII
(n = 21)
QIV
(n = 22)
Age (years)a†
Male/femaleb
Smokerb
47.7 ± 2.9
11/11
6
44.8 ± 2.6
7/14
5
47.6 ± 2.8
10/11
7
49.0 ± 2.6
12/10
6
Length (m)a
Weight (kg)a
BMI (kg/m2)a
OBP systolica,‡
OBP diastolica,‡
Pulse pressure (mm Hg)
Heart rate (beats/mina)
Plasma glucose (mmol/L)a
Plasma cholesterol (mmol/L)a
Alcohol intake (units/week)a
Number of antihypertensive drugs at inclusion:
0 (not treated pharmacologically)b
1†
2†
⬎2b
Diabetes Mellitus (type 2)b
Symptomatic atherosclerotic diseaseb
Orally treated hypercholesterolaemiab
1.72 ± 0.02
78.2 ± 3.4
26.2 ± 0.8
161 ± 4
95 ± 1
66 ± 2
73 ± 1
5.13 ± 0.12
6.0 ± 0.3
6±2
1.68 ± 0.02
79.1 ± 4.1
27.8 ± 1.3
163 ± 4
103 ± 0***
63 ± 3
77 ± 2
5.07 ± 0.12
6.0 ± 0.3
6±2
1.68 ± 0.03
80.9 ± 4.4
28.8 ± 1.4
174 ± 3*,§
107 ± 0***,§§
72 ± 4
74 ± 3
5.89 ± 0.50
5.8 ± 0.2
6±2
1.71 ± 0.02
81.3 ± 3.9
27.6 ± 1.0
189 ± 5***,얏
118 ± 2***,§§,얏얏
70 ± 4
82 ± 2
5.57 ± 0.25
5.7 ± 0.2
11 ± 3
11
8
2
1
0
5
2
6
10
1
4
0
2
0
0
8
7
6
1
4
1
4
7
9
2
3
7
2
Data are presented as mean ± s.e. †P ⬍ 0.05, ‡P ⬍ 0.001 overall testing over the four quartiles (Kruskal–Wallis); bData are presented
as absolute numbers; *P ⬍ 0.05, ***P ⬍ 0.001 compared with QI; §P ⬍ 0.05, 얏P ⬍ 0.01, §§P ⬍ 0.001 compared with QII; 얏얏P ⬍ 0.001
compared with QIII (Mann–Whitney U test).
a
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Arterial wall stiffening in hypertension
FWPJ van den Berkmortel et al
688
tension (rCCA: 7.9 ⫾ 0.2 (QIII) and 7.9 ⫾ 0.2 (QIV)
mm; lCCA: 7.8 ⫾ 0.2 (QIII) and 7.7 ⫾ 0.2 (QIV) mm)
compared with subjects of QII with less severe
hypertension (rCCA: 7.3 ⫾ 0.2 and lCCA: 7.2 ⫾
0.1 mm). D of the rCFA also showed a tendency to
increment although no significance was reached.
Figure 1b shows that CC of both CCA decreased
gradually with increasing diastolic OBP (r/lCCA:
0.61 ⫾ 0.04/0.55 ⫾ 0.05(QI), 0.54 ⫾ 0.04/0.47 ⫾
0.03(QII), 0.53 ⫾ 0.05/0.45 ⫾ 0.02(QIII), 0.42 ⫾
0.04/0.39 ⫾ 0.04(QVI) mm2/kPa). CC of the rCFA
was not significantly different between all quartiles.
Figure 1c presents data on DC. DC of both CCA
decreased gradually with increasing diastolic OBP.
Although DC of the rCFA changed significantly
between the quartiles (P = 0.001 Kruskal–Wallis; P
⬍ 0.05 when QI and QII were compared with QIII
and QIV) a gradual decrease was less obvious.
Additionally, DC of both CCA were analysed
according to the moving average method of Chau.12
Results of this analysis for the rCCA are shown in
Figure 2. This figure shows a gradual decline in DC
of the rCCA with increasing diastolic OBP. A similar
graph was obtained from data of the lCCA (not
shown).
In Table 2 the results of stepwise regression analysis to study the influence of the independent factors:
age, gender, systolic OBP, diastolic OBP, smoking
habit, previous use of antihypertensive drugs, heart
rate, length, weight, total cholesterol and glucose on
the dependent variables: D, CC and DC of all investigated arteries are presented. Age and diastolic OBP
were important factors mainly contributing to DC of
both carotid arteries (age: R2: 0.278 (rCCA) and 0.410
(lCCA); diastolic OBP: R2: 0.125 (rCCA) and 0.123
(lCCA)). Dynamic vessel wall properties of the right
common femoral artery were not influenced significantly by age and diastolic OBP. Other factors contributing to the dynamic vessel wall properties of
the investigated arteries are shown in Table 2.
