Hyperhomocysteinemia is Associated with Aortic Atheroma Progression in Stroke/TIA Patients

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DOI: 10.3389/fneur.2010.00131 · Source: PubMed
Significance: Aortic arch (AA) atheroma and AA atheroma progression are independent risk factors for recurrent vascular events in stroke/transient ischemic attack (TIA) patients. Total homocysteine level (tHcy) is an independent risk marker for atherosclerosis including that found in AA. The purpose of this study was to prospectively test the association between AA atheroma progression and tHcy. Methods: This is a cohort study of 307 consecutive hospitalized stroke/TIA patients undergoing transesophageal echocardiogram (TEE) as a part of their clinical workup. Measurable AA atheroma was detected in 167 patients of whom 125 consented to a protocol-mandated follow-up TEE at 12 months. Patients had evaluation for vascular risk factors, dietary factors (folate, B12 and pyridoxine), and methylene tetrahydrofolate reductase (MTHFR) polymorphism. One hundred eighteen stroke/TIA patients had tHcy, acceptable paired AA images, and detailed plaque measurements. An increase by ≥1 grade of AA atheroma was defined as progression. Results: Of the 118 patients, 33 (28%) showed progression and 17 (14%) showed regression of their index arch lesion at 1 year. tHcy (≥14.0 μmol/l) was significantly associated with progression on both univariate (RR = 3.4, 95% CI 2.0-5.8) and multivariate analyses (adjusted RR = 3.6, 95% CI 2.2-4.6). The changes in AA plaque thickness (r(2) = 0.11; p < 0.001) and AA plaque area (r(2) = 0.08; p = 0.002) correlated with tHcy. tHcy was associated with change in plaque thickness over 12 months, independent of age, dietary factors, renal function and MTHFR polymorphism (Standardized β-coefficient 0.335, p = 0.02). Conclusions: Our results validate the association and a linear correlation between tHcy and progression of AA atheroma.
www.frontiersin.org November 2010 | Volume 1 | Article 131 | 1
Original research article
published: 26 November 2010
doi: 10.3389/fneur.2010.00131
Hyperhomocysteinemia is associated with aortic atheroma
progression in stroke/ TIA patients
Souvik Sen1*, P. Leema Reddy2, Raji P. Grewal3, Marjorie Busby 4, Patricia Chang 4 and Alan Hinderliter4
1 Department of Neurology, University of South Carolina School of Medicine, Columbia, SC, USA
2 The Neurogenetics Foundation, Cranbury, NJ, USA
3 Neuroscience Institute, Saint Francis Medical Ceter, Trenton, NJ, USA
4 University of North Carolina, Chapel Hill, NC, USA
Significance: Aortic arch (AA) atheroma and AA atheroma progression are independent risk
factors for recurrent vascular events in stroke/transient ischemic attack (TIA) patients. Total
homocysteine level (tHcy) is an independent risk marker for atherosclerosis including that
found in AA. The purpose of this study was to prospectively test the association between AA
atheroma progression and tHcy. Methods: This is a cohort study of 307 consecutive hospitalized
stroke/TIA patients undergoing transesophageal echocardiogram (TEE) as a part of their clinical
workup. Measurable AA atheroma was detected in 167 patients of whom 125 consented to
a protocol-mandated follow-up TEE at 12 months. Patients had evaluation for vascular risk
factors, dietary factors (folate, B12 and pyridoxine), and methylene tetrahydrofolate reductase
(MTHFR) polymorphism. One hundred eighteen stroke/TIA patients had tHcy, acceptable paired
AA images, and detailed plaque measurements. An increase by 1 grade of AA atheroma
was defined as progression. Results: Of the 118 patients, 33 (28%) showed progression
and 17 (14%) showed regression of their index arch lesion at 1 year. tHcy (14.0 μmol/l) was
significantly associated with progression on both univariate (RR = 3.4, 95% CI 2.0–5.8) and
multivariate analyses (adjusted RR = 3.6, 95% CI 2.2–4.6). The changes in AA plaque thickness
(r2 = 0.11; p < 0.001) and AA plaque area (r2 = 0.08; p = 0.002) correlated with tHcy. tHcy was
associated with change in plaque thickness over 12 months, independent of age, dietary
factors, renal function and MTHFR polymorphism (Standardized β-coefficient 0.335, p = 0.02).
