doi: 10.1111/j.1475-097X.2009.00871.x
Clin Physiol Funct Imaging (2009)
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Atherosclerosis measured by whole body magnetic
resonance angiography and carotid artery ultrasound is
related to arterial compliance, but not to endotheliumdependent vasodilation – the Prospective Investigation
of the Vasculature in Uppsala Seniors (PIVUS) study
Lars Lind1, Jessika Andersson1, Tomas Hansen2, Lars Johansson2,3 and Håkan Ahlström2
1
Departments of Medicine and 2Radiology, Uppsala University Hospital, Uppsala, Sweden, and 3AstraZeneca R&D Mölndal, Mölndal, Sweden
Abstract
Correspondence
Lars Lind M.D., Department of Medicine, University
Hospital, 751 85 Uppsala, Sweden
E-mail: [email protected]
Accepted for publication
Received 18 September 2008;
accepted 27 March 2009
Key words
angiography; artery; atherosclerosis; carotid artery;
compliance; endothelium; magnetic resonance;
ultrasound; vasodilation
Background: Arterial compliance and endothelium-dependent vasodilation are two
characteristics of the vessel wall. In the Prospective Investigation of the Vasculature
in Uppsala Seniors (PIVUS) study, we studied the relationships between arterial
compliance and endothelium-dependent vasodilation versus atherosclerosis as
measured with two imaging modalities.
Methods: In the population-based PIVUS study (1016 subjects aged 70), arterial
compliance was determined by ultrasound in the carotid artery and the stroke
volume to pulse pressure ratio by echocardiography, while endothelium-dependent
vasodilation was assessed by the invasive forearm technique with acetylcholine and
brachial artery ultrasound. Intima-media thickness was evaluated by ultrasound in
the carotid artery (n = 954). Stenosis in the carotid, aorta, renal, upper and lower
leg arteries were determined by magnetic resonance angiography in a random
subsample of 306 subjects.
Results: After adjustments for gender, Framingham risk score, obesity, myocardial
infarction and stroke, distensibility in the carotid artery and the stroke volume to pulse
pressure ratio were both significantly related to a weighted index of stenosis in the five
arterial territories evaluated by magnetic resonance angiography (p<0Æ02 for both).
Distensibility in the carotid artery (P = 0Æ021), but not the stroke volume to pulse
pressure ratio (P = 0Æ08), was also significantly related to intima-media thickness.
Conclusion: In the elderly population, atherosclerosis is mainly related to arterial
compliance, but not to endothelium-dependent vasodilation in peripheral conduit or
resistance vessels.
Introduction
Arterial compliance and endothelium-dependent vasodilation
are two major characteristics of the arteries. These two vascular
features are both related to the main cardiovascular risk factors
(Creager et al., 1990; Linder et al., 1990; Celermajer et al., 1992;
Roman et al., 1992; Johnstone et al., 1993; Laurent et al., 1994;
Lehmann et al., 1998), and have both the ability to predict
future cardiovascular outcomes in prospective studies (Blacher
et al., 1998; Schachinger et al., 2000; London et al., 2001;
Perticone et al., 2001; Lind et al., 2004).
Atherosclerosis is the major disease affecting the arteries. It is
today recognized as being a generalized disorder most likely to
affect most arterial territories if present. Endothelium-dependent
vasodilation is thought of as an early event in the atherosclerosis
development and an impaired endothelium-dependent vasodilation could be detected even before no major atherosclerosis
could be detected at angiography (Zeiher et al., 1991). On the
contrary, arterial compliance might not be affected during the
early stages of atherosclerosis.
In large scale epidemiological research, measurements of
intima-media thickness in the carotid arteries by ultrasound
have been the most commonly used technique to evaluate
atheroslerosis. The intima-media thickness has been shown to be
related to overt atherosclerotic places and to predict future
stroke and myocardial infarction (OÕLeary et al., 1999). In the
2009 The Authors
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Journal: CPF CE: T.M.Prasath
No. of pages: 9 PE: Vasugi
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recent years, also the echogenecity of plaques, reflecting plaque
composition, has been shown to have a predictive value
(Mathiesen et al., 2001). We have just recently shown the
echogenecity of the intima-media complex to be closely related
to the echogenecity in the plaques (Lind et al., 2007) and to be
related to major risk factors (Lind et al., 2008), suggesting also
this vascular wall characteristic to be of interest.
