Clinical Science (2001) 100, 509–516 (Printed in Great Britain)
Radial artery hypertrophy occurs in
coronary atherosclerosis and is
independent of blood pressure
Alison J. MACKAY*, Carlene A. HAMILTON*, Kenneth McARTHUR†, Geoffrey BERG†,
Anne-Isabelle TROPEANO‡, Pierre BOUTOUYRIE‡, John L. REID*
and Anna F. DOMINICZAK*
*Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, Scotland, U.K.,
†Department of Cardiothoracic Surgery, Western Infirmary, Glasgow G11 6NT, Scotland, U.K., and ‡Service Cardiovasculaire,
Ho# pital Broussais, 96 rue Didot, F-75674 Paris cedex 14, France
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Endothelial dysfunction, believed to underlie the structural changes of atherosclerosis, is a
systemic phenomenon. Despite this, the radial artery has been considered as devoid of
atherosclerosis and is commonly used as a conduit in coronary artery bypass grafting (CABG).
Recently, histological study has shown intimal hyperplasia and other structural changes
consistent with early atherosclerosis in the radial artery. The objective of the present study was
to determine if structural changes in the radial artery could be detected in vivo in patients with
coronary atherosclerosis. Using high resolution echo-tracking, measurements of radial artery
internal diameter, wall thickness and wall cross-sectional area were made in 25 patients awaiting
CABG and in 20 controls. Digital and brachial blood pressures were also recorded. Mean arterial
pressures did not differ between the patient and control groups. All measures of wall thickness
were greater in the patient than the control group. Neither current arterial pressures nor past
history of hypertension correlated with wall thickness. Using a model of analysis of covariance,
coronary artery disease was the best single predictor of intima-media thickness, R2 l 48 %, n l
44, P 0.0005. We concluded that increased radial artery wall thickness can be demonstrated in
vivo in patients with coronary atherosclerosis. This is a novel observation which seems to be
independent of blood pressure, and is consistent both with the hypothesis of systemic endothelial
dysfunction leading to systemic structural changes and also to the recent histological evidence
for atherosclerotic changes in this vessel.
INTRODUCTION
Atherosclerosis of conduit vessels supplying heart, brain,
kidneys and peripheral vascular beds results in significant
morbidity and mortality due to ischaemia of these
territories. The ‘ response-to-injury ’ hypothesis of
atherosclerosis [1] suggests that one or several systemic
insults, such as hypercholesterolaemia [2], hypertension
[3], diabetes [4] and hyperhomocysteinaemia [5] result in
dysfunction of the anti-atherosclerotic properties of the
vascular endothelium [6]. This dysfunction, in turn, leads
to development of structural changes. The features of
atherosclerosis are an initial accumulation of lipid-laden
macrophages and T lymphocytes within the intima.
Within this layer there next occurs a proliferation of
smooth muscle cells with macrophages interspersed.
Finally, complex fibrous plaques containing vascular
smooth muscle cells, and a core of lipid and necrotic
Key words : vasculature, pathophysiology, ultrasound, atherosclerosis, hypertension, radial artery, hypertrophy.
Abbreviations : CABG, coronary artery bypass grafting ; MID, mean internal diameter ; PWT, posterior wall intima-media
thickness ; BMI, body-mass index ; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA reductase ; CI, confidence interval.
Correspondence : Dr A. J. Mackay (e-mail alisonjmackay!hotmail.com).
# 2001 The Biochemical Society and the Medical Research Society
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A. J. Mackay and others
debris encroach on the lumen of the vessel [7,8]. As there
is evidence of endothelial dysfunction in coronary,
cerebral and upper limb regions [9–11], with upper limb
circulations correlating well with coronary arteries [12],
many consider endothelial dysfunction to be a systemic
phenomenon [13]. We consider that, as a consequence of
this, one might expect to find atherosclerosis as a systemic
phenomenon. However, the regions supplied by the
radial artery are generally spared the symptoms of
the structural lesions of atherosclerosis and the radial
artery is commonly used as a graft for coronary artery
bypass grafting (CABG) [14]. Recently, a histological
study of arterial sections removed from patients with
advanced atherosclerosis identified structural changes of
atherosclerosis in radial arteries. Ruengsakulrach et al.
[15] reported histopathological findings from paired
samples of radial arteries and internal thoracic arteries
obtained from 150 patients undergoing CABG. Structural changes attributable to atherosclerosis were found
more frequently in the radial artery than in the internal
thoracic artery, with intimal hyperplasia in 94 % of radial
arteries and in 69 % of internal thoracic arteries ; calcification was present in 13.3 % of radial arteries and
none was found in internal thoracic artery ; atherosclerotic plaques or overt stenoses were observed in 5 %
of radial arteries and in 0.7 % of internal thoracic arteries.
It is notable that the finding of intimal hyperplasia, rather
than more advanced lesions, was highly prevalent, suggesting an early stage of atherosclerotic development.