Discussion
In this study a gradual decline in cross-sectional
compliance and distensibility coefficient with
increasing diastolic OBP was seen at the carotid
artery (both sides). This relation was less clear at the
femoral artery.
The study population was divided into quartiles
with increasing diastolic OBP. The main baseline
characteristics were similar between the quartiles.
In QIII and QIV a larger number of subjects used at
least two antihypertensive drugs before inclusion
and suffered more frequently from symptomatic
atherosclerotic disease. These data demonstrate the
presence of more severe hypertension and therefore
higher cardiovascular risk in the upper quartiles.
Figure 1 Diameters (a), cross-sectional compliance (b) and distensibility coefficients (c) of both common carotid arteries and of
the right common femoral artery of the quartiles (Q) based on
increasing diastolic office blood pressure (QI: white bars, QII:
light grey bars, QIII: dark grey bars, QIV: black bars). Mean ±
s.e.m. are given. Further abbreviations; r, right; 1l left; CCA, common carotid artery; CFA, common femoral artery; CC, cross-sectional compliance; DC, distensibility coefficient. *P ⬍ 0.05, **P
⬍ 0.01 (Mann–Whitney U test).
Journal of Human Hypertension
Arterial wall stiffening in hypertension
FWPJ van den Berkmortel et al
carotid arteries, this parameter was not changed in
the right common femoral artery with higher diastolic OBP (Figure 1). Similar results were obtained
in the stepwise regression analysis. Thus, diastolic
blood pressure seems to affect arterial wall dynamics of various arteries differently which is in accordance with the results of others.7,14 One possible
explanation for the heterogeneity between the elastic carotid and the muscular femoral artery may be
the fact that elastic properties in muscular arteries
can be modified by vasoactive substances (such as
angiotensin, noradrenaline and atrial natriuretic
factor) or the central nervous system.10 There were
small nonsignificant differences in dynamic vessel
wall properties of the right compared with the left
common carotid artery. Significant differences
between the left and the right common carotid artery
have not been described in literature. One possible
explanation for this is the right-handedness of the
single observer, who performed all measurements.
We used brachial artery pulse pressures to calculate dynamic vessel wall properties of the carotid as
well as of the femoral artery. The assumption that
pulse pressure is identical at different sites of the
arterial tree is incorrect, thereby creating a deviation
from the real cross-sectional compliance and distensibility coefficient. As we compared between
groups we feel this inaccuracy has not affected our
results.
There were differences in mean heart rate
although these were not significant when tested
with Kruskal–Wallis analysis. In anaesthetised rats
acute increases in heart rate are accompanied by
reductions in arterial compliance and distensibility.15 Differences in mean heart rate, of similar
magnitude, did not influence arterial wall dynamics
in smokers.16 To exclude the influence of heart rate
on our results we analysed the current data with
stepwise regression and found that heart rate was
only of significance for the cross-sectional compliance of the right common femoral artery.
Figure 2 Moving means (according to method of Chau12) for
changes in distensibility coefficients of the right common carotid
artery with increasing diastolic office blood pressure.
Considering the whole study population, there were
differences in dynamic vessel wall properties
between the various arteries. The common femoral
artery diameter was larger than the carotid artery
diameter. Cross-sectional compliance and distensibility coefficients were lower in the muscular femoral artery compared with the elastic carotid artery.
This is in accordance with earlier findings13 that
dynamic vessel wall properties such as CC and DC
decrease from the proximal elastic to the distal muscular arteries.