We have recently used whole body magnetic resonance
angiography to evaluate the atherosclerosis burden in the in five
different arterial territories, the carotid artery, aorta, renal
arteries, upper leg and lower leg arteries, at the same
examination (Hansen et al., 2006). Using that approach in the
Prospective Investigation of the Vasculature in Uppsala Seniors
(PIVUS) study, we could confirm the global nature of
atherosclerosis.
In the present study, we aim to investigate the relationships
between arterial compliance and endothelium-dependent vasodilation versus atherosclerosis measured by whole body magnetic resonance angiography and intima-media thickness in the
carotid artery by ultrasound in the PIVUS cohort (Lind et al.,
2005) with the hypothesis that both arterial compliance and
endothelium-dependent vasodilation are closely related to the
degree of atherosclerosis.
Material and methods
This section has previously been given in detail in different
publications (Lind et al., 2005, 2006; Hansen et al., 2006).
n
Females (%)
Height (cm)
Weight (kg)
Waist circumference (cm)
BMI (kg m)2)
Waist⁄hip ratio
SBP (mmHg)
DBP (mmHg)
LDL-cholesterol (mmol l)1)
HDL-cholesterol (mmol l)1)
Serum triglycerides (mmol l)1)
Fasting blood glucose (mmol l)1)
Current smoking (%)
EDV (%)
EIDV (%)
FMD (%)
CCA distensibility (% per mmHg)
SV⁄PP ratio (ml mmHg)1)
TAS
Subjects
All subjects aged 70 were eligible for living in the community of
Uppsala, Sweden. The subjects were randomly chosen from the
register of community living. 1016 subjects participated giving
a participation rate of 50Æ1%. Of those, a random of 306 subjects
was evaluated with magnetic resonance angiography.
The study was approved by the Ethics Committee of the
University of Uppsala.
All subjects were investigated in the morning after an overnight fast. No medication or smoking was allowed after
midnight. An arterial cannula was inserted in the brachial artery
for blood sampling and later regional infusions of vasodilators.
The participants were asked to answer a questionnaire about
their medical history, smoking habits and regular medication.
Blood pressure was measured using a calibrated mercury
sphygmomanometer in the non-cannulated arm to nearest
mmHg after at least 30 min of rest and the average of three
recordings was used. Lipid variables and fasting blood glucose
were measured by standard laboratory techniques.
From these data, the Framingham risk score was calculated
(Wilson et al., 1998). Basic characteristics of the total sample
and the magnetic resonance angiography subsample are given in
Table 1.
Approximately 10% of the cohort reported a history of
coronary heart disease, 4% reported stroke and 9% diabetes
mellitus. Almost half the cohort reported any cardiovascular
medication (45%), with antihypertensive medication being the
Total PIVUS sample
Subsample with
TAS measurement
1016
50Æ2
169 ± 9Æ1
77 ± 14
91 ± 12
27Æ0 ± 4Æ3
0Æ90 ± 0Æ075
150 ± 23
79 ± 10
3Æ3 ± 0Æ88
1Æ5 ± 0Æ42
1Æ3 ± 0Æ60
5Æ3 ± 1Æ6
11
459 (199–909)
328 (149–629)
4Æ4 (0Æ0–9Æ7)
0Æ086 (0Æ021–0Æ15)
1Æ3 (0Æ80–2Æ3)
–
287
48Æ5
169 ± 9Æ3
77 ± 14
91 ± 11
27Æ1 ± 4Æ0
0Æ90 ± 0Æ070
149 ± 22
78 ± 9Æ8
3Æ3 ± 0Æ85
1Æ5 ± 0Æ38
1Æ3 ± 0Æ64
5Æ3 ± 1Æ6
8Æ5
489 (200–907)
332 (158–627)
4Æ5 (0Æ0–9Æ7)
0Æ088 (0Æ026–0Æ13)
1Æ3 (0Æ82–2Æ2)
0Æ19 (0–0Æ68)
Table 1 Basic characteristics, major cardiovascular risk factors and measures of endothelium-dependent vasodilation and adipose tissue
in the total sample and in the present sample.