The study of radial artery dimensions in vivo is
possible using very-high-resolution ultrasound echotracking devices, allowing internal diameter and intimamedia thickness to be measured directly and wall crosssectional area to be calculated. This therefore permits
accurate assessment of combined intima and medial
thickness in vivo without, however, distinguishing between these layers in the same way that histological
examination would allow.
We designed a study to test the hypothesis that, in
patients with confirmed coronary atherosclerosis and, by
assumption, underlying endothelial dysfunction, structural changes in the radial artery, consistent with early
atherosclerotic changes in this vessel, could be detected
non-invasively.
METHODS
Patients and controls
The study protocol was approved by the Western
Infirmary Ethics Committee as conforming to the
principles outlined in the declaration of Helsinki, and all
subjects gave informed written consent to participation.
Patients with angiographically proven coronary artery
disease, who were awaiting CABG, were recruited by
letter and telephone. Those with diabetes were excluded.
# 2001 The Biochemical Society and the Medical Research Society
We sought controls matched for age and sex but free of
cardiovascular disease. These healthy volunteers were
recruited by advertisement. By necessity the patient and
control groups differed in terms of prevalence of cardiovascular risk factors. Data on age, sex and cardiovascular risk factors are shown in Table 1.
The control group was deemed free of vascular disease
on the basis of clinical history, physical examination and
electrocardiographic findings. Coronary angiography
was not performed in this group. In contrast with their
controls, concurrent vascular disease was prevalent
within the patient group, with one case of renal artery
stenosis, six subjects with peripheral vascular disease and
two with evidence of cerebrovascular disease. A history
of treated hypertension was given by 12 individuals in the
patient group, although their blood pressures at the time
of study did not differ from the never-hypertensive
patients. The meanpS.D. duration of treatment of
hypertension was 7.75p4.67 years, range 4–20 years.
Lipid subfractions were measured in the patient group.
As shown in Table 1, the meanpS.D. fasting total
cholesterol concentration was 5.5p1.0 mmol\l. In keeping with their pathology, the patients were also prescribed
multiple vasoactive drugs in different combinations. The
total numbers of patients using any one class of drug are
as follows : aspirin, n l 25 ; long acting nitrates, n l 20 ;
calcium-channel antagonists, n l 15 ; beta-blockers, n l
18 and potassium-channel openers, n l 3. Angiotensinconverting enzyme (‘ ACE ’) inhibitors were prescribed
for four patients, with the indication being hypertension
in three of the four. The most frequently prescribed
combination of drugs was aspirinjnitratejbetablockerjcalcium-channel antagonist, a combination
being taken by nine of 25 in this group. As stated above,
12 had been prescribed an HMG-CoA reductase
(3-hydroxy-3-methylglutaryl-CoA reductase) inhibitor.
None of the controls was taking any vasoactive medication, although hormone replacement preparations were
prescribed for four females in this group. Body size was
similar in the two groups, as judged by weight, height and
body-mass index (BMI) measurements.
Arterial measurements
A high-resolution echo-tracking device (NIUS O2 ;
Asulab, Neuchatel, Switzerland) was used for arterial
measurements. This utilizes both Doppler and A-mode
ultrasound to make continuous measurements of arterial
structure throughout the cardiac cycle. After comfortably
restraining the non-dominant arm of the supine subject
in a moulded arm-rest, an aqueous gel was applied to the
anterior surface of the wrist to prevent any pressure being
applied by the transducer over the artery. The 10 MHz
ultrasound probe was then positioned over the radial
artery, using Doppler ultrasound to accurately place it
perpendicular to the axis of the artery, with its height
adjusted to correspond to the focal distance of 11 mm
Radial artery wall hypertrophy
Table 1
Clinical details of patients and controls
Continuous variables given as meanpS.D.
Variable
Patients (n l 25)
Controls (n l 20)
Sex ratio (M/F)
Mean age (range in parentheses)
Height (m)
Weight (kg)
BMI (kg/m2)
Number of current/ex smokers
Number with treated hypertension
Fasting total cholesterol
Brachial blood pressure (mmHg)
Digital blood pressure (mmHg)
15/10
62 (41–73)
1.66p0.1
74.6p12.3
26.9p3
13
12
5.5p1.0 mmol/l
132p24/76p10
142p39/52p12
10/10
50 (40–63)
1.58p0.37
70.8p11.6
25.5p2.7
1
0
Not known
131p13/77p9
129p22/61p14
[16]. It was situated between 1–3 cm proximal to the
crease of the wrist, choosing the site which gave
the clearest ultrasound signal. As the diameter of the
radial artery is constant in this part of the arm, this
amount of flexibility in position does not alter results to
any significant degree [17,18]. The stereotactic arm
supporting the probe was screwed into place. To monitor
the echoes obtained from the artery walls with A-mode
ultrasound, the final probe positioning was completed by
fine adjustment of the micrometric screws in x, y and z
planes. The operator then detected and ‘ tagged ’ with
electronic markers, oscilloscopic signals from the blood–
intima interface of the anterior wall and the interfaces
between blood and intima, and intima and adventitia of
the posterior wall. The operator was blinded to the scale
of the echoes on the screen and placed the trackers
according to the typical radiofrequency signals. The
posterior wall is characterized by two high amplitude
signals separated by an area of relative acoustic silence
[19]. The electronic markers were followed throughout
the cardiac cycle, resulting in measurements of internal
diameter and wall thickness at the full range of pressure
changes in the artery. This method has been extensively
validated [20–22] and is accepted as a highly accurate
means of measuring structure and stiffness of
peripherally-placed medium-sized conduit arteries, such
as the radial. The operator (A. J. M.) performed repeated
training sessions in the Reference Centre at the Ho# pital
Broussais (Paris, France), a centre in which there is the
greatest expertise in this method [23–26]. Reproducibility, assessed in our laboratory using the methods
described above, in which two repeated measurements
were made 15 min apart in 12 healthy volunteers, resulted
in coefficients of variance of 2.1 % for mean internal
diameter (MID) and 5.6 % for posterior wall intimamedia thickness (PWT). We further assessed the interobserver variation by submitting 17 ‘ blinded ’ arterial
traces to two experienced operators (P. B. and A.-I. T.).
