© 1998 American Heart Association, Inc.
Original Contributions |
Carotid and Femoral Artery Wall Thickness and Stiffness in Patients at Risk for Cardiovascular Disease, With Special Emphasis on Hyperhomocysteinemia
From the Department of Medicine, Division of General Internal Medicine (T.J.S., F.W.P.J.v.d.B., G.H.J.B., H.W., A.F.H.S.), the Department of Medical Statistics (T.d.B.), and the Clinical Vascular Laboratory (H.v.L.), University Hospital Nijmegen, Nijmegen, The Netherlands.
Correspondence to T.J. Smilde, MD, Department of Medicine, Division of General Internal Medicine 541, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail t.smilde{at}aig.azn.nl
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Abstract |
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Abstract—Recent developments in ultrasound technology enable the noninvasive measurement of structural and functional vessel wall changes. Until now, the effect of homocysteine on the arterial wall has remained unclear: reports on intima-media thickness (IMT) yield conflicting results, whereas data on vessel wall stiffness are lacking. Because several cardiovascular risk factors result in an increased IMT or stiffness, different groups at risk for atherosclerotic disease, with special emphasis on hyperhomocysteinemia, were studied. Nineteen patients homozygous and 14 subjects heterozygous for cystathionine ß-synthase (CBS) deficiency, 21 patients with familial hypercholesterolemia (FH), 15 patients with essential hypertension, 20 smokers, and 28 control subjects were studied. The IMT values (both right and left) of the common carotid artery (CCA), bulb (BUL), internal carotid artery (ICA), and common femoral artery (CFA) were measured in millimeters by high-resolution ultrasound (Biosound). The distensibility (DC, in 10-3 · kPa-1) and compliance (CC in mm2 · kPa-1) coefficients of the CCA (right and left) and CFA (right) were determined by a wall track system (Pie Medical). The mean IMT of the posterior wall in the CCA was 0.70±0.09 mm in healthy controls. For patients with vascular disease, FH, and hypertension and in smokers, the mean CCA IMT was larger, whereas no major differences in IMT were observed in patients either homozygous or heterozygous for CBS deficiency. The DC and CC in the right CCA were 23.5±6.9 (10-3 · kPa-1) and 0.9±0.3 (mm2 · kPa-1) in healthy subjects, slightly lower in patients homozygous for CBS deficiency, and clearly lower in patients with vascular disease, FH, and hypertension. No positive correlation was found between plasma homocysteine level and either IMT, CC, or DC. Because smoking was a confounder in each risk group, a stepwise regression analysis was carried out to assess the contribution of each risk factor on IMT and arterial wall stiffness. Age explained most of the variation in IMT of the CCA (coefficient of determination R2 of 0.34), whereas R2 values for serum low density lipoprotein cholesterol, smoking (pack-years), and systolic blood pressure were 0.08, 0.07, and 0.06, respectively. Homocysteine did not contribute to variation in IMT in both the CCA and CFA. Age and smoking contributed to the variation in IMT in the CFA. The variation in DC and CC in the right CCA and right CFA could in part be explained by age, low density lipoprotein cholesterol, and blood pressure. Plasma homocysteine concentration explained only a small proportion of the variation in DC in the CCA (R2=0.02) and in CC in the CFA (R2=0.04). In this study, no relationship was found between homocysteine level and the thickness of the arterial wall, with only a marginal influence on stiffness.
Key Words: intima-media thickness • artery wall stiffness • cardiovascular risk factors • hyperhomocysteinemia
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Introduction |
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Established risk factors for atherosclerotic disease are hypercholesterolemia, hypertension, and smoking. In the last 10 years, hyperhomocysteinemia has also been recognized as a risk factor for thromboembolism and atherosclerosis.1 2 3 4 Arterial intima-media thickness (IMT) and functional vessel wall properties, like distensibility and compliance, of superficial arteries (carotid and femoral)5 6 7 8 9 10 11 can be evaluated by high-resolution B- and M-mode ultrasound and are associated with the presence of atherosclerotic disease elsewhere.5 6 7 Because various risk factors may affect the arterial wall to a different extent, it is of interest to explore whether the changes can be measured by these noninvasive ultrasound techniques in patients with different cardiovascular risk factors to monitor either progression or regression of vessel wall damage.