Although distensibility coefficients of all investigated arteries were lower in the higher diastolic OBP
groups, gradual changes with diastolic blood pressure increase were most clearly seen in the carotid
arteries (Figures 1 and 2). In contrast with the gradual decrease of cross-sectional compliance in both
689
Table 2 Results of stepwise regression analysis with diameter (D), cross-sectional compliance (CC) and distensibility coefficients (DC)
of both common carotid (CCA) and the right common femoral (CFA) as dependent variables. Numbers represent the value of R2, the
coefficient of determination. Only variables with at least a single significance are given. (+), (−) and gender (m ⬎ f) indicate the sense
of the relation
Artery
dependent
variables:
Independent variables:
Age
Gender (m⬎f)
Diastolic OBP
Systolic OBP
Heart rate
Weight
Cholesterol
Glucose
Previous drug therapy
Right CCA
D
CC
Left CCA
DC
0.286 (+) 0.057 (−) 0.278 (−)
0.073 (m⬎f)
—
—
—
0.122 (−) 0.125 (−)
0.049 (−)
—
—
—
—
—
—
—
0.042 (−)
—
—
—
—
—
—
—
0.068 (+)
—
D
CC
0.049 (+)
0.105 (−)
0.291 (m⬎f) 0.049 (m⬎f)
—
0.114 (−)
—
—
—
—
—
—
0.073 (−)
—
—
—
—
—
Right CFA
DC
0.410 (−)
—
0.123 (−)
—
—
0.029 (−)
—
—
—
D
CC
DC
—
—
—
0.186 (m⬎f)
—
—
—
—
—
—
—
0.165 (−)
—
0.067 (−)
—
—
—
—
—
—
—
—
—
0.079 (−)
—
—
0.079 (−)
Journal of Human Hypertension
Arterial wall stiffening in hypertension
FWPJ van den Berkmortel et al
690
In our study age was the strongest contributor to
dynamic vessel wall properties of the carotid artery
but not for arterial wall function of the femoral
artery. This is in accordance with the literature.17,18
Studies that investigated the influence of gender
on arterial wall stiffness parameters have revealed
conflicting results.19–21 We found that gender had
little effect on cross-sectional compliance and distensibility coefficient of the carotid as well as of the
femoral artery.
Gender did contribute to diameters of the carotid
as well as of the femoral artery which could have
influenced the results in QII as in this quartile gender distribution differed from that in other quartiles.
As in our study previously treated hypertensives
as well as never treated hypertensives participated,
the effect of former treatment on arterial wall
dynamics was investigated. Stepwise regression
analysis showed that there was a small contribution
of former treatment to the distensibility coefficient
of only the right common carotid artery. Therefore,
former treatment was not a major contributor to our
results concerning arterial wall dynamics. Smokers
refrained from smoking only 1 h before measurement. As in stepwise regression analysis smoking
was not a contributor to dynamic vessel wall properties, it is unlikely that this has affected our results.
Moreover our results are in accordance with a
study16 in which arterial wall dynamics between
smokers and non-smokers were compared.
The results of dynamic vessel wall measurements
in hypertensives are difficult to interpret because of
their pressure dependency. Pulse pressures are used
in the calculation of cross-sectional compliance and
distensibility coefficient. As pulse pressures were not
significantly different between the quartiles it is
unlikely that they accounted for the differences in
cross-sectional compliance and distensibility coefficients with increasing diastolic OBP. In contrast
with a comparable study performed by Duprez et al22
the contribution of office systolic blood pressure to
dynamic vessel wall properties was of minor importance in our group which is probably due to the
stronger influence of office diastolic blood pressure.
Arterial wall stiffening in hypertension is not
necessarily associated with an increase in atherosclerotic damage but may merely be a reflection of
the elevated mean arterial pressure. Therefore individual distensibility–pressure curves were made by
others7,23,24 to compare arterial wall dynamics at a
standardised pressure. At 100 mm Hg enhanced
arterial wall stiffening was only present at the femoral artery which suggests structural alterations at
this site.7
Individual distensibility–pressure curves show a
logarithmic relationship between pressure and distensibility with only minimal changes in distensibility in the presence of high pressure.7,23,24 We
showed gradual changes in cross-sectional compliance and distensibility coefficients of the carotid
arteries throughout a wide range of hypertension
Journal of Human Hypertension
(systolic OBP range: 120–237 mm Hg, diastolic OBP
range: 90–140 mm Hg). If we assume that the
relationship between pressure and arterial wall stiffness in groups can be described by a similar logarithmic curve we can conclude from our data that we
remain in the middle part of the curve over a wide
range of hypertension.
Although it is not clear whether progressive
arterial wall stiffening in hypertension is associated
with structural changes, a recent study provides evidence for the value of pulse wave velocity as a
powerful predictor of cardiovascular risk in hypertension.3 Our data support this study as dynamic
vessel wall function was affected most in the upper
quartiles which consisted of subjects with severe
hypertension and probably highest cardiovascular
risk. Pulse wave velocity provides information
regarding arterial stiffness over a certain distance of
the arterial tree. We advise cautiousness to use data
on arterial wall dynamics of isolated arteries as heterogeneity exists within the arterial tree.
In conclusion we found enhanced arterial wall
stiffening with increasing diastolic OBP. Gradual
stiffening was obvious at the common carotid artery
and less clear at the common femoral artery which
illustrates the heterogenic vessel wall behaviour of
the arterial tree.
Acknowledgements
This research project was financially supported by
grant NHS 94.035 from the Dutch Heart Foundation,
The Netherlands
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