Conclusions: Our results validate the association and a linear correlation between tHcy and
progression of AA atheroma.
Keywords: cerebrovascular disease, stroke, cardiac embolism, aorta, homocysteine
Edited by:
Scott Silliman, University of Florida,
Reviewed by:
Kevin M. Barrett, Mayo Clinic, USA
Nader Antonios, University of Florida,
Souvik Sen, Department of Neurology,
University of South Carolina School of
Medicine, 8 Medical Park Drive, Suite
420, Columbia, SC 29203, USA.
e-mail: souvik.sen@uscmed.sc.edu
not been developed and factors that may influence the association
between homocysteine and atherosclerosis such as diet and genetic
polymorphism were not assessed.
In order to respond to these issues, we designed a prospective
12-month study to analyze sequential changes in AA atheroma and
to examine the role of stroke risk factors in promoting the progres-
sion of AA atheroma. Measurements of the rate of progression
were obtained at two time points by using standardized criteria to
quantitate plaque thickness and measure sectional areas. In order
to ensure accurate sequential measurements at the same location,
we established imaging landmarks in each segment.
Hyperhomocysteinemia is an independent risk factor for
atherosclerotic vascular disease including cerebrovascular disease
(Coull et al., 1990; Stampfer et al., 1992; Malinow et al., 1993;
Spence et al., 1999), coronary artery disease (Stampfer et al.,
1992), peripheral vascular disease (Malinow et al., 1989), and
aortic plaque thickness (Konecky et al., 1997; Tribouilloy et al.,
2000). Common factors known to influence homocysteine levels
are age, intake of vitamin B12, folic acid levels, and genetic meth-
ylene tetrahydrofolate reductase (MTHFR) polymorphism (Kaul
et al., 2006). Therefore, an additional objective of this study was
Significant aortic arch (AA) atheroma is the second most prevalent
cardioembolic risk factor for stroke after atrial fibrillation, and is
present in 16–20% of all stroke and transient ischemic attack (TIA)
patients (Sen et al., 2000; Cheitlin et al., 2003). While there is no
definitive treatment (Tunick and Kronzon, 2000), AA atheroma is
an independent risk factor for new and recurrent stroke (Amarenco
et al., 1994; The French Study of Aortic Plaques in Stroke Group,
1996). Recently, we have shown that AA atheroma progression is
an independent risk factor for recurrent vascular events in stroke/
TIA patients (Sen et al., 2007). Detection and measurement of AA
atheroma is a safe procedure in stroke/TIA patients using the well-
established, validated, and cost-effective method of transesopha-
geal echocardiogram (TEE) (Daniel et al., 1991; McNamara et al.,
1997; Cheitlin et al., 2003). In a retrospective analysis of sequential
TEE data, we have shown that AA atheroma has a high rate of
progression (Sen et al., 2002); in 29% of stroke/TIA patients AA
atheroma worsened 1 grade in 9 months compared to <10% that
worsened annually in the carotid arteries (Olin et al., 1998; Liapis
et al., 2000; Schminke et al., 2000). The study was limited by the fact
that methods to control for the location of those measurements had
Frontiers in Neurology | Neurocritical and Neurohospitalist Care November 2010 | Volume 1 | Article 131 | 2
Sen et al. Hyperhomocysteinemia and aortic atheroma progression
plaque progression and regression in the ascending (κ = 0.77),
arch (κ = 0.85) and descending segment (κ = 0.86) of thoracic
aorta. Excellent intraobserver reliabilities were noted for the first
observer (κ = 0.93–1.00) and the second observer (κ = 0.91–0.94).