The mechanism by which homocysteine exerts its effects on the arterial wall is still unclear. Until now, reports on an association of hyperhomocysteinemia with increased IMT have yielded conflicting results.12 13 14 15 16 Furthermore, no ultrasound data are available on the effect of elevated levels of homocysteine on functional vessel wall properties. Several studies indicate that even mild hypercholesterolemia is associated with intima-media thickening, which may be reduced by cholesterol lowering.17 18 19 Little is known about the influence of hypercholesterolemia on arterial stiffness in the carotid and femoral artery.20 Patients with hypertension demonstrate increases in IMT,21 and even in borderline hypertension, the distensibility and compliance of the common carotid artery are diminished.11 Smoking is an important risk factor for cardiovascular disease, which may affect both IMT and arterial wall stiffness.22 23
The aim of the current study was to assess the contribution of different risk factors for cardiovascular disease, such as hyperlipidemia, hypertension, and smoking, with special emphasis on severe and mild hyperhomocysteinemia, to the variation in IMT, distensibility, and compliance.
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Methods |
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In a cross-sectional design, 19 patients with homocystinuria due to homozygous cystathionine ß-synthase (CBS) deficiency, 14 of their heterozygous relatives, and 15 patients with premature vascular disease (coronary heart, cerebral vascular, and/or peripheral vascular disease before the age of 50 years) in the presence of mild hyperhomocysteinemia were investigated. All received vitamin supplements (vitamin B6, folic acid, and vitamin B12). In addition, 21 patients with familial hypercholesterolemia characterized by elevated plasma LDL cholesterol levels and the presence of tendon xanthomas were studied. They participated in a cholesterol-lowering trial and were in the placebo run-in phase by the time measurements were performed. Furthermore, 20 subjects who had smoked for at least 20 pack-years (1 pack-year was defined as smoking 20 cigarettes a day for a period of 1 year), 15 patients with untreated essential hypertension (systolic blood pressure >160 mm Hg and diastolic blood pressure >95 mm Hg, measured on 3 separate occasions after 5 minutes of supine rest), and 28 nonsmoking healthy controls were studied. In all participants, special attention was given to the presence of cardiovascular disease, medication, smoking behavior, and family medical history. Patients with diabetes or impaired renal function were excluded. None of the participants used antihypertensive drugs. After an overnight fast, serum total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and homocysteine levels were measured. The study was approved by the Ethics Committee of our hospital, and informed consent was obtained from each individual.
Homocysteine and Cholesterol Determination
An EDTA-blood sample for determination of the fasting
homocysteine concentration was obtained and centrifuged for 10
minutes at 1800g, and the plasma was stored at -30°C
until analysis. In all hyperhomocysteinemic subjects, both the
homozygotes and heterozygotes for CBS deficiency as well as the
vascular disease patients with mild hyperhomocysteinemia, an oral
methionine loading test was performed. During this procedure, an oral
dose of L-methionine (0.1 g/kg body weight) was
administered in orange juice. Six hours after the methionine load, a
second EDTA-plasma sample was drawn for postload homocysteine
concentration. Total (free plus bound) homocysteine levels were
measured by using tri-n-butylphosphine as the reducing agent
and ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate as the
fluorochromophore, followed by high-performance liquid
chromatography with fluorescence
detection.24 Hyperhomocysteinemia was defined as
elevated fasting homocysteine levels (>18 µmol/L) and/or a
postmethionine load homocysteine level >97.5th percentile in healthy
controls, ie, 51 µmol/L for females and 54 µmol/L for
males.25 Plasma cholesterol and
triglycerides were determined by commercially available
enzymatic methods (Boehringer Mannheim No. 237574 and Sera-PAK,
Miles No. 6639, respectively); to determine HDL
cholesterol, the PEG 6000 precipitation method was
used.26 LDL cholesterol was
calculated by the Friedewald formula. Normal values of serum total
cholesterol were defined as 4.7 to 6.5 mmol/L (divide
by 0.026 for mg/dL); of HDL cholesterol, 1.10 to 1.70
mmol/L for females and 0.95 to 1.50 mmol/L for males; of LDL
cholesterol, <4.5 mmol/L; and of
triglycerides, 0.8 to 2.0 mmol/L (divide by 0.011 for
mg/dL).