For this analysis, the coefficient of variance was 0.4 %
and 6.7 % for MID and PWT respectively.
Blood pressure measurement
Digital artery pressure of the middle finger of the hand
ipsilateral to the radial artery being measured was
recorded concurrently with NIUS echo-tracking
measurements. The arterial pressure was measured
continuously using a digital photoplethysmograph
(Finapres). In addition to digital pressures, brachial artery
blood pressure was recorded with the subject relaxed and
recumbent, using a standard sphygmomanometer, and
the mean of three sequential readings was obtained.
There is well recognized heterogeneity between peripheral and more central pressure recordings, with
peripheral pressures being consistently higher than those
obtained more centrally [27]. This is due, in part, to the
phenomenon of pressure wave reflection from distant
sites (particularly resistance arterioles [28]). The effect of
reflected waves augmenting the incident pressure wave is
greatest in distal arteries, and is dependent to an extent on
the intrinsic compliance of arterial material [29].
Study protocol
All subjects attended at 09.00 after a 12 h fast. Morning
medication was taken as usual by the patient group as it
was felt unethical to withhold medication from this
group. Details of medical history were documented
before each subject underwent a full physical examination
in which particular attention to the cardiovascular system
was paid. The examination included, in addition to blood
pressure measurement performed in accordance with
current British Hypertension Society guidelines, the
recording of a 12-lead ECG in the controls as an extra
screen for occult ischaemic heart disease. Prior to the
arterial measurements, the subject was given time to settle
into the surroundings of the examination room ; a
darkened, quiet, temperature-controlled environment.
NIUS recordings were made over 30–60 s periods, with
simultaneous digital artery pressure recordings. According to standard procedure, the most technically satisfactory 10 s of each recording, as judged by smooth
contour of arterial diameter, wall thickness and blood
# 2001 The Biochemical Society and the Medical Research Society
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A. J. Mackay and others
pressure wave forms, was sampled to allow generation of
measures of arterial structure. MID, defined as the
distance between anterior wall blood–intima interface
and posterior wall blood–intima interface, was measured
directly, as was PWT, which is the distance between the
posterior wall blood–intima interface and the intima–
adventitia interface. Wall cross-sectional area was calculated as π(Re#–Ri#), where Re is the mean internal
radiusjPWT and Ri is the mean internal radius. Wall\
lumen ratio was subsequently calculated as the ratio of
PWT\MID, expressed as a percentage. The same operator
made all the measurements in the present study. During
the positioning of the probe and the recording and
selection of the trace, the operator was blinded to arterial
dimensions. Systolic and diastolic blood pressure,
measured by the Finapres during the same 10 s period,
were also recorded.
Statistics
Two-way ANOVA was used to compare blood pressure and structural data between sexes and between
patient and control groups. Confidence intervals were
calculated for differences between patient and control
means. An analysis of covariance, adjusted for patient–
control difference, was then used to determine factors
predicting wall thickness.
RESULTS
Mean systolic and diastolic blood pressures did not differ
between the patient and control groups, whether
measured by sphygmomanometer or photoplethysmograph (Table 1). The greater S.D. for systolic
pressures in the patient group compared with those of
controls was because two female patients had pulse
pressures greater than normal when measured by photoplethysmograph (digital blood pressure 202\30 and
233\34 respectively), although their brachial blood pressures were close to the group mean (105\85 and 136\76
respectively).
