Circulation. 1998;98:2276-2281
(Circulation. 1998;98:2276-2281.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Evidence of Carotid Artery Wall Hypertrophy in Homozygous Homocystinuria
Jean-Louis Megnien, MD;
Jérôme Gariepy, MD;
Jean-Marie Saudubray, MD;
Jean-Marc Nuoffer, MD;
Nicolas Denarie, MD;
Jaime Levenson, MD;
;
Alain Simon, MD
From Centre de Médecine Préventive Cardiovasculaire,
Hôpital Broussais (J.-L.M., J.G., N.D., J.L., A.S.), and
Département de Pédiatrie Clinique et de Génétique,
Hôpital Necker (J.-M.S., J.-M.N.), Paris, France.
Correspondence to Professeur Alain Simon, Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.
 |
Abstract
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BackgroundWe aimed to determine
whether intima-media thickness
(IMT) was increased in the carotid
artery of subjects with homocystinuria
to better understand the in vivo
contribution of homocysteine
to early atherogenesis.
Methods and ResultsWe investigated ultrasonographically the
right common carotid artery in 14 subjects with homozygous
homocystinuria aged 3 to 34 years (mean, 13 years) and in 15 of their
heterozygous parents aged 32 to 47 years (mean, 41 years) by comparison
with 2 control groups of 15 healthy subjects of the same age. Far-wall
IMT and lumen diameter were measured with a computerized program, and
the cross-sectional area of the intima-media complex (CSA-IMC) was
calculated from IMT and diameter. Comparison with their respective
controls, adjusted for body surface area or height, showed that
homozygotes had greater IMT (P<0.001) and CSA-IMC
(P<0.05) and smaller diameter (P<0.05),
whereas heterozygotes had values similar to their controls.
Multivariate analysis of the
arterial parameters with age, body surface area
(or height), and plasma total homocysteine in the homozygous and
heterozygous groups combined showed that IMT was related to age
(P<0.05) and homocysteine (P<0.01),
diameter was related to body surface area (P<0.001) or
height (P<0.05), and CSA-IMC was related to age
(P<0.05), body surface area (P<0.05)
(but not height), and homocysteine (P<0.05).
ConclusionsHomozygous homocystinuria was associated with common
carotid wall hypertrophy, whereas heterozygous disease was
not. Such hypertrophy may reflect a smooth muscle
proliferation induced by hyperhomocysteinemia and represent a
promising target for testing vascular effects of therapeutic measures
to lower homocysteine.
Key Words: homocysteine atherosclerosis ultrasonics carotid arteries
 |
Introduction
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Homocysteine is a highly reactive amino
acid.
1 Its severe elevation,
seen in homozygous
homocystinuria, a rare disease due to inborn
errors of homocysteine
metabolism,
1 is associated with
premature
cardiovascular complications induced by
accelerated atherosclerosis
and/or
thromboembolism.
2 3 The toxic effects of
homocysteine
on the vasculature have been well documented in
experimental
studies, consisting in particular of
endothelial cell injury
and smooth muscle cell
proliferation, which represent 2 prominent
features of
atherogenesis.
4 5 6 7 In contrast, the in
vivo
contribution of hyperhomocysteinemia to
atherosclerosis in humans
has been less fully
investigated. One interesting way of investigation
is to assess the
effects of homocystinuria on markers of early
atherosclerosis
such as endothelial
dysfunction or arterial wall
thickening.
8 9 Large-artery
endothelial dysfunction has been reported in
children
with homozygous homocystinuria.
8 In the
present study,
we hypothesized that homocystinuria might be
associated with
arterial wall hypertrophy
because it has been shown experimentally
that homocysteine at
concentrations similar to those seen in
homozygous homocystinuria has a
direct growth-promoting effect
on vascular smooth muscle
cells.
7 To this end, we used high-resolution
B-mode
ultrasonography to measure intima-media thickness (IMT) and
lumen
diameter in a large peripheral
artery,
9 10 the common carotid
artery, of
subjects with and without homozygous and heterozygous
homocystinuria.