Addition to grading of plaque thickness, cross-sectional plaque area
was measured by tracing the outline of the atheroma as described
by Khoury et al. (1998) and Ti et al. (2003).
demographIcs, rIsk Factors and etIology oF stroke
Cerebrovascular risk factors were classified as follows: age was based
on the age at the time of presentation for initial TEE and dichot-
omized around a mean age of 65 years; hypertension was based on a
previous diagnosis or prescription of anti-hypertensive medication;
diabetes was based on a previous diagnosis with or without treatment
with an anti-diabetic agent; hypercholesterolemia was based on a pre-
vious diagnosis or prescription of cholesterol-lowering medications;
a cigarette smoker was defined as smoking 1 cigarette daily. A TIA was
defined as a brief episode of neurologic dysfunction caused by focal
brain or retinal ischemia, with clinical symptoms typically lasting
less than 1 h, and without evidence of acute infarction on diffusion
MRI scan (Albers et al., 2002). Patients suspected of complicated
migraine, seizures or presenting with vague neurological symptoms
were excluded. Stroke was defined as a persistent neurological defi-
cit of sudden onset (non-convulsive) lasting more than 24 h with
confirmation by infarction noted on diffusion weighted MRI or
follow-up CT, when MRI was not feasible (example Pacemaker).
Stroke etiology was classified using the Trial of Org 10172 in Acute
Stroke Treatment (TOAST) criteria (Adams et al., 1993).
homocysteIne measurement
Patients without renal failure (creatinine 2.5 mg/dl) were included
for assessment of fasting plasma homocysteine level (tHcy). None
were taking medications (example: Dilantin) known to elevate tHcy.
Fasting blood samples were transported on ice and plasma sepa-
rated and stored at 4°C until measurement of total tHcy using high
performance liquid chromatography with fluorescence detection.
mthFr polymorphIsm
Following informed consent, blood samples were col-
lected and genomic DNA was extracted (Puregene
Systems, Gentra). The MTHFR polymorphism was geno-
typed as previously described by PCR using the follow-
5-AGGACGGTGCGGTGAGAGTG-3 (Frosst et al., 1995). A 198
base pair (bp) product is amplified and following digestion with
Hinf1 (New England Biolabs), the common “C” allele of the C677T
polymorphism remains undigested (Frosst et al., 1995). However,
digestion of the PCR product containing the “T” polymorphism
results in the generation of two fragments (175 and 23 bp) which
are resolved by gel electrophoresis (6% polyacrylamide gel). The
allele frequency was obtained by direct gene counting.
dIetary assessment usIng Food Frequency questIonnaIre
The Block FFQ, a validated questionnaire (Subar et al., 2001) was
administered to all study patients. The 1998 version of the full-
diet Block FFQ (Block98) was used to convert information on
food and supplement consumption to average daily energy and
to assess whether the association between homocysteine and AA
atheroma progression is independent of these determinants of
homocysteine level.
materIals and methods
Three hundred and seven consecutive patients with stroke/TIA
underwent TEE assessment within 1 month of symptom onset, as
a part of their clinical evaluation to determine stroke etiology. All
patients received a brain CT and/or MRI to confirm the diagnosis of
stroke, had assessment of stroke risk factors, and were classified into
stroke sub-types based on clinical assessment of etiology. Exclusion
criteria were: absence of measurable aortic atheroma on the first
TEE, age <18 years, intracerebral hemorrhage, subarachnoid hemor-
rhage, coma and serious medical conditions limiting life expectancy.