Ultrasound Imaging
The ultrasound examinations were performed using a Biosound
phase-2 real-time scanner (Biosound Esaote) equipped with a 10-MHz
transducer, 2 monitors for displaying the B-mode ultrasound images, and
a spectrum analyzer for the Doppler signals. Three 10-mm
segments were scanned bilaterally: the distal portion of the common
carotid artery (CCA), the carotid bulb (BUL), and the proximal portion
of the internal carotid artery (ICA). Images were "grabbed" by a
computer, stored on optical disk, and analyzed with a
semiautomatic software program (Eurequa, TSA
Co).27 IMT measurements were performed on both
anterior and posterior walls of the CCA and BUL, and on the posterior
wall of the ICA and right side of the common femoral artery (CFA).
Intraobserver and interobserver coefficients of variation were
<5%.28
Distensibility and Compliance
The vessel wall movement-detector system has been described in
detail by Hoeks et al.10 The system used
consisted of a wall track system (Pie Medical) and a data acquisition
system connected to a personal computer. With a 7.5-MHz transducer, a
2-dimensional B-mode image was made from the CCA, 2 cm proximal to the
BUL. An M-mode line perpendicular to the vessel was selected. After
switching to M-mode, storage of data was started during 3 to 5 cardiac
cycles. The RF signals during this period were digitized and
temporarily stored. For both the anterior and posterior wall windows,
the cumulative change in phase between successive RF lines was
calculated. The difference between the anterior and posterior wall
represents arterial distension, which is the change
in diameter during 1 heart cycle. Data for arterial
diastolic diameter (D) and distension (
D) were obtained
for each heart beat. Brachial blood pressure was measured every 3
minutes with a semiautomatic oscillometric device (Dinamap). The mean
of the total blood pressure recordings during 40 minutes was
taken. Pulse pressure was defined as systolic minus
diastolic blood pressure (P). Vessel wall properties
were calculated according to the following equations:
 | (1) |
 | (2) |
Statistical Analysis
The Pearson correlation was used to assess the
univariate association between different risk factors and
IMT, DC, and CC in different segments of the carotid and femoral artery
and the correlation between DC and IMT and CC and IMT. To determine
which factor explained a given dependent variable, a stepwise
regression procedure was carried out. Dependent variables were IMT,
DC, and CC. Independent variables were age, sex, body mass index,
blood pressure, smoking (pack-years), and LDL cholesterol,
HDL cholesterol, triglyceride and homocysteine
levels. In addition, a regression analysis was performed in
which the interactions (cross products) of smoking with each of the
above-mentioned independent variables were added as independent
variables. Statistical analyses were performed using SAS
(version 6.12, SAS Institute Inc).
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Results |
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Clinical and biochemical characteristics of the study groups are summarized in Table 1
. The IMT of the
posterior and anterior walls of the different groups are given in Table 2 and functional vessel wall properties
are presented in Table 3. In
healthy controls, the IMT of the posterior wall of the CCA was
0.70±0.09 mm. In patients with premature vascular disease, FH,
and hypertension and in smokers, the IMT was larger, especially when
the transducer was moved cranially along the carotid artery. The IMT of
the posterior wall in the BUL was 0.88±0.25 in healthy controls and
1.31±0.45, 1.25±0.35, 1.36±0.36, and 1.23±0.37 mm in patients
with premature vascular disease, patients with FH, hypertensives, and
smokers, respectively. Pearson correlation coefficients between
different risk factors and dependent variables such as IMT, DC, and
CC are given in Table 4. The levels of
serum LDL cholesterol, blood pressure, body mass index, and
smoking were positively correlated with the IMT in the carotid artery,
whereas smoking and LDL cholesterol were positively
correlated with the IMT of the CFA (Table 4). A negative correlation
was found between homocysteine and IMT in the CCA. The results of the
stepwise regression procedure are given in Table 5. Age, serum LDL
cholesterol, smoking, and systolic blood pressure
explained partially the variation in arterial wall
thickness. The effect of LDL cholesterol was especially
important in the ICA, where 17% of the variation in IMT could be
explained by LDL cholesterol. When smoking and elevated LDL
cholesterol were present at the same time, the effect
on IMT in the ICA increased to almost 30%. For the mean IMT in the
carotid artery, ie, after combining the measurements of the posterior
and anterior walls of the CCA and BUL and the posterior wall of the
ICA, the contribution of LDL cholesterol alone on IMT was
9% but increased to 30% whenever patients smoked. Homocysteine showed
no relationship with IMT, and there was no additional effect of
homocysteine on the effect of smoking on IMT.