Mean total fasting cholesterol for the patient group
was 5.5p1.0 mmol\l (Table 1). The lipoprotein
subfractions for this group (meanspS.D.) were :
triglycerides, 1.87p1.0 mmol\l ; very-low-density lipoprotein, 1.03p0.5 mmol\l ; low-density lipoprotein
3.28p0.86 mmol\l ; high-density lipoprotein, 1.22p
0.3 mmol\l ; and the cholesterol\high-density lipoprotein ratio was 4.73p0.7. Total cholesterol 5.2 mmol\l was measured in 16 patients, of whom eight
had already been prescribed an HMG-CoA reductase
inhibitor. A further four patients, whose total fasting
cholesterol range was 3.45–4.52 mmol\l, were also taking
an HMG-CoA reductase inhibitor. Division of the
patient group into those prescribed HMG-CoA reductase inhibitors and those not taking the drug showed no
# 2001 The Biochemical Society and the Medical Research Society
Figure 1 Scatter diagram of (a) MID measurements, (b) PWT
measurements, (c) wall cross-sectional area calculations and
(d) wall/lumen ratio calculations
Patients (P, n l 25) and controls (C, n l 20) are shown with means marked by
wide horizontal bars and S.E.M. indicated by narrower horizontal bars.
difference in mean (pS.D.) cholesterol levels (5.3p
1.1 mmol\l and 5.7p0.8 mmol\l respectively). BMI
(Table 1) did not differ significantly between patients and
controls.
MID was greater in males than females in both patient
[P 0.00005 ; 95 % confidence interval (CI) 1.83, 2.48]
and control groups (P 0.00005 ; 95 % CI 1.65, 2.29),
reflecting the larger size of men’s arms. However, there
was no difference in resting internal diameter between
patient and control groups. Results of directly measured
MID and PWT and calculated wall cross-sectional area
and wall\lumen ratio are shown in Figure 1. There was
no effect of gender on measurements of posterior wall
dimensions, therefore measurements from both sexes
were combined. All measurements of wall thickness were
greater in the patient than the control group (PWT, P
0.0005, 95 % CI 0.095, 0.174 ; wall cross-sectional area,
P 0.0005, 95 % CI 1.03, 1.89 ; wall\lumen ratio, P
0.0005, 95 % CI 2.4, 6.6). In summary, the structural
findings demonstrated an increase in intima-media thickness without obvious reduction of lumen diameter.
Although mean blood pressure did not differ between
patients with treated hypertension and those that had
Radial artery wall hypertrophy
never been hypertensive, in order to determine the effect
of previously treated hypertension, the analysis was
repeated omitting the sub-group of 12 individuals with a
past history of hypertension. This did not alter either the
mean results or their levels of significance.
Statistical analysis for correlation between structural
findings and clinical parameters was undertaken. No
significant correlation was found between systolic or
diastolic pressures, whether obtained with sphygmomanometer or photoplethysmograph, and any of the
three measures of wall thickness when the results of all
45 subjects were analysed. Similarly, analysis of mean
arterial pressure (Finapres derived) in the patient group
failed to show a positive correlation with PWT, wall
cross-sectional area, or wall\lumen ratio. Furthermore, a
history of treated hypertension did not correlate with
wall hypertrophy. None of the measures of lipid subfractions in the patient group showed significant correlation with any of the structural measurements.
Mean internal diameter was positively correlated with
males (Pearson correlation coefficient, 0.469 ; P, 0.001 ;
n l 45) and more strongly with height (r l 0.511 ;
P, 0.0005 ; n l 45).
We then applied a model of analysis of covariance
adjusted for obvious patient–control differences, using
15 possible predictors of wall thickness : systolic and
diastolic pressures, obtained both using photoplethysmograph and sphygmomanometer, past history of hypertension, age, sex, ever having smoked, height, weight,
BMI, co-existent renal, peripheral or cerebral vascular
disease and presence of coronary artery disease. The
presence of coronary artery disease was found to be the
best single predictor of wall cross-sectional area (R# l
44 % ; P, 0.0005 ; n l 44), and the second best predictor
was weight, with a combined R# of 59 % ; P, 0.0005 ; n l
44. For PWT, the variable with the strongest positive
predictive value was the presence of coronary artery
disease (R# l 48 % ; P, 0.0005 ; n l 44). The second best
predictor was BMI, giving a combined R# of 56 % (P,
0.006). For wall\lumen ratio, the presence of coronary
artery disease was again the strongest predictor (R# l
34 % ; P, 0.0005 ; n l 39), with an R# of 44.4 % (P, 0.006 ;
n l 39) when combined with height.
DISCUSSION
The salient finding of this study is that greater intimamedia thickness of radial arteries of patients with
coronary atherosclerosis compared with healthy control
subjects is detectable in vivo using ultrasound echotracking. As radial arteries from patients with advanced
atherosclerosis have never been studied non-invasively in
vivo before, this is a novel observation. Furthermore, the
finding is consistent with the recent demonstration of
histological changes of atherosclerosis in radial arteries.
We propose that, in patients with coronary atherosclerosis, the radial artery should not be assumed to be
free of structural changes but that early atherosclerotic
changes should be considered likely. The extent of any
structural abnormalities might be evaluated when considering these arteries as donor grafts for coronary artery
bypass surgery.
The finding of intima-media hypertrophy outwith the
coronary circulation in patients with coronary atherosclerosis is not a novel observation. This phenomenon is
well recognized in the carotid arteries of patients with
atherosclerosis, to the extent that carotid intima-media
thickness is used as a marker for coronary risk in studies
[30–33]. Carotid intima-media thickening is also found in
individuals with single risk factors, such as hyperlipidaemia [34], hyperhomocysteinaemia [35] and diabetes [36], as well as those with essential hypertension
[37] and is considered in these subjects to be a marker of
presymptomatic atherosclerosis.