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Methods
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Study Subjects
Fourteen subjects with homozygous homocystinuria (10
cystathionine-ß-synthase
deficiencies and 4 defects of
remethylation), including 2 pairs
of siblings aged 3 to 34 years (mean,
13 years) and 15 of their
heterozygous parents coming from 8 families
and aged 32 to 47
years (mean, 41 years) underwent ultrasonographic
investigation
of the carotid artery between 1996 and 1997. They were
compared
with 2 control groups of healthy subjects of similar ages
studied
with the same technique of carotid investigation during the
same
period: (1) a control group for homozygotes including 7 males
and
8 females aged 2 to 25 years (mean, 13 years) and (2) a
control group
for heterozygotes including 7 men and 8 women
aged 32 to 49
years (mean, 41 years). The age at diagnosis of
homozygous subjects
ranged from 0 to 22 years (mean, 5 years).
At the time of
investigation, 12 homozygous subjects were consuming
a low methionine
diet, 3 were taking pyridoxine (of whom 2 were
pyridoxine sensitive), 6
were taking folic acid supplements,
3 were taking cobalamin, and 11
were prescribed betaine. Three
homozygous subjects had a previous
history of cardiovascular
disease, including 1 cerebral
trunk thrombosis, 1 stroke with
iliac artery stenosis, and 1
cerebral arterial spasm with iliac
artery thrombosis. No
homozygous subject had any ultrasonic
evidence of arterial
narrowing or plaque in the carotid arteries.
Heterozygous subjects had
no present or past history or sign
of
cardiovascular disease and did not take any
cardiovascular
drug treatment, but 1 subject had
ultrasonic evidence of plaque
in the left carotid artery bifurcation.
The reasons that 9 heterozygous
parents did not participate in the
study were related to domestic
or professional constraints and excluded
any present or past
history of cardiovascular
disease. All homozygous and heterozygous
subjects underwent evaluation
of body size and traditional cardiovascular
risk
factors, including hypertension,
hypercholesterolemia,
diabetes mellitus, and
smoking history estimated in pack-years
(Table 1

).
Arterial Investigations
A high-resolution ATL Ultramark 9 B-mode ultrasound system was
used to measure IMT in the far wall of the right common carotid artery
according to a standardized procedure previously described in
detail.10 In brief, the IMT image, consisting of
2 parallel echogenic lumen-intima and media-adventitia interfaces
visible on
1 cm of length of the vessel, was frozen in
telediastole by ECG triggering and transferred to a
computer for automated measurement by means of an edge-detection
program (Iôtec system, Iôdata), the principles and
detailed description of which have been provided
elsewhere.10 Simultaneously, the
lumen diameter was imaged between the far-wall and near-wall
lumen-intima interfaces (leading edges), frozen in
telediastole, and transferred to the computer for automated
measurement with the edge-detection program.10
The cross-sectional area of the intima-media complex (CSA-IMC) was
calculated from IMT and lumen diameter (D) as
xIMTx(IMT+D).11
Homocysteine Measurement
In all homozygous and heterozygous subjects, plasma total
homocysteine was measured by a radioenzymatic assay by condensation of
homocysteine in the presence of
S-adenosyl-L-homocysteine hydrolase with
C14-adenosine to form
C14-adenosyl-homocysteine, which was then
quantified.12 In the homozygous subjects, the
value of homocysteine was the average of several measurements over time
(2 to 9 measurements over 2 to 8 years), whereas in the heterozygous
subjects, homocysteine was measured once at the time of
investigation.
Statistical Analysis
Comparisons between groups were performed by use of Student's
t test for quantitative parameters and
2 analysis for qualitative
variables. Univariate regressions were assessed by
linear regression analysis. Multiple regression
analysis was used with arterial
parameters as the dependent variables and age, body
surface area (or height), and plasma total homocysteine as independent
variables.
 |
Results
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In the homozygous group, plasma total homocysteine was elevated
(>15
µmol/L) in 12 subjects but normal in the 2
pyridoxine-sensitive
subjects. Compared with their control group, the
homozygous
group had greater IMT (
P<0.001) and CSA-IMC
(
P<0.05) but
similar lumen diameter; all these
arterial parameters were derived
from the
common carotid (Figure 1

, Table 2

). After adjustment
for height or body
surface area, IMT and CSA-IMC remained greater
in homozygotes than in
controls (
P<0.001 and
P<0.05, respectively),
whereas
lumen diameter was smaller in homozygotes than in controls
(
P<0.05)
(Table 2

). In the homozygous group, positive
univariate correlations
existed between lumen diameter and
age (
r=0.80,
P<0.001),
height
(
r=0.85,
P<0.001), and body surface area
(
r=0.87,
P<0.001) and between CSA-IMC and height
(
r=0.62,
P<0.01)
and body surface area
(
r=0.67,
P<0.01). No correlation existed
between
plasma total homocysteine and any arterial
parameter,
even after adjustment for age and height or body
surface area.