Means are given ± SD or as median and 10th and 90th percentiles in parenthesis.
SBP, Systolic blood pressure; DBP, Diastolic blood pressure; BMI, Body mass index; EDV, endothelium-dependent vasodilation (invasive forearm technique); EIDV, endothelium-independent
vasodilation (invasive forearm technique); FMD, flow mediated dilatation; CCA, common carotid
artery; SV, Stoke volume; PP, pulse pressure; AIx, Augmentation index; TAS, Total atherosclerosis
score.
2009 The Authors
Journal compilation 2009 Scandinavian Society of Clinical Physiology and Nuclear Medicine
Atherosclerosis and vascular function, L. Lind et al. 3
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most prevalent (32%). Fifteen percent reported use of statins,
while insulin and oral antiglycemic drugs were reported in 2%
and 6% respectively (see reference Lind et al., 2005 for details).
The invasive forearm technique
Forearm blood flow was measured by venous occlusion
plethysmography (Elektromedicin, Kullavik, Sweden). After
evaluation of resting forearm blood flow, local intra-arterial
drug-infusions were given during 5 min for each dose. The
infused dosages were 25 and 50 lg min)1 for acetylcholine
1 (Clin-Alpha, Switzerland) to evaluate endothelium-dependent
vasodilation in forearm resistance vessels and 5 and
10 lg min)1 for SNP (Nitropress, Abbot, UK) to evaluate
endothelium-independent vasodilation.
Endothelium-dependent vasodilation in forearm resistance
vessels was defined as forearm blood flow during infusion of
50 lg min)1 of acetylcholine minus resting forearm blood flow
divided by resting forearm blood flow. Endothelium-independent vasodilation in forearm resistance vessels was defined as
forearm blood flow during infusion of 10 lg min)1 of SNP
minus resting forearm blood flow divided by resting forearm
blood flow.
The brachial artery ultrasound technique
The brachial artery was assessed by external B-mode ultrasound
imaging 2–3 cm above the elbow (Acuson XP128 with a
10 MHz linear transducer; Acuson Mountain View, CA, USA).
Blood flow increase was induced by inflation of a pneumatic
cuff placed around the forearm to a pressure at least 50 mmHg
above systolic blood pressure for 5 min. Flow-mediated
vasodilation was defined as the maximal brachial artery diameter
recorded between 30 and 90 s following cuff release minus
diameter at rest divided by the diameter at rest.
Pulse wave analysis
A micromanometer tipped probe (Sphygmocor; Pulse Wave
2 Medical Ltd., Australia) was applied to the surface of the skin
overlying the radial artery and the peripheral radial pulse wave
was continuously recorded. The mean values of around 10 pulse
waves were used for analyses. On the Basis of transfer functions,
aortic systolic and diastolic blood pressure were calculated from
the radial recordings with the Sphygmocor software.
Stroke volume to pulse pressure ratio
Echocardiography was performed (2Æ5 MHz transducer; Acuson
XP124, CA, USA) and using Teichholz formula ejection fraction
and stroke volume were calculated. The stroke volume to pulse
pressure ratio was calculated as stroke volume divided by central
pulse pressure (achieved by pulse wave analysis).
Carotid artery ultrasound evaluation
The carotid artery was assessed by external B-mode ultrasound
imaging (Acuson XP128 with a 10 MHz linear transducer;
Acuson Mountain View). The intima-media thickness was
evaluated in the far wall in the common carotid artery
1–2 cm proximal to the bulb.
