(Chest. 2000;118:1685-1689.)
© 2000
American College of Chest Physicians
Plasma Homocysteine and Severity of Thoracic Aortic Atherosclerosis*
Christophe M. Tribouilloy, MD, PhD;
Marcel Peltier, MD;
Michele C. Iannetta Peltier, MD;
Faouzi Trojette, MD;
Michel Andrejak, MD and
Jean-Philippe M. Lesbre, MD
*
From the Department of Cardiology, South Hospital, University of Picardie, Amiens, France.
Correspondence to: Christophe Tribouilloy, MD, PhD, Service de Cardiologie, Hôpital Sud, 80000 Amiens, Cédex, France
 |
Abstract
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|---|
Study objectives: Plasma homocysteine level is a risk
factor for coronary events, stroke, and peripheral atherosclerotic
disease. However, few data are available concerning the relationship
between homocysteine level and severity of thoracic aortic
atherosclerosis. We hypothesized in this multiplane transesophageal
echocardiography (TEE) study that homocysteine level is a marker of the
presence and severity of thoracic aortic atherosclerosis.
Design: Cross-sectional study.
Setting:
University hospital.
Patients: Risk factors,
angiographic features, and TEE findings were analyzed prospectively in
82 valvular patients.
Measurements and results: The
following risk factors were recorded: age, gender, hypertension,
smoking, lipid parameters, diabetes, body mass index, and family
history of coronary artery disease. Plasma levels of homocysteine,
vitamin B12, and folic acid were measured for each patient.
By univariate analysis, age, diabetes, hypertension, smoking, family
history of coronary artery disease, and levels of homocysteine, total
cholesterol, low-density lipoprotein cholesterol, and high-density
lipoprotein cholesterol were significant predictors of the presence of
thoracic aortic plaques. There was a positive correlation between the
plasma homocysteine levels and the score of severity of thoracic
atherosclerosis (r = 0.48; p = 0.0001) as well as
between the homocysteine levels and the grades of severity of aortic
intimal changes (p = 0.0008). Multivariate regression analysis
revealed that homocysteine was an independent predictor of the presence
and severity of thoracic aortic atherosclerosis.
Conclusion: This prospective study indicates that plasma
homocysteine level is a marker of severity of thoracic atherosclerosis
detected by multiplane TEE. These findings emphasize the role of
homocysteine as a marker of atherosclerotic lesions in the major
arterial locations.
Key Words: aorta • atherosclerotic plaque • homocysteine • transesophageal echocardiography
|
Introduction
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The
identification of risk factors of atherosclerotic lesions leads to a
better understanding of atherosclerosis. Such knowledge is fundamental
for development of strategies for prevention of cardiovascular disease
and of its complications. Conventional risk factors for coronary artery
disease (CAD) include hyperlipidemia, smoking, hypertension, diabetes,
and a positive family history of CAD. Plasma homocysteine level is an
emerging risk factor for the development of atherosclerotic
disease.1
2
3
4
5
6
7
8
Thus, increased plasma levels of homocysteine
are associated with the presence and the severity of
CAD,2
3
4
5
as well as with an increased risk of cerebral
vascular disease and peripheral vascular disease.6
7
8
9
It
might confer a risk of atherosclerotic vascular disease similar to that
of smoking or hyperlipidemia.10
However, few data are
available concerning the relation between homocysteine and
atherosclerosis of the thoracic aorta.11
Transesophageal
echocardiography (TEE), which provides high-resolution imaging of the
thoracic aorta, is a reliable tool to study the degree of the thoracic
aortic atherosclerosis.12
13
14
The aim of this prospective
study was to examine, using TEE, the relationship between the severity
of aortic atherosclerosis and the plasma homocysteine level.