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The DC and CC of the right CCA were 23.5±6.9
10-3 · kPa-1 and
0.9±0.3 mm2 ·
kPa-1 in healthy controls and tended to be lower
in patients at risk. The levels of serum LDL cholesterol,
blood pressure, and body mass index were negatively correlated with CC
and DC in both the CCA and CFA. Smoking was negatively correlated with
the DC in the right CCA only. There was a strong, negative correlation
between IMT and the DC and the CC in the CCA and CFA. No negative
correlation was found between functional vessel wall properties and
homocysteine levels. Age, serum LDL cholesterol, and
systolic blood pressure partially explained the variation in
DC. Plasma homocysteine contributed to a small proportion of the
variation in the DC of the CCA and in the CC of the CFA (Table 5
).
There was only a slight increase in the effect of homocysteine on the
CC of the CFA whenever subjects smoked (from 4% to 7%). The diameters
of both the CCA and CFA were explained by age and sex only, 9% and
10%, respectively, in the CCA and 5% and 23%, respectively, in the
CFA. Homocysteine did not contribute to the variation in
systolic diameter.
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Discussion |
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LDL cholesterol, systolic blood pressure, and smoking are related to the IMT in the carotid artery. The effect of serum cholesterol on arterial wall thickness is well known, and measuring IMT in intervention trials is an important tool to estimate the progression or regression of early atherosclerosis.17 18 19 In the current study, the contribution of LDL cholesterol to IMT was more pronounced in the ICA, especially whenever patients smoked. Therefore, it is important to consider local changes and more general changes in IMT separately, especially in patients with increased LDL cholesterol. Higher LDL cholesterol levels result in stiffer arteries, although the effect on DC and CC was less pronounced than on IMT.
Increases in IMT and the stiffness of carotid arteries have been demonstrated in patients with hypertension,11 21 29 but it is still not known whether this stiffness is a consequence of an elevated distending pressure or the result of intima-media thickening in the vessel wall. Smoking contributed to IMT thickening but did not explain the variation in the DC. It is well known that smoking even 1 cigarette causes a short-term increase in arterial wall stiffness, whereas no obvious long-term effect of smoking on arterial stiffness has been observed.23
Plasma homocysteine was not related to IMT in both the CCA and CFA, despite a marked increase in homocysteine in patients homozygous for CBS deficiency. Vascular disease patients were selected because of the presence of early-onset disease (ie, before the age of 50 years) and the presence of mild hyperhomocysteinemia; unfortunately, all vascular disease patients smoked, thereby disturbing an independent analysis of the effects of vascular disease alone versus those of smoking alone. In our study, homocysteine did not add to the effect of smoking on arterial wall thickness. However, homocysteine contributed to a minor proportion of the variation in the DC in the CCA and in the CC in the CFA on the right side, and this contribution increased whenever patients smoked. Age, LDL cholesterol, and systolic blood pressure explained most of the observed variation in the DC.