The images were digitized and imported into the AMS (Artery
Measurement Software) automated software (Liang et al., 2000)
for dedicated analysis of intima-media thickness and the grey
scale median of the intima-media complex. A maximal 10 mm
segment with good image quality was chosen for intima-media
thickness-analysis from the carotid artery. The programme
automatically identifies the borders of the intima-media
thickness of the far wall and the inner diameter of the vessel
and calculates intima-media thickness and the diameter from
around 100 discrete measurements through the 10 mm long
segment. This automated analysis could be manually corrected if
not found appropriate at visual inspection. The given value for
carotid artery intima-media thickness is the mean value from
both sides.
A region of interest was placed manually around the intimamedia segment that was evaluated for intima-media thickness
and the programme calculates the echogenecity in the intimamedia complex from analysis of the individual pixels within the
region of interest on a scale from 0 (black) to 256 (white). The
blood was used as the reference for black and the adventitia was
the reference for white. The GSM-value given is the mean value
from both sides.
The mean length of the evaluated intima-media segments was
9Æ0 (SD 2Æ1) mm when subjects with a segment recording less
than 5 mm were excluded, leaving 946 subjects with valid
recordings.
The measurements of intima-media thickness were repeated
in 30 random subjects giving a coefficient of variation of carotid
artery intima-media thickness of 7Æ2% and 7Æ5% for echogenecity in the intima-media complex.
Carotid artery compliance
Magnetic resonance angiography
The diameter of the common carotid artery of the right side
1–2 cm proximal of the bifurcation was measured at its
maximal diameter in systole and the minimal diameter in
diastole. The distensibility of the carotid artery was calculated as
the change in diameter maximum to minimum in relation to the
minimal diameter in diastole divided by the central pulse
pressure obtained by pulse wave analysis.
Imaging was performed on a 1Æ5 Tesla MRI system (Gyroscan
Intera, Philips Medical Systems, Best, the Netherlands) with a
25 mT m)1 gradient system, using the standard quadrature
body coil.
The whole body was scanned in the supine position using a
3D RF-spoiled T1-weighted gradient echo sequence before and
after injection of 40 ml Gd-DTPA-BMA (OmniscanTM; GE
2009 The Authors
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Healthcare, Oslo, Norway) at a rate of 0Æ6 ml s)1. The acquired
slice thickness was 4 mm with a resolution of 1Æ76 · 1Æ76 mm.
Imaging did not include the coronary arteries.
The arterial tree was categorized into five territories: (i) the
carotids including internal carotid artery and common carotid
artery, (ii) the aorta including both the thoracic and abdominal
part, (iii) the renal arteries, (iv) the pelvic⁄upper limbs including
common iliac artery, external iliac artery, common femoral
artery, superficial femoral artery and popliteal artery, (v) the
lower legs including tibio-peroneal trunk, anterior tibial artery,
peroneal artery and posterior tibial artery.
To obtain a comparable graded number reflecting the
atherosclerosis in each territory, an atherosclerotic score was
calculated for each territory. A normal vessel segment received
null points, less than 50% stenosis was given one point and 50%
reduction or more of the vessel diameter including occlusions
was given two points. The points for the vessel segments in a
territory were summarized. That sum was than divided with the
maximum sum that would be achieved if all included segments
had a more than 50% stenosis or occlusion.
A global total atherosclerosis score was defined as the sum of
the five territories (Hansen et al., 2008). Aneurysms and vessel
segments that could not be evaluated were excluded from the
calculations.
Statistics
Non-normally distributed variables were transformed to achieve
a normal distribution. Relationships between pairs of variables
were evaluated by PearsonÕs or SpearmansÕ correlation coefficient. Multiple regression analysis was applied to relate several
independent variables to a dependent variable. Two-tailed
significance values were given with p<0Æ05 regarded as
significant. The statistical programme package StatView (SAS
3 Inc., NC, USA) was used.
Results
Endothelial function and arterial compliance versus carotid
artery ultrasound
In univariate analysis, intima-media thickness was inversely
related to endothelium-independent vasodilation in forearm
resistance vessels, carotid artery distensibility and the stroke
volume to pulse pressure ratio, but not significantly related to
endothelium-dependent vasodilation in forearm resistance
vessels or flow-mediated vasodilation (Table 2). Echogenecity
in the intima-media complex was not significantly related to any
of the variables reflecting endothelial function or arterial
compliance.