Finally, IMT correlated negatively with age at diagnosis
(
r=0.54,
P=0.05), whereas lumen diameter and
CSA-IMC did not.

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Figure 1. Common carotid artery dimensions in subjects
homozygous for homocystinuria (HMZ) and in their controls (C). Data are
given as individual values (circles) and mean (horizontal bar). The 2
full circles indicate the 2 homozygotes with pyridoxine
sensitivity.
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Table 2. Comparisons of Common Carotid Artery Dimensions
Before and After Adjustment for Height or Body Surface Area Between
Homozygotes, Heterozygotes, and Their
Controls
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In the heterozygous subjects, plasma total homocysteine was normal in
13 subjects but elevated (>15 µmol/L) in 2 subjects. Compared
with their control group, the heterozygous group did not have different
values of IMT, lumen diameter, and CSA-IMC (Figure 2
, Table 2
), and this lack of difference
persisted after adjustment for height or body surface area (Table 2
).
In the heterozygous group, age, height, and body surface area did not
correlate with any arterial parameter with the
exception that body surface area correlated with diameter
(r=0.61, P<0.05). IMT and CSA-IMC correlated
positively and almost significantly with plasma total homocysteine
(r=0.47, P=0.06 and r=0.48,
P=0.07, respectively), whereas lumen diameter did not
(r=0.18). After adjustment for age and body surface area,
IMT remained almost significantly associated with homocysteine
(P=0.06), whereas CSA-IMC did not.

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Figure 2. Common carotid artery dimensions in subjects
heterozygous for homocystinuria (HTZ) and in their controls (C). For
abbreviations and data, see Figure 1 .
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In homozygous and heterozygous groups combined,
multivariate analysis with arterial
parameters as dependent variables and age, body surface
area (or height), and plasma total homocysteine as independent
variables showed the following: (1) IMT was positively related to
age (P<0.05) and plasma total homocysteine
(P<0.01); (2) lumen diameter was positively related to body
surface area (P<0.001) (or height [P<0.05]);
and (3) CSA-IMC was positively related to age (P<0.05),
body surface area (P<0.05) (but not height), and plasma
total homocysteine (P<0.05) (Table 3
).
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Table 3. Multiple Regression Analysis of Common Carotid
Artery Dimensions and Age, Body Surface Area (Model 1) or Height (Model
2), and Plasma Total Homocysteine in Homozygous and Heterozygous Groups
Combined
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 |
Discussion
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The important new finding in this study is that compared with
healthy
children and young adults of their age, homozygotes for
homocystinuria
had a clear-cut premature, large, artery-wall
hypertrophy reflected
by increased IMT and CSA-IMC. Such an
increase persisted after
adjustment for height or body surface area,
which was performed
because of the associations of carotid dimensions
with height
or body surface area found in our work, in agreement with a
previous
report.
9 However, our result is in
contrast to results of another
study that showed that 12 homozygotes
for homocystinuria (mean
age, 24 years) were similar to healthy control
subjects with
regard to carotid artery IMT.
13
Such a discrepancy might be
due to important differences in the
population age (11 years
older than in the present study) and in
the IMT measurement
having been obtained from multiple sites (common
carotid, bifurcation,
and internal carotid) without the assistance of a
computerized
automated program of image
analysis.
13 Furthermore, the thickening
process
found in homozygotes in the present study existed despite
appropriate
medical management, perhaps because such management did not
normalize
homocysteine except in the 2 pyridoxine-sensitive subjects.
This
possibility is supported by the fact that the 2 homozygotes
with
pyridoxine sensitivity had values of IMT among the 3 lowest
values of
the homozygous group (full circles in Figure 1

). We
also
observed a negative correlation of IMT with age at diagnosis.