|
Materials and Methods
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Study Patients
Between September 1996 and March 1998, 82 consecutive patients
considered for surgery or valvuloplasty for valvular heart disease
underwent prospectively a multiplane TEE, a coronary angiography, and a
measurement of plasma homocysteine level, folate, and vitamin
B12. The diagnoses were as follows: mitral stenosis with or
without mitral regurgitation in 9 patients, isolated pure mitral
regurgitation in 18 patients, aortic stenosis with or without
regurgitation in 35 patients, isolated aortic regurgitation in 12
patients, and combined mitral and aortic valve disease in 8
patients. Informed consent was obtained for each patient prior to
the procedures. Age, gender, lipid concentrations, and conventional
cardiovascular risk factors for CAD were recorded. Blood was drawn
after a 14-h overnight fast for determination of serum total
cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein
(HDL) cholesterol, and triglycerides using standard
methods.15
Diabetes mellitus was considered present if the
fasting glucose in the hospital was > 140 mg/dL or requiring previous
or ongoing therapy. Systemic hypertension was defined as either
systolic pressure 
160 mm Hg and/or diastolic pressure 95 mm Hg
or elevation of diastolic or systolic pressure requiring
pharmacologic therapy for BP control. A history of smoking
was defined as 10 pack-years. Body mass index was
computed as weight divided by height squared. A
positive family history of CAD was defined as myocardial infarction
or known CAD in a parent or sibling noted before age 65.
Homocysteine, Vitamin B12, and Folic Acid
Measurements
No patient was treated using folic acid, vitamin B6,
and vitamin B12. Conditions thought to influence
homocysteine concentrations, such as renal disease (serum creatinine
> 120 µmol/L), thyroid disease, or anticonvulsant therapy, served
as exclusion criteria. Plasma homocysteine level was measured by
high-power liquid chromatography and fluorescence
detection.16
Plasma level of vitamin B12 and
folic acid were simultaneously measured by use of a
radioimmunoassay.17
TEE Examination
Multiplane TEE was performed within 2 days of coronary
angiography using an ultrasonograph (Sonos 2000 or 5500;
Hewlett-Packard; Andover, MA) without procedural complication. A
well-standardized protocol described previously was applied to cardiac
examinations in all patients, especially for the study of the thoracic
aorta.14
All studies were recorded on a videotape and were
interpreted independently by two experienced observers. The thoracic
aorta was considered normal when the intimal surface was smooth and
continuous without lumen irregularities or increased echo density. If
the intimal surface increased in echo density but remained smooth and
continuous without lumen irregularities, it was defined as grade 1.
Intimal thickening < 5 mm with highly echogenic areas disrupting the
normal smooth surface of the vessel wall and causing lumen
irregularities was classified as grade 2. Grade 3 changes consisted of
intimal thickening < 5 mm and/or obvious lumen irregularities
associated with localized highly echogenic mobile lesions protruding
into the vessel lumen.14
Grade 2 or 3 lesions were
considered to be atherosclerotic aortic plaques. The two observers had
an excellent agreement regarding the presence or absence of
atherosclerotic aortic plaques (100%). For calculating an aortic
atherosclerotic score, the thoracic aorta was divided in five
segments as previously described.18
The sum of the maximal
plaque thickness in millimeters of the ascending aorta (segment 1), of
the horizontal aorta (segment 2), and of the upper, mild, and
lower third of the descending aorta (segments 3, 4, 5, respectively)
was calculated; this score was considered a measure of the extent and
severity of aortic atherosclerosis.
Coronary Angiography
Selective coronary angiography was performed by the Judkins
technique for patients with normal or moderately atherosclerotic aortic
intima (grade 1 or 2) and by the Sones method for those with severe
aortic plaque (grade 3). There were no complications of procedure in
any patient. The number of vessels with significant stenosis ( 70%
narrowing of luminal diameter for left anterior descending, left
circumflex, or right coronary arteries) was recorded. Left main CAD
with 50% reduction of its internal diameter was considered to be
two-vessel disease involving left anterior and circumflex coronary
arteries. Mildly atherosclerotic coronary lesion was defined as a
reduction of the internal diameter without significant coronary
stenosis. Coronary angiographic findings were classified in five
grades: normal coronary angiography (grade 1), mildly atherosclerotic
coronary lesion (grade 2), one-vessel disease (grade 3), two-vessel
disease (grade 4), and three-vessel disease (grade 5). Patients without
angiographic coronary lesions were considered as patients without CAD.