In multivariate analysis with distensibility of the carotid
artery, stroke volume to pulse pressure ratio and endotheliumindependent vasodilation in forearm resistance vessels as
dependent variables in three different models with intimamedia thickness, gender, Framingham risk score, BMI, myocar-
Table 2 Relationships between endothelium-dependent vasodilation
(invasive forearm technique, EDV), endothelium-independent vasodilation (invasive forearm technique, EIDV), flow mediated dilatation
(FMD), distensibility of the common carotid artery (CCA) and stroke
volume to pulse pressure ratio (SV⁄PP) and intima-media thickness
(IMT) and the grey scale median of the intima-media complex (IMGSM) of the common carotid artery evaluated by ultrasound given as
correlation coefficients and P-values in parenthesis if significant.
EDV
FMD
EIDV
CCA distensibility
SV⁄PP ratio
IMT
IM-GSM
)0Æ05
)0Æ06
)0Æ07 (0Æ040)
)0Æ16 (0Æ0001)
)0Æ10 (0Æ0047)
)0Æ02
0Æ01
0Æ06
0Æ01
)0Æ05
Table 3 Multiple regression analysis with distensibility of the common carotid artery (CCA) and stroke volume to pulse pressure ratio
(SV⁄PP) as dependent variables in two different models with intimamedia thickness (IMT) of the common carotid artery, gender,
Framingham risk score, BMI, myocardial infarction and stroke as
independent variables.
CCA distensibility
SV⁄PP ratio
Regression
Regression
coefficient P-value coefficient P-value
IMT
Gender
Framingham score
BMI
Myocardial infarction
Stroke
)0Æ25
)0Æ19
)0Æ050
)0Æ001
)0Æ10
0Æ001
0Æ021
0Æ0001
0Æ0001
0Æ72
0Æ15
0Æ98
)0Æ13
)0Æ38
)0Æ045
0Æ019
)0Æ08
0Æ01
0Æ081
0Æ0001
0Æ0001
0Æ0001
0Æ078
0Æ88
dial infarction and stroke as independent variables in all models,
carotid artery distensibility, but not stroke volume to pulse
pressure ratio (P = 0Æ08) or endothelium-independent vasodilation in forearm resistance vessels (P = 0Æ36), were significantly related to total atherosclerotic score (see Table 3 for
details).
Endothelial function and arterial compliance versus total
atherosclerotic score at magnetic resonance angiography
Total atherosclerotic score was significantly related in univariate
analysis to carotid artery distensibility and endothelium-independent vasodilation in forearm resistance vessels, while a
tendency was also seen for the stroke volume to pulse pressure
ratio (P = 0Æ06). However, no relationships between endothelium-dependent vasodilation in forearm resistance vessels, flowmediated vasodilation and total atherosclerotic score were found
(see Table 4).
When the vascular variables being significantly related to total
atherosclerotic score in the univariate analysis were evaluated
regarding their relationships with the AS in the five different
vascular territories, it was mainly the carotid artery, aorta and
the upper leg arteries that were related to the distensibility of the
2009 The Authors
Journal compilation 2009 Scandinavian Society of Clinical Physiology and Nuclear Medicine
Atherosclerosis and vascular function, L. Lind et al. 5
Table 4 Relationships between change in reflectance index at pulse wave analysis (RI), endothelium-dependent vasodilation (invasive forearm
technique, EDV), endothelium-independent vasodilation (invasive forearm technique, EIDV), flow mediated dilatation (FMD), distensibility of the
common carotid artery (CCA) and stroke volume to pulse pressure ratio (SV⁄PP) and total atherosclerosis score (TAS) measured by MR angiography
given as correlation coefficient and P-value in parenthesis. In the five columns at the left, the P-value for relationship in the five different territories is
given for indices of vascular function being related to TAS.