Radial artery intima-media hypertrophy has been
demonstrated previously in individuals with essential
hypertension [38]. In contrast with the pathological
findings of intimal hypertrophy in atherosclerosis, the
structural changes of hypertension are seen in the medial
layer, in which smooth muscle cells hypertrophy and
proliferate, resulting in thick-walled vessels with no
external diameter increase, but a narrowing of the internal
lumen [39]. The term ‘ remodelling ’ has been used to
describe these structural changes when they occur in the
resistance vasculature [40]. It is suggested that such
remodelling is a response by smooth muscle cells of the
vascular media to the increased tensile stress which
hypertension places on the arterial wall. Structural
adaptations are thought to be the result of homoeostatic
mechanisms which maintain pressures at the level of
resistance arteries [41]. However, in the present study,
the differences between the arteries of the patient group
and those of the controls was unrelated to any past or
present measure of arterial pressures, reducing the likelihood of the structural phenomenon resulting from
direct pressure-related mechanical forces. Although it is
arguable that including a sub-set of treated hypertensives
in the patient group may have affected the findings, their
exclusion did not alter the results or the level of
significance which was achieved. Furthermore, as treatment had reduced previously elevated blood pressures to
those of the control group, one would expect to see
regression to normal of any pressure-related wall
changes, as demonstrated in the study of Girerd et al.
[42].
Although there are very few studies investigating
vascular function of radial and brachial arteries in subjects
with advanced atherosclerosis, the functional effects of
individual biological variables and cardiovascular risk
factors have been studied in upper limb conduit arteries
[2,5,43,44]. Work has concentrated on the analysis of
# 2001 The Biochemical Society and the Medical Research Society
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A. J. Mackay and others
endothelium-mediated vascular function, disruption
of which predisposes towards structural abnormalities.
Impaired vasodilation to flow, an NO-dependent response, has been shown in the brachial arteries both of
children with familial hyperlipidaemia [2] and of elderly
individuals with hyperhomocysteinaemia [5]. Studies in
smokers have shown both reduced basal nitric oxide
bioavailability in the resistance circulation [45] and
altered wall properties in conduit vessels [43]. Greater
arterial stiffness has been shown in the radial artery wall
of those with Type I diabetes [44], and impaired NOmediated vasodilation has been demonstrated in the
resistance vessels of a group with Type II diabetes [46].
A study of radial artery functional properties in vitro
has been undertaken in samples from patients similar to
those in the present study. In internal thoracic arteries,
basal vasorelaxation appeared to be entirely NOmediated, whereas within the radial artery there was
evidence for both NO-dependent and -independent
vasorelaxation [47].
It is likely that the brachial arteries of the individuals
we studied with advanced coronary atherosclerosis
would show significant endothelial dysfunction. However, whereas this vessel is continuous with and has
structural similarities to the radial artery, the evidence for
dichotomy of results amongst peripheral vessels makes
any extrapolation speculative.
Atherosclerotic disease has been demonstrated, albeit
to a limited extent, within this vascular region. KaneToddHall et al. [48] studied histological specimens of
radial artery, internal mammary artery and long saphenous vein from patients undergoing CABG. They
classified the degree of stenosis, extent of intimal thickening and presence or absence of medial calcification in
order to quantify the severity of atherosclerotic change
present. Although their conclusion was that pre-existing
vascular disease in donor arteries was not severe, their
findings, and those of Ruengsakulrach et al. [15], are
consistent with the presence of early atherosclerotic
changes. Considering these observations, and the absence
of any evidence for hypertension contributing to the
structural changes noted in the present study, we hypothesize that the greater intima-media measurements of
our patient group are due to hypertrophy of the intimal
layer. However, the limits of ultrasound technology,
which do not allow differentiation between intima and
media, prevent this being established in an entirely noninvasive study. A study correlating histopathology with
results in vivo from the same patient would establish if
this is the case and add to our understanding of this
phenomenon.
Although the control group differed from the study
group slightly in age and sex ratio, both of these variables
were included in the analysis of covariance and did not
show any predictive value. Although it is possible that
some of the control group may have had silent athero# 2001 The Biochemical Society and the Medical Research Society
sclerosis, this would serve rather to under- than overestimate the differences between patients with atherosclerosis and the healthy population.
Polypharmacy was unavoidable for the patient group
and it is likely that the resting degree of vasoconstriction
or dilatation of the vessels was affected. This, in turn, will
have had some effect on the measured PWT. For this
reason, we consider the wall cross-sectional area result to
be the most reliable under these experimental conditions.
As the matter of the arterial wall is incompressible, this
result is constant irrespective of the degree of vasodilation
or constriction of the arterial smooth muscle [20,49].