Because
IMT did not correlate with age in the homozygous group,
the correlation
of IMT with age at diagnosis did not mean that
older homozygotes had
smaller IMTs. A possible explanation was
that an older age at diagnosis
might be evidence of a more benign
clinical course of the disease with
a less adverse effect on
the arterial wall structure.
Another interesting finding in
homozygotes was a reduced common carotid
artery lumen diameter
compared with controls. Such a reduction in
diameter reached
statistical significance only after adjustment for
height or
body surface area because these 2 parameters were
strongly and
positively associated with lumen diameter, as previously
noted
by others.
9 This original finding suggests
that homozygous
homocysteinemia could be associated with some degree of
vasoconstriction
of the common carotid artery.
By contrast, values of IMT, CSA-IMC, and lumen diameter were not
different in heterozygote parents than in their controls. The lack of
significant increase in IMT in heterozygotes is in agreement with a
recent investigation14 that showed that the mean
IMT values obtained in multiple carotid and femoral
arterial segments were similar in 13 heterozygotes for
cystathionine-ß-synthase deficiency younger than 50 years of age and
in 12 healthy controls. Therefore, our work indicates that any
increased risk of atherosclerosis in heterozygotes may
not be reflected by early structural change of the common carotid
artery walls, at least in the absence of hyperhomocysteinemia, as in
the majority of our heterozygous subjects. It may also be that the
heterozygotes were too young to have developed structural vascular
changes. Nevertheless, because our B-mode measurements were obtained
from only the proximal common carotid artery, it is possible that there
might be demonstrable IMT differences with regard to the bifurcation or
the internal carotid artery, which were not studied in the present
investigation. In addition, our results in heterozygotes show some
discrepancy compared with results from several previous
studies.15 16 17 18 Both the ARIC and the Framingham
studies15 16 showed associations of elevated
homocysteine with carotid wall thickening, albeit in older populations
and with the use of quite different methodology, such as the
incorporation of intrusive plaque in IMT measurement and IMT
measurement at multiple carotid arterial segments or at the
carotid bifurcation. Two other studies showed that an early sign of
premature arterial disease in the carotid and femoral
arteries was present in heterozygotes for
cystathionine-ß-synthase deficiency17 and that
premature arterial occlusive disease was associated with a
higher prevalence of moderate
hyperhomocysteinemia,18 but the characteristics
of these subjects and the arterial methodology of these
studies were too different from the current work to allow a pertinent
comparison to be made.
The mechanisms by which homocystinuria, in its homozygous trait,
predisposes to atherosclerosis might be related to
abnormal vascular growth. Indeed, homozygous subjects exhibited an
elevation not only of IMT but also of CSA-IMC, a parameter
that incorporates in its calculation both IMT and lumen diameter and
which is therefore more appropriate to describe arterial
mass than IMT alone.11 The increased common
carotid arterial mass observed in homozygous patients is
consistent with the recent in vitro demonstration that
homocysteine at concentrations similar to those seen in homozygotes
enhances smooth muscle proliferation.7 This
phenomenon is an important component of medial and intimal
hypertrophy, which can both participate in the thickening
process of the carotid wall.10 11 Nevertheless in
the present study, the role of elevated homocysteine in carotid
arterial wall hypertrophy was not obvious in
separate analysis of the homozygous and heterozygous groups. In
the homozygous group, plasma total homocysteine did not correlate with
IMT and CSA-IMC, possibly because of a confounding effect of therapy.
In the heterozygous group, the correlation of IMT and CSA-IMC with
plasma total homocysteine almost attained statistical significance,
even after adjustment for age and body surface area (or height) in the
case of IMT. One can speculate that these correlations, observed with
fasting plasma homocysteine values that were within the normal ranges
except in 2 subjects, would have been closer if the heterozygous
patients had been further characterized with a methionine-loading
test.19 However, the methionine-loading test is a
cumbersome procedure that was judged impracticable in the investigation
of our heterozygous volunteers. By contrast, the influence of
homocysteine on carotid wall hypertrophy was better
evidenced by multivariate analysis of carotid
artery dimensions with plasma total homocysteine, age, and body surface
area as independent variables (model 1) or homocysteine, age, and
height as independent variables (model 2) in the homozygous and
heterozygous groups combined. Such analyses showed that
IMT and CSA-IMC were related to homocysteine and age in both models,
whereas lumen diameter was related only to body surface area in model 1
or to height in model 2. These findings suggest that
hyperhomocysteinemia can be a strong risk factor for
arterial wall hypertrophy, as suggested in a
few recent epidemiological studies.15 20 However,
the independence of its association with IMT and CSA-IMC should be
considered with caution in the current work because the
multivariate analysis was limited by the small
number of subjects and by restricting attention to only homocystinuric
patients.