EDV
FMD
EIDV
CCA distensibility
SV⁄PP ratio
TAS
Carotid
Aorta
Renal
Upper leg
Lower leg
)0Æ05
)0Æ05
)0Æ13 (0Æ036)
)0Æ21 (0Æ0006)
)0Æ12 (0Æ062)
(0Æ048)
(0Æ010)
(0Æ11)
(0Æ30)
(0Æ051)
(0Æ023)
(0Æ60)
(0Æ31)
(0Æ65)
(0Æ15)
(0Æ034)
(0Æ028)
(0Æ25)
(0Æ34)
(0Æ52)
carotid artery, stroke volume to pulse pressure ratio and
endothelium-independent vasodilation in forearm resistance
vessels. Atherosclerosis in the renal artery or the lower leg
arteries were not significantly related to any of the vascular
measurements (see Table 4 for details).
In multivariate analysis with distensibility of the carotid
artery, stroke volume to pulse pressure ratio and endotheliumindependent vasodilation in forearm resistance vessels as
dependent variables in three different models with total
atherosclerosis score, gender, Framingham risk score, BMI,
myocardial infarction and stroke as independent variables in all
models, carotid artery distensibility and stroke volume to pulse
pressure but not endothelium-independent vasodilation in
forearm resistance vessels (P = 0Æ17), were significantly related
to total atherosclerotic score (see Table 5 for details).
Endothelium-dependent vasodilation
In the present study, endothelium-dependent vasodilation was
not significantly related to the degree of stenosis or to intimamedia thickness. This might at the first sight seem contradictory
since we have previously found all three techniques to be related
with Framingham risk score, an established marker of coronary
risk (Lind et al., 2005). However, this unexpected finding could
be explained by different mechanisms. First, atherosclerosis is a
1·4
1·2
1
TAS
0·8
Discussion
The present study showed that indices of arterial compliance
(carotid artery distensibility and the stroke volume to pulse
pressure ratio), but not endothelium-dependent vasodilation in
peripheral resistance arteries or a conduit artery, were related to
atherosclerotic stenosis evaluated by magnetic resonance angiography after adjustment for the classical cardiovascular risk
factors. A similar picture emerged when intima-media thickness
of the carotid artery was used as a measure of atherosclerosis.
0·6
0·4
0·2
0
–0·2
4
4·5
5
5·5
6
6·5
7
7·5
8
ln EDV
1·4
1·2
1
Table 5 Multiple regression analysis with distensibility of the common carotid artery (CCA) and stroke volume to pulse pressure ratio
(SV⁄PP) as dependent variables in two different models with total
atherosclerosis score (TAS), gender, Framingham risk score, BMI,
myocardial infarction and stroke as independent variables.
0·8
TAS
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0·6
0·4
0·2
CCA distensibility
SV⁄PP ratio
Regression
Regression
coefficient P-value coefficient P-value
TAS
Gender
Framingham score
BMI
Myocardial infarction
Stroke
)0Æ23
)0Æ17
)0Æ056
0Æ005
0Æ14
)0Æ019
0Æ012
0Æ0021
0Æ0001
0Æ42
0Æ22
0Æ89
)0Æ15
)0Æ38
)0Æ05
0Æ014
)0Æ13
0Æ064
0Æ019
0Æ0001
0Æ0001
0Æ0076
0Æ096
0Æ54
0
–0·2
0·25 0·5 0·75
1
1·25 1·5 1·75
2
2·25 2·5 2·75
3
ln FMD
Figure 1 Relationships between total atherosclerosis score (TAS)
evaluated by MR angiography and endothelium-dependent vasodilation
evaluated with the invasive forearm technique (ln EDV, relative increase
in FBF at the highest dose Ach, top panel, ln-transformed, r = )0Æ05,
P = 0Æ44) and the brachial artery ultrasound technique (ln FMD, lower
8 panel, ln-transformed, r = )0Æ05, P = 0Æ48).
2009 The Authors
Journal compilation 2009 Scandinavian Society of Clinical Physiology and Nuclear Medicine
6 Atherosclerosis and vascular function, L. Lind et al.
in hypertensives (Ghiadoni et al., 1998). However, it should be
remembered that intima-media thickness is not only determined
by atherosclerosis and that intima-media thickness is not
equivalent to the degree of stenosis evaluated by magnetic
resonance angiography in the present study. There are however
no studies in the past relating the degree of stenosis in the major
conduit arteries to endothelium-dependent vasodilation.