Statistical Analysis
Results are expressed as mean ± SD. Discrete variables were
analyzed by the 
2 test. A p < 0.05 was
considered statistically significant. Simple linear regression was used
for continuous variables. For incremental data, the Spearman
correlation analysis was applied. All variables with a p < 0.15 in
the univariate analysis were examined by linear or logistic
multivariate stepwise regression analysis.
|
Results
|
|---|
Of the 82 patients, 43 patients (53%) were men and 39 patients
(47%) were women, with a mean age of 66 ± 13 years (range, 32 to 81
years). Hypertension was present in 43%, history of smoking in 28%,
diabetes mellitus in 16%, and 24% had a family history of CAD. Mean
body mass index was 25.9 ± 4.7 kg/m2. Mean
plasma levels of homocysteine, vitamin B12, folic acid,
total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides
are reported in Table 1
. Plasma homocysteine levels correlated significantly with age
(r = 0.28; p = 0.0001), LDL cholesterol
(r = 0.25; p = 0.02), folic acid
(r = -0.23; p = 0.04), and vitamin B12
(r = -0.22; p = 0.05), but not with body mass index
(p = 0.26). There was no relation between the mean level of
homocysteine and the presence or absence of diabetes, history of
smoking, systemic hypertension, and family history of CAD.
Homocysteine and Thoracic Aortic Atherosclerosis
TEE examination detected thoracic aortic plaques in 49 patients
(59%). By univariate analysis, age, systemic hypertension, history of
smoking, diabetes mellitus, and family history of CAD were significant
predictors of thoracic aortic plaque (Table 2
). Higher homocysteine level, total cholesterol and LDL cholesterol
levels, and lower HDL cholesterol level were significant predictors of
thoracic aortic plaque (Table 2)
. In the selected groups of 39 women
and of 43 men, homocysteine remained a significant marker of thoracic
aortic plaque (all p < 0.001). There was a positive correlation
(r = 0.48; p = 0.0001) between the homocysteine plasma
levels and the thoracic aortic score, as well as between the plasma
homocysteine levels and the grades of aortic intimal changes
(p = 0.0008). Multivariate logistic regression analysis of
homocysteine level, age, sex and others risk factors revealed four
independent predictors of thoracic atherosclerotic disease:
homocysteine, age, LDL cholesterol, and diabetes (Table 3
). By stepwise multiple regression analysis, homocysteine, age, LDL
cholesterol, and male gender were also independent predictors of the
aortic score (Table 3)
.
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Table 2.. Univariate Analysis of Risk Factors Related to the
Presence of Thoracic Aortic Atherosclerotic Plaque and of Significant
Coronary Atherosclerosis*
|
|
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Table 3.. Multivariate Analysis of Risk Factors Related to the
Presence and Severity of Thoracic Aortic
Atherosclerosis*
|
|
Homocysteine and CAD
Coronary angiography revealed atherosclerotic coronary arteries in
39 patients (48%): mildly atherosclerotic coronary lesions in 15
patients (18%), one-vessel disease in 4 patients (5%), two-vessel
disease in 12 patients (15%), and three-vessel disease in 8 patients
(10%). The remaining 43 patients (52%) were found to have strictly
normal coronary arteries on angiographic evaluation. Patients with
significant angiographic CAD had higher homocysteine levels (Table 2)
.