Vasodilator drugs may be the explanation too behind the
surprising failure to find encroachment of the vascular
lumen, a feature noted by Ruengsakulrach et al. [15] yet
missing from our results. However, as it is recognized
that the histological fixation techniques used for vessels
with early atherosclerotic change results in over-estimation of the degree of lumenal encroachment [50], it is
important not to attempt too many comparisons between
different investigational techniques. It is hard to speculate
whether long-term drug therapy has affected arterial
structure in these patients. There is evidence in rat models
of hypertension that betablockade may reduce medial
thickening [51], and in vitro work with these compounds
suggests reduction of smooth muscle cell proliferation
[52]. Long acting calcium-channel antagonists have
caused regression of increased media\lumen ratio in
gluteal resistance vessels of hypertensive humans, as
have angiotensin-converting enzyme inhibitors and
angiotensin-II-receptor antagonists [53–55]. However,
the structural effects of anti-anginal agents in individuals
who are normotensive have not been investigated.
In conclusion, this is the first report that radial artery
intima-media hypertrophy may be detected noninvasively in patients with coronary atherosclerosis. Its
presence is likely to be independent of blood pressure
effects, which allows us to hypothesize that it may be due
to endothelial dysfunction. These observations suggest
that structural changes of atherosclerosis are more
widespread than formerly believed and this knowledge
could be further utilized in the assessment of potential
donor arteries.
ACKNOWLEDGMENTS
This study was funded by the British Heart Foundation
Programme Grant RG\97009 to A. F. D.
REFERENCES
1 Ross, R. (1993) The pathogenesis of atherosclerosis : a
perspective for the 1990s. Nature (London) 362, 801–809
Radial artery wall hypertrophy
2 Sorensen, K. E., Celermajer, D. S., Georgakopoulos, D.,
Hatcher, G., Betteridge, D. J. and Deanfield, J. E. (1994)
Impairment of endothelium-dependent dilation is an early
event in children with familial hypercholesterolemia and is
related to the lipoprotein(a) level. J. Clin. Invest. 93, 50–55
3 Schmieder, R. E., Weihprecht, H., Schobel, H. et al. (1997)
Is endothelial function of the radial artery altered in
human essential hypertension ? Am. J. Hypertens. 10,
323–331
4 Johnstone, M. T., Creager, S. J., Scales, K. M., Cusco, J. A.,
Lee, B. K. and Creager, M. A. (1993) Impaired
endothelium-dependent vasodilation in patients with
insulin-dependent diabetes mellitus [see comments].
Circulation 88, 2510–2516
5 Tawakol, A., Omland, T., Gerhard, M., Wu, J. T. and
Creager, M. A. (1997) Hyperhomocyst(e)inemia is
associated with impaired endothelium-dependent
vasodilation in humans. Circulation 95, 1119–1121
6 Vane, J. R., Anggard, E. E. and Botting, R. M. (1990)
Regulatory functions of the vascular endothelium.
N. Engl. J. Med. 323, 27–36
7 Faggiotto, A. and Ross, R. (1984) Studies of
hypercholesterolemia in the nonhuman primate. II. Fatty
streak conversion to fibrous plaque. Arteriosclerosis 4,
341–356
8 Faggiotto, A., Ross, R. and Harker, L. (1984) Studies of
hypercholesterolemia in the nonhuman primate. I.
Changes that lead to fatty streak formation.
Arteriosclerosis 4, 323–340
9 Werns, S. W., Walton, J. A., Hsia, H. H., Nabel, E. G.,
Sanz, M. L. and Pitt, B. (1989) Evidence of endothelial
dysfunction in angiographically normal coronary arteries
of patients with coronary artery disease. Circulation 79,
287–291
10 Bassenge, E. (1996) Endothelial function in different
organs. Prog. Cardiovasc. Dis. 39, 209–228
11 Levy, B. I., Stefas, L., Babalis, D. and Benetos, A. (1992)
Vascular endothelium, mechanical properties of the arterial
wall and local angiotensin converting enzyme inhibition.
J. Hypertens. (Suppl.) 10, S21–S27
12 Anderson, T. J., Uehata, A., Gerhard, M. D. et al. (1995)
Close relation of endothelial function in the human
coronary and peripheral circulations. J. Am. Coll. Cardiol.
26, 1235–1241
13 Anderson, T. J., Gerhard, M. D., Meredith, I. T. et al.
(1995) Systemic nature of endothelial dysfunction in
atherosclerosis. Am. J. Cardiol. 75, 71B–74B
14 Acar, C., Ramsheyi, A., Pagny, J. Y. et al. (1998) The
radial artery for coronary artery bypass grafting : clinical
and angiographic results at five years [see comments].
J. Thorac. Cardiovasc. Surg. 116, 981–989
15 Ruengsakulrach, P., Sinclair, R., Komeda, M., Raman, J.,
Gordon, I. and Buxton, B. (1999) Comparative
histopathology of radial artery versus internal thoracic
artery and risk factors for development of intimal
hyperplasia and atherosclerosis. Circulation 100,
II139–II144
16 Tardy, Y., Meister, J. J., Perret, F., Brunner, H. R. and
Arditi, M. (1991) Non-invasive estimate of the mechanical
properties of peripheral arteries from ultrasonic and
photoplethysmographic measurements. Clin. Phys.