1·4
1·2
1
TAS
0·8
0·6
0·4
0·2
Arterial compliance
0
–0·2
–4
–3·5
–3
–2·5
–2
–1·5
–1
ln CCA distensibility
1·4
1·2
1
0·8
TAS
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2
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0·6
0·4
0·2
0
–0·2
–0·75 –0·5 –0·25
0
0·25
0·5
0·75
1
1·25
1·5
ln SV/PP
Figure 2 Relationships between total atherosclerosis score (TAS)
evaluated by MR angiography and three indices of arterial compliance;
distensibility in the common carotid artery (CCA distensibility,
ln-transformed, r = )0Æ21, P = 0Æ0006) and the stroke volume to pulse
pressure ratio (SV⁄PP, ln-transformed, r = )0Æ12, P = 0Æ062).
disorder mainly affecting conduit arteries. The invasive forearm
model with acetylcholine infusion is thought to mainly evaluate
endothelium-dependent vasodilation in forearm resistance
vessels, a type of vessels not generally affected by atherosclerosis. Secondly, flow-mediated vasodilation is measured in a
conduit artery, but as recently shown in two separate studies
(Witte et al., 2005; Lind, 2007), flow-mediated vasodilation is
affected by the reduced arterial compliance in the elderly
making this technique of less value in this age-group. Third,
both flow-mediated vasodilation and endothelium-dependent
vasodilation in forearm resistance vessels are measured in the
upper extremity, not clinically affected by atherosclerosis to a
major extent, although it recently has been shown that intimamedia thickness in the carotid and brachial arteries are correlated
(Agewall et al., 2005).
A number of studies have shown flow-mediated vasodilation
(Hashimoto et al., 1999; Haraki et al., 2002; Olsen et al., 2002;
Poredos et al., 2003; Jarvisalo et al., 2004; Juonala et al., 2004;
Suzuki et al., 2004; Yan et al., 2005) to be inversely related to the
thickness of the intima-media complex of the carotid arteries,
mainly in different diseased populations. One study has also
reported a relationship between endothelium-dependent vasodilation in forearm resistance vessels and intima-media thickness
Arterial compliance was consistently related to atherosclerotic
stenosis. In this case, two different markers of arterial
compliance, carotid artery distensibility and the stroke volume
to pulse pressure ratio were related to total atherosclerotic score.
We have previously shown these two markers of arterial
compliance to be independently related to coronary risk in this
cohort (Lind et al., 2006), but they were still both related to total
atherosclerotic score after adjustment for coronary risk factors.
Arterial compliance is possibly more affected by structural
changes in the vascular wall than endothelium-dependent
vasodilation and therefore a relationship with atherosclerosis is
more likely to be disclosed. Both carotid artery distensibility and
the stroke volume to pulse pressure ratio have previously been
linked to intima-media thickness of the carotid arteries (Riley
et al., 1997; Liang et al., 1998; de Simone et al., 2001; Jourdan
et al., 2005). This was also seen in the present study in
the univariate analysis, but following multiple adjustments
only carotid artery distensibility was related to intima-media
thickness.
Location of atherosclerotic stenosis
In the present study, we differed between five arterial territories
regarding the extent of atherosclerotic stenosis at the magnetic
resonance angiography. The degree of atherosclerosis in the
carotid artery, aorta and the upper leg arteries contributed most
to the variation in carotid artery distensibility and the stroke
volume to pulse pressure ratio, while atherosclerosis in the renal
arteries and lower leg did not. Although atherosclerosis is a
generalized disorder and we previously have shown that
occurrence of atherosclerosis in these five arterial territories
are inter-related (Hansen et al., 2006), there are regional
differences and the carotid artery, aorta and the upper leg
arteries are in fact the vascular segments in which carotid artery
distensibility and the stroke volume to pulse pressure ratio are
evaluated. If endothelium-dependent vasodilation and arterial
compliance would be evaluated in the renal or lower leg arteries
another picture might have emerged.