There was a correlation between the homocysteine levels and the
angiographic grades of coronary lesions (r = 0.34;
p = 0.0008). After adjustment by age, gender, and conventional risk
factors, homocysteine was identified as an independent predictor of
significant angiographic CAD (odds ratio, 1.13; 95% confidence
interval, 1.03 to 1.24).
|
Discussion
|
|---|
Homocystinuria is a rare autosomal recessive disease characterized
by markedly elevated plasma homocysteine level that results in severe
neurologic manifestations, widespread vascular thromboses, and early
death from rapidly progressive atherosclerosis.19
The most
common genetic disorder involved in homocystinuria is a deficiency of
cystathionine ß-synthetase. Deficiencies of other enzymes, such as
5,10-methyltetrahydrofolic acid reductase and methionine synthetase,
have also been reported.20
Case-control and prospective
studies reported that increased plasma homocysteine level in patients
who do not have homozygous homocystinuria is common, occurring in
approximately 5 to 7% of the general population,21
22
and
it is associated with a greater likelihood of atherosclerotic vascular
disease compared to that in the general
population.10
23
24
Thus, the United States Physician
Heath Study identifies homocysteine as an independent risk factor for
myocardial infarction.2
A meta-analysis of 27
studies estimated that 10% of the risk of CAD was due to elevated
blood level of homocysteine.24
Our study confirms that
homocysteine level correlated well with the presence and severity of
CAD evaluated angiographically.4
Increased plasma
homocysteine levels are also related to stroke, extracranial carotid
artery disease, and peripheral vascular
diseases.6
7
8
9
25
26
The current prospective TEE study
identified plasma homocysteine level as a marker of the presence
and severity of thoracic aortic atherosclerotic lesions, independent of
age, gender, hypertension, history of smoking, lipid parameters,
diabetes mellitus, and family history of CAD. This finding is
consistent with the observation of Konecky et al.11
Although the exact mechanism has not been fully elucidated,
homocysteine may act through many mechanisms, including direct injury
to endothelial cells, platelet activation, and effects on clotting
factors.5
We found a positive correlation between
homocysteine and age, illustrating that homocysteine increases with age
for reasons that remain unclear.23
27
Although some
studies did not report an association between serum cholesterol and
homocysteine,7
a correlation with LDL cholesterol was
present in our study, as reported by Wu et al.28
Plasma
levels of both folic acid and vitamin B12 were negatively
correlated to plasma homocysteine in the current study, in agreement
with previous series in normal subjects or coronary
patients.29
30
It is known that vitamin supplementation
with folic acid, pyridoxine, and vitamin B12 reduces
homocysteine level, but the benefit of such a treatment in the
prevention of mortality and morbidity from vascular atherosclerotic
disease remains uncertain.5
31
The present study is limited by several aspects. No quantitative
standard method has yet been established for assessing the severity of
aortic atherosclerosis. It is possible, even with a multiplane probe,
that we have slightly underestimated the incidence of atherosclerotic
plaques in the aorta, especially in the upper ascending aorta due to
the interposition of the trachea. The aortic atherosclerotic score
selecting the largest plaques may also have underestimated or
overestimated the severity of the thoracic aortic atherosclerosis,
which is a diffuse but not a uniform process. This method does not
consider complicated atheromatous plaques like mobile debris causing
embolism downstream. However, using the aortic score, we found a strong
relation between homocysteine and severity of aortic atherosclerosis.
Furthermore, atherosclerotic changes in the thoracic aorta have been
widely studied using TEE,12
13
14
and an excellent
reproducibility of transesophageal grading and stratification of
atheroma in the thoracic aorta has been reported.14
32
In
this study, patients were selected for valvular heart disease.
Nevertheless, no random sample of the general population undergoes TEE,
and this group of valvular patients provided the opportunity to study a
population almost similar to the general population for standard risk
factors.33
In conclusion, plasma homocysteine level is a marker of the severity of
thoracic aortic atherosclerosis detected by multiplane TEE. This
finding emphasizes the role of homocysteine as a marker of
atherosclerotic lesions in the major arterial locations. Because folic
acid and vitamins B6 and B12 may reduce or even
normalize plasma homocysteine level, interventional randomized
controlled trials on the effectiveness of such treatment on the primary
and secondary prevention of cardiovascular morbidity and mortality are
now required.
|
Footnotes
|
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Abbreviations: CAD = coronary
artery disease; HDL = high-density lipoprotein; LDL = low-density
lipoprotein; TEE = transesophageal echocardiography
Received for publication December 22, 1999.
Accepted for publication May 12, 2000.
|
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TOP
Abstract
Introduction