Physiol. Meas. 12, 39–54
17 Snell, R. S. (1986) Clinical Anatomy for Medical Students.
Little, Brown and Co., Boston
18 Wiedeman, M. P. (1963) Dimensions of blood vessels from
distributing artery to collecting vein. Circ. Res. 12,
375–378
19 Girerd, X., Mourad, J. J., Acar, C. et al. (1994)
Noninvasive measurement of medium-sized artery intimamedia thickness in humans : in vitro validation. J. Vasc.
Res. 31, 114–120
20 Girerd, X. J., Acar, C., Mourad, J. J., Boutouyrie, P., Safar,
M. E. and Laurent, S. (1992) Incompressibility of the
human arterial wall : an in vitro ultrasound study.
J. Hypertens. (Suppl.) 10, S111–S114
21 Tardy, Y., Hayoz, D., Mignot, J. P., Richard, P., Brunner,
H. R. and Meister, J. J. (1992) Dynamic non-invasive
measurements of arterial diameter and wall thickness.
J. Hypertens. (Suppl.) 10, S105–S109
22 Mooser, V., Etienne, J. D., Farine, P. A. et al. (1988) Noninvasive measurement of internal diameter of peripheral
arteries during the cardiac cycle. J. Hypertens. (Suppl.) 6,
S179–S181
23 Boutouyrie, P., Bussy, C., Lacolley, P., Girerd, X., Laloux,
B. and Laurent, S. (1999) Association between local pulse
pressure, mean blood pressure, and large-artery
remodeling. Circulation 100, 1387–1393
24 Girerd, X., Hanon, O., Mourad, J. J., Boutouyrie, P.,
Laurent, S. and Jeunemaitre, X. (1998) Lack of association
between renin-angiotensin system, gene polymorphisms,
and wall thickness of the radial and carotid arteries.
Hypertension 32, 579–583
25 Safar, M. E., Girerd, X. and Laurent, S. (1996) Structural
changes of large conduit arteries in hypertension.
J. Hypertens. 14, 545–555
26 Girerd, X., London, G., Boutouyrie, P., Mourad, J. J.,
Safar, M. and Laurent, S. (1996) Remodeling of the radial
artery in response to a chronic increase in shear stress.
Hypertension 27, 799–803
27 Remington, J. W. and Wood, E. H. (1956) Formation of
peripheral pulse contour in man. J. Appl. Physiol. 9,
433–442
28 O’Rourke, M. F. (1982) Vascular impedance in studies of
arterial and cardiac function. Physiol. Rev. 62, 570–623
29 Kelly, R., Hayward, C., Avolio, A. and O’Rourke, M.
(1989) Noninvasive determination of age-related changes
in the human arterial pulse. Circulation 80, 1652–1659
30 Chambless, L. E., Heiss, G., Folsom, A. R. et al. (1997)
Association of coronary heart disease incidence with
carotid arterial wall thickness and major risk factors : the
Atherosclerosis Risk in Communities (ARIC) Study,
1987–1993. Am. J. Epidemiol. 146, 483–494
31 Westendorp, I. C., Veld, B. A., Bots, M. L. et al. (1999)
Hormone replacement therapy and intima-media thickness
of the common carotid artery : the Rotterdam study.
Stroke 30, 2562–2567
32 de Kleijn, M. J., Bots, M. L., Bak, A. A. et al. (1999)
Hormone replacement therapy in perimenopausal women
and 2-year change of carotid intima-media thickness.
Maturitas 32, 195–204
33 Stumpe, K. O., Ludwig, M., Heagerty, A. M. et al. (1995)
Vascular wall thickness in hypertension : the Perindopril
Regression of Vascular Thickening European Community
Trial : PROTECT. Am. J. Cardiol. 76, 50E–54E
34 Tonstad, S., Joakimsen, O., Stensland-Bugge, E., Ose, L.,
Bonaa, K. H. and Leren, T. P. (1998) Carotid intima-media
thickness and plaque in patients with familial
hypercholesterolaemia mutations and control subjects [see
comments]. Eur. J. Clin. Invest 28, 971–979
35 Demuth, K., Moatti, N., Hanon, O., Benoit, M. O., Safar,
M. and Girerd, X. (1998) Opposite effects of plasma
homocysteine and the methylenetetrahydrofolate reductase
C677T mutation on carotid artery geometry in
asymptomatic adults. Arterioscler. Thromb. Vasc. Biol. 18,
1838–1843
36 Hanefeld, M., Koehler, C., Schaper, F., Fuecker, K.,
Henkel, E. and Temelkova-Kurktschiev, T. (1999)
Postprandial plasma glucose is an independent risk factor
for increased carotid intima-media thickness in nondiabetic individuals. Atherosclerosis 144, 229–235
37 Ohya, Y., Abe, I., Fujii, K., Kobayashi, K., Onaka, U. and
Fujishima, M. (1997) Intima-media thickness of the carotid
artery in hypertensive subjects and hypertrophic
cardiomyopathy patients. Hypertension 29, 361–365
38 Laurent, S., Girerd, X., Mourad, J. J. et al. (1994) Elastic
modulus of the radial artery wall material is not increased
in patients with essential hypertension. Arterioscler.