In previous reports, data on the effect of homocysteine on
arterial wall thickness are conflicting. Clarke et
al15 reported that hyperhomocysteinemia is a weak
risk factor for asymptomatic extracranial carotid
atherosclerosis. The mean IMT of the posterior wall of
the CCA between heterozygous CBS subjects and controls was not
statistically different. In 1993, Malinow et al12
published a study of 310 case-control pairs. Subjects without a history
of occlusive arterial disease were defined as cases when at
least 2 unilateral measurements of the carotid artery (CCA, BUL, and
ICA) showed an increased IMT >1.6 mm in the CCA. Paired controls
were selected among persons without evidence of carotid thickening. In
that study, levels of homocysteine were positively correlated with
carotid arterial wall thickness. Nevertheless, this
positive correlation was no longer significant after adjustment for
age, waist-hip ratio, serum cholesterol, smoking, and blood
pressure. Rubba et al14 found no differences
between IMT in patients homozygous for homocystinuria compared with
controls. This result is in accordance with that of de Valk et
al,13 who also reported no difference in IMT
between heterozygous relatives of patients with homozygous
homocystinuria and controls. Tonstad et al30
found a positive relation between homocysteine level and IMT in
children with FH and controls. No subject had homocysteine levels
>14.1 µmol/L. In a study of elderly subjects, homocysteine was
associated with isolated systolic hypertension. In this
population of older subjects, homocysteine was related to
atherosclerosis only among normotensive
individuals.31 Duplex scanning of the carotid
artery was performed to assess the amount of stenosis, but IMT
was not measured. Aronow et al32 demonstrated
that high plasma homocysteine levels and low plasma folate and vitamin
B12 levels were associated with a higher
prevalence of extracranial carotid arterial disease in a
cohort of elderly women. Selhub et al16 found
that nonfasting plasma homocysteine concentrations were associated with
extracranial carotid artery stenosis in a population-based
cohort of elderly people with a mean age of 75 years. In this study,
the risk of stenosis 
25% was increased even in subjects with
homocysteine levels considered normal or slightly elevated. It is
possible that the stenosis measured in the studies of Selhub,
Aronow, and Sutton-Tyrrell31 and their coworkers
was not specific arterial wall thickening but the result of
arterial thrombosis.16 31 32
Although our groups are relatively small and smoking is a major confounder, it is remarkable that arterial wall thickening could not be explained by homocysteine level, despite the almost 10-fold elevated in patients homozygous for CBS deficiency. In contrast, LDL cholesterol, blood pressure, and smoking all contributed to IMT. The effect of LDL cholesterol was stronger when the transducer was moved cranially along the carotid artery, especially whenever patients smoked. Furthermore, smoking contributed to IMT in the CFA. The effect of homocysteine on arterial wall stiffness was only marginal. Because cross-sectional and prospective studies demonstrate an association between hyperhomocysteinemia and atherosclerotic disease,1 2 3 4 we suggest that other mechanisms may contribute to vascular obstruction, such as activation of the coagulation cascade or impaired NO generation by the endothelium. It is also possible that homocysteine has an important synergistic effect with other (unknown) factors. A synergistic effect of homocysteine and smoking on arterial wall thickness could not be demonstrated in this study, although some additional decrease in DC was observed when both smoking and hyperhomocysteinemia were present. Furthermore, the effect of homocysteine in genetically inherited disorders may differ from that in the control population.
A criticism on the method used for determining DC and CC in the CCA could be the measurement of pulse pressure at the site of the brachial artery rather than the CCA, which was neglected because of the noninvasive nature of the study. We assumed that the pulse pressure in the brachial artery was representative of CCA pressure. The positive relationship between this pulse pressure and the relative diameter increase of the CCA during systole, as found by Reneman et al,33 supports this assumption. It is well known that pulse pressure measured on the arm is not representative of pulse pressure in the femoral artery; however, we presumed that the error is systematic and thus does not affect comparative studies.
Because of an inherent disadvantage of a cross-sectional study, the time relationship between structural and functional vessel wall changes cannot be answered. The obvious correlation between structural and functional changes indicates that they both express the same phenomenon. Long-term follow-up studies in healthy subjects and patients with asymptomatic cardiovascular risk factors are necessary to establish the additional value of measuring functional as well as structural vessel wall properties.
In conclusion, age, LDL cholesterol, blood pressure, and smoking contribute to a variation in arterial wall thickness. The DC of the CCA was influenced by age, LDL cholesterol, and systolic blood pressure. Homocysteine did not explain any variation in IMT and only marginally contributed to the variation in DC in the CCA and in CC in the CFA. Long-term, prospective, follow-up studies in patients homozygous for CBS deficiency and in the general population are necessary to reveal more of the effects of homocysteine on the arterial wall.
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Acknowledgments |
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This study was supported by the Dutch Institute of Internal Medicine (support to G.H.J.B.).
Received April 12, 1997; accepted June 6, 1998.