The small number of subjects was a study limitation that merits careful
consideration, as does the fact that the B-mode measurements were
obtained only from the proximal common carotid artery. The small number
of homozygotes and, consequently, of their obligate heterozygote
parents is due to the extreme rarity of the homozygote trait. In
addition to the possibility that the multivariate
analysis will be compromised with regard to the independence of
the association between homocysteine and IMT, this small number of
patients may be responsible for a type II error when IMT is compared
between heterozygotes and controls. Because the observed IMT difference
between heterozygotes and controls is quite small (0.026 mm), the
probability of a type II error is high. On the other hand, this IMT
difference is too small, compared with the greater IMT differences
previously found with the same technique between hypertensive or
hypercholesterolemic adults and controls (0.05 to
0.10 mm),10 21 to have a real
physiopathological relevance. B-mode measurement of
arterial dimensions in the proximal common carotid artery
precludes the possibility of obtaining information from the bifurcation
or the internal carotid artery, where turbulent flow may predispose to
effects related to both thrombosis and atherosclerosis
and therefore may induce the greatest effects of homocysteine on
arterial structure. Nevertheless, the limitation due to the
focus of attention on the common carotid artery may be put into
perspectiveby considerations of methodological order. First, IMT
measurement is the most accurate in the common carotid artery because
this vessel is straight, superficial, and almost parallel to the
skin.22 Such geometric conditions are not met by
the bifurcation and the internal carotid artery, thus explaining why
IMT measurement in these arterial segments has 2 or 3 times
greater variability than in the common carotid
artery.22 This greater variability would increase
considerably the number of patients required to demonstrate a
difference in IMT even if one would expect the greatest difference in
the internal carotid or in the bifurcation. Second, the accuracy of the
CSA-IMC calculation is based on the assumption that IMT has
approximately the same value along the artery
circumference.11 Such an assumption can be
accepted in the proximal common carotid artery, which is a cylindrical
tube with a laminar flow inside its lumen. In contrast, it is not valid
in the bifurcation or in the internal carotid artery. These
arterial segments do not have a cylindrical geometry, and
they present local variations in flow and turbulence capable of
inducing different IMT values along the artery circumference, which
does not permit the calculation of CSA-IMC by use of a cylindrical
model. Finally, measurement of lumen diameter only in the common
carotid artery may constitute a limitation of greater importance,
because previous investigation has identified important differences
between the association of risk factors in the common carotid as
opposed to the internal carotid artery.23 Such a
difference may exist regarding the effect of homocysteine on lumen
diameter. Therefore, in the future, scanning procedures specifically
aimed at diameter measurement in various carotid artery segments should
be performed in patients with homocystinuria.
In conclusion, because arterial wall thickening
assessed in the carotid artery reflects generalized changes elsewhere
in the arterial tree24 25 and may be
related to subsequent vascular events,26 27 our
work suggests that this early arterial alteration is a
potential method by which hyperhomocysteinemia may predispose to
vascular disease. It is also suggested that more aggressive therapy may
be required in homozygous homocystinuria to retard or even reverse
arterial wall hypertrophy and that further
clinical trials are needed to demonstrate this point.
 |
Acknowledgments
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This study is supported in part by the CRI-INSERM No. 4U010B.
We
thank Maria Crichi for her excellent secretarial assistance.
We
gratefully acknowledge collaboration with Pr Pierre Kamoun
and
Bernadette Chadefaux, Department of Biochemistry, Necker
Hospital,
for measuring plasma total homocysteine.
Received May 10, 1998;
revision received June 23, 1998;
accepted July 21, 1998.
 |
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