Thromb. 14, 1223–1231
39 Korsgaard, N., Aalkjaer, C., Heagerty, A. M., Izzard, A. S.
and Mulvany, M. J. (1993) Histology of subcutaneous
small arteries from patients with essential hypertension.
Hypertension 22, 523–526
# 2001 The Biochemical Society and the Medical Research Society
515
516
A. J. Mackay and others
40 Gibbons, G. H. and Dzau, V. J. (1994) The emerging
concept of vascular remodeling. N. Engl. J. Med. 330,
1431–1438
41 Rachev, A., Stergiopulos, N. and Meister, J. J. (1996)
Theoretical study of dynamics of arterial wall remodeling
in response to changes in blood pressure. J. Biomech. 29,
635–642
42 Girerd, X., Mourad, J. J., Copie, X. et al. (1994)
Noninvasive detection of an increased vascular mass in
untreated hypertensive patients. Am. J. Hypertens. 7,
1076–1084
43 Brunel, P., Girerd, X., Laurent, S., Pannier, B. and Safar,
M. (1992) Acute changes in forearm haemodynamics
produced by cigarette smoking in healthy normotensive
non-smokers are not influenced by propranolol or
pindolol. Eur. J. Clin. Pharmacol. 42, 143–146
44 Giannattasio, C., Failla, M., Piperno, A. et al. (1999) Early
impairment of large artery structure and function in type I
diabetes mellitus. Diabetologia 42, 987–994
45 McVeigh, G. E., Lemay, L., Morgan, D. and Cohn, J. N.
(1996) Effects of long-term cigarette smoking on
endothelium-dependent responses in humans. Am.
J. Cardiol. 78, 668–672
46 Ting, H. H., Timimi, F. K., Boles, K. S., Creager, S. J.,
Ganz, P. and Creager, M. A. (1996) Vitamin C improves
endothelium-dependent vasodilation in patients with noninsulin-dependent diabetes mellitus. J. Clin. Invest 97,
22–28
47 Hamilton, C. A., Williams, R., Pathi, V. et al. (1999)
Pharmacological characterisation of endotheliumdependent relaxation in human radial artery : comparison
with internal thoracic artery. Cardiovasc. Res. 42, 214–223
48 Kane-ToddHall, S. M., Taggart, S. P., Clements-Jewery, H.
and Roskell, D. E. (1999) Pre-existing vascular disease in
the radial artery and other coronary artery bypass
conduits. Eur. J. Med. Res. 4, 11–14
49 Meister, J. J., Tardy, Y., Stergiopulos, N., Hayoz, D.,
Brunner, H. R. and Etienne, J. D. (1992) Non-invasive
method for the assessment of non-linear elastic properties
and stress of forearm arteries in vivo. J. Hypertens.
(Suppl.) 10, S23–S26
50 Siegel, R. J., Swan, K., Edwalds, G. and Fishbein, M. C.
(1985) Limitations of postmortem assessment of human
coronary artery size and luminal narrowing : differential
effects of tissue fixation and processing on vessels with
different degrees of atherosclerosis. J. Am. Coll. Cardiol. 5,
342–346
51 Ohlstein, E. H., Vickery, L., Arleth, A. et al. (1994)
Carvedilol, a novel cardiovascular agent, inhibits
development of vascular and ventricular hypertrophy in
spontaneously hypertensive rats. Clin. Exp. Hypertens. 16,
163–177
52 Sung, C. P., Arleth, A. J. and Ohlstein, E. H. (1993)
Carvedilol inhibits vascular smooth muscle cell
proliferation. J. Cardiovasc. Pharmacol. 21, 221–227
53 Schiffrin, E. L., Deng, L. Y. and Larochelle, P. (1995)
Progressive improvement in the structure of resistance
arteries of hypertensive patients after 2 years of treatment
with an angiotensin I-converting enzyme inhibitor.
Comparison with effects of a beta-blocker. Am.
J. Hypertens. 8, 229–236
54 Thybo, N. K., Stephens, N., Cooper, A., Aalkjaer, C.,
Heagerty, A. M. and Mulvany, M. J. (1995) Effect of
antihypertensive treatment on small arteries of patients
with previously untreated essential hypertension [see
comments]. Hypertension 25, 474–481
55 Schiffrin, E. L., Park, J. B., Intengan, H. D. and Touyz,
R. M. (2000) Correction of arterial structure and
endothelial dysfunction in human essential hypertension
by the angiotensin receptor antagonist losartan [see
comments]. Circulation 101, 1653–1659
Received 19 September 2000/14 December 2000; accepted 26 January 2001
# 2001 The Biochemical Society and the Medical Research Society