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 M. Junyent, R. Gilabert, D. Zambon, M. Pocovi, M. Mallen, M. Cofan, I. Nunez, F. Civeira, D. Tejedor, and E. Ros Femoral Atherosclerosis In Heterozygous Familial Hypercholesterolemia: Influence Of The Genetic Defect Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): 580 - 586. [Abstract] [Full Text] [PDF]
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 A. V. Ovechkin, N. Tyagi, U. Sen, D. Lominadze, M. M. Steed, K. S. Moshal, and S. C. Tyagi 3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L905 - L911. [Abstract] [Full Text] [PDF]
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A. C. Sposito, S. Gonbert, G. Turpin, M. J. Chapman, and J. Thillet Common Promoter C516T Polymorphism in the ApoB Gene Is an Independent Predictor of Carotid Atherosclerotic Disease in Subjects Presenting a Broad Range of Plasma Cholesterol Levels Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2192 - 2195. [Abstract] [Full Text] [PDF]
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 C. M. Hutter, M. A. Austin, and S. E. Humphries Familial Hypercholesterolemia, Peripheral Arterial Disease, and Stroke: A HuGE Minireview Am. J. Epidemiol., September 1, 2004; 160(5): 430 - 435. [Abstract] [Full Text] [PDF]
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 D. N. O'Neal, G. Dragicevic, K. G. Rowley, M. Z. Ansari, N. Balazs, A. Jenkins, and J. D. Best A Cross-Sectional Study of the Effects of Type 2 Diabetes and Other Cardiovascular Risk Factors on Structure and Function of Nonstenotic Arteries of the Lower Limb Diabetes Care, January 1, 2003; 26(1): 199 - 205. [Abstract] [Full Text] [PDF]
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 G. L. Baumbach, C. D. Sigmund, T. Bottiglieri, and S. R. Lentz Structure of Cerebral Arterioles in Cystathionine {beta}-Synthase-Deficient Mice Circ. Res., November 15, 2002; 91(10): 931 - 937. [Abstract] [Full Text] [PDF]
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 K.-S. Cheng, D. P. Mikhailidis, G. Hamilton, and A. M. Seifalian A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors Cardiovasc Res, June 1, 2002; 54(3): 528 - 538. [Abstract] [Full Text] [PDF]
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J. D. Symons, A. E. Mullick, J. L. Ensunsa, A. A. Ma, and J. C. Rutledge Hyperhomocysteinemia Evoked by Folate Depletion: Effects on Coronary and Carotid Arterial Function Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 772 - 780. [Abstract] [Full Text] [PDF]
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 K. E. Ferrier, M. H. Muhlmann, J.-P. Baguet, J. D. Cameron, G. L. Jennings, A. M. Dart, and B. A. Kingwell Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension J. Am. Coll. Cardiol., March 20, 2002; 39(6): 1020 - 1025. [Abstract] [Full Text] [PDF]
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R. A.J.M. van Dijk, J. A. Rauwerda, M. Steyn, J. W.R. Twisk, and C. D.A. Stehouwer Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness: A 2-Year, Randomized, Placebo-Controlled Trial Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 2072 - 2079. [Abstract] [Full Text] [PDF]
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A. M. Dart and B. A. Kingwell Pulse pressure--a review of mechanisms and clinical relevance J. Am. Coll. Cardiol., March 15, 2001; 37(4): 975 - 984. [Abstract] [Full Text] [PDF]
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 F. A. Dinenno, P. P. Jones, D. R. Seals, and H. Tanaka Age-associated arterial wall thickening is related to elevations in sympathetic activity in healthy humans Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1205 - H1210. [Abstract] [Full Text] [PDF]
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 L. A. Bortolotto, M. E. Safar, E. Billaud, C. Lacroix, R. Asmar, G. M. London, and J. Blacher Plasma Homocysteine, Aortic Stiffness, and Renal Function in Hypertensive Patients Hypertension, October 1, 1999; 34(4): 837 - 842. [Abstract] [Full Text] [PDF]
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 A. G. Bostom and J. Selhub Homocysteine and Arteriosclerosis : Subclinical and Clinical Disease Associations Circulation, May 11, 1999; 99(18): 2361 - 2363. [Full Text] [PDF]
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