Reproducibility
We have previously shown the reproducibility (coefficient of
variation, CV) at repeated measurements to be 3% for baseline
brachial artery diameter and 29% for flow-mediated vasodilation (Lind et al., 2000) and the corresponding CVs for
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endothelium-dependent vasodilation in forearm resistance
vessels and endothelium-independent vasodilation in forearm
resistance vessels to be 8–10% (Lind et al., 1998). For the
compliance measures carotid artery distensibility and stroke
volume to pulse pressure ratio the CVs were 21% and 14%
respectively. When measurements of intima-media thickness
were repeated in 30 random subjects a coefficient of variation of
carotid artery intima-media thickness of 7Æ2% and 7Æ5% for
echogenecity in the intima-media complex were obtained (Lind
et al., 2007) and repeated readings in the magnetic resonance
angiography images yielded a kappa-value of 0Æ73 for intraobserver variability and 0Æ83 for inter-observer variability
(Hansen et al., 2007).
Thus, the reliability for the atherosclerotic measures was
generally good. The lack of relationship between flow-mediated
vasodilation and the atherosclerotic measures might be due to a
poor reproducibility of flow-mediated vasodilation, but almost
1000 individuals with values for both flow-mediated vasodilation and intima-media thickness would nevertheless have
disclosed any existing relationship. The most consistent finding
was seen for carotid artery distensibility versus the atherosclerotic measures despite the fact that the CV for carotid artery
distensibility was rather high (21%), further supporting the
assumption that the sample size is sufficient to disclose
pathophysiological associations.
Relationships between vascular measures
We have previously shown that no relationship exists between
endothelial function in conduit arteries (flow-mediated vasodilation) and resistance vessels (endothelium-dependent vasodilation in forearm resistance vessels) in the PIVUS study (Lind
et al., 2005), as well as in younger subjects (Lind et al., 2002).
On the contrary, a fairly close relationship exists between the
two compliance measures used in the present study (Lind et al.,
2006). We have also recently shown that no close associations
exists between the two endothelial function measures and the
two arterial compliance methods used in the present study (Lind
et al., 2008).
Validation of the measurements
In terms of validation, we have previously shown that both of the
two endothelial function measures (Lind et al., 2005) and both of
the two arterial compliance methods (Lind et al., 2006) used in
the present study are related to coronary risk as estimated by the
Framingham risk score. Since we do not have enough follow-up
time yet in the PIVUS study to relate the vascular measures to
future cardiovascular events, we have to await these data in the
present cohort, but both of the two endothelial function
measures (Schachinger et al., 2000; Perticone et al., 2001) and
both of the two arterial compliance methods (Blacher et al.,
1998; Lind et al., 2004) have been shown to predict CV events in
other cohorts. This is also true for the atherosclerosis measures
intima-media thickness and echogenecity in the intima-media
complex (Wohlin et al., 2009). No data yet exists on the value of
total atherosclerotic score to predict CV events, but we have
recently shown total atherosclerotic score to be related to
coronary risk (Hansen et al., 2008).
Limitations
The present sample is limited to Caucasians aged 70. Caution
should therefore be made to draw conclusions to other ethnic
and age groups.
The PIVUS study had a moderate participation rate. However,
an analysis of non-participants showed the present sample to be
fairly representative of the total population regarding most
cardiovascular disorders and drug intake (Lind et al., 2005).
Endothelium-independent vasodilation in forearm resistance
vessels was only assessed by one of the methods for practical and
ethical reasons not to prolong the investigation procedure. We
have previously shown that endothelium-independent vasodilation in forearm resistance vessels evaluated by SNP infusion in
the brachial artery and nitroglycerine provoked change in
brachial artery diameter are closely related (Lind et al., 2000), so
additional measurements of endothelium-dependent vasodilation in forearm resistance vessels would probably not add
substantial information to the study.
Another limitation is that aortic pulse wave velocity, the most
commonly used index of arterial compliance, was not evaluated
in the present cohort.
In conclusion, atherosclerosis is mainly related to arterial
compliance, but not to endothelium-dependent vasodilation in
peripheral conduit or resistance vessels in the elderly population.
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