Of these patients, 167 had evidence of aortic atheroma (measur-
able plaque 1 mm in ascending, arch or descending segment) and
125/167 eligible patients consented to a protocol-mandated follow-up
TEE at 12 months. One hundred eighteen (79 strokes and 39 TIAs)
had adequate paired aortic images allowing detailed measurements
of the AA plaque. Qualifying patients underwent a fasting plasma
homocysteine level measurement as part of their stroke risk assess-
ment at the time of admission for the index cerebrovascular event
prior to the initial TEE. Of these 118 patients, 116 provided blood
samples for assessment of MTHFR polymorphism and 110lled out
a self-administered food frequency questionnaire (FFQ) just prior to
the 12-month TEE. All patients enrolled in the study signed informed
consent and the study was approved by the Biomedical Institutional
Review Board of the University of North Carolina at Chapel Hill.
tee assessment oF aa atheroma
A comprehensive TEE with detailed imaging of the aorta was per-
formed using a Hewlett-Packard 21364A omniplane probe. Details
of the imaging procedure and quantification of AA atheroma have
been previously described (Sen et al., 2000). Briefly, the proximal
and mid-ascending aorta were imaged at a probe depth of approxi-
mately 30 cm with a multi-plane angle of 100–150° to view the ves-
sel in the long axis. Examination of the descending thoracic aorta
was accomplished by advancing the probe to the distal esophagus,
imaging the aorta in cross-section (at 0°), and then slowly with-
drawing the probe to image the more proximal segments. As the
transducer reached the AA, the multi-plane angle was rotated to
between 0° and 90° to acquire sequential short axis views.
Digital images were acquired of the diseased areas in each seg-
ment of the AA with annotation of the distance of the transducer
from the incisors. Identical locations in the AA were evaluated
on the 1-year examination, using the depth of the transducer,
plaque morphology, and (when available) surrounding anatomical
landmarks for guidance.
Two observers blinded to clinical data independently quanti-
fied atheroma size for each imaged segment. Plaque thickness was
measured as the maximal thickness of the intimal and medial lay-
ers and graded as mild (<1 mm), moderate (1–3.9 mm), or severe
(4 mm), using the criteria of Amarenco et al. (1994) AA atheroma
progression was defined as an increase in maximal thickness of the
plaque in the AA by 1 grade(s) and regression defined as a decrease
in maximal thickness by 1 grade(s). There was good interobserver
reliability between the two observers, in the assessment of aortic
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Sen et al. Hyperhomocysteinemia and aortic atheroma progression
level <14.0 mcm/l (0.08 ± 0.10 mm). The tHcy on baseline exami-
nation was higher (p = 0.001) in patients with progression of AA
atheroma (14.6 ± 1.3 mcm/l) than in those without progression
(9.7 ± 0.4 mcm/l). Although in a limited sample (N = 85), the conva-
lescent tHcy (measured >3 months from index event) was higher in
patients with progression of AA atheroma (N = 27, 13.9 ± 1.6 mcm/l)
than in those without progression (N = 58, 11.7 ± 0.9 mcm/l), the dif-
ference was not significant (p = 0.2). There were no significant differ-
ences between the progression and non-progression groups in total
cholesterol (189 ± 44 vs. 184 ± 39 mg/dl), LDL cholesterol (111 ± 44
vs. 105 ± 35 mg/dl), HDL cholesterol (51 ± 16 vs. 53 ± 17 mg/dl) and
serum triglycerides (158 ± 130 vs. 149 ± 82 mg/dl).
The frequency of the MTHFR 677T allele in the 116 subjects that
participated in the study was 0.328. There were 55 MTHFR 677C/C
homozygotes (45.2%), 46 677C/T heterozygotes (44.1%), and 15
677T/T homozygotes (10.7%). The observed MTHFR genotype
frequencies did not deviate from those predicted by the Hardy-
Weinberg equilibrium (p = 0.38, NS). ANOVA showed that MTHFR
genotype was not a significant determinant of plasma homocysteine
concentration (p = 0.43).
Of the 118 subjects, nutritional data was available in 110 sub-
jects. Although the progression group had a higher mean energy
intake (1546 kCal) compared with those who did not progress
(mean energy intake = 1306 kCal), the difference did not attain
statistical significance (p = 0.1). There was no significant differ-
ence between the progression and no-progression groups in the
energy adjusted folate (295 vs. 287 mcg, p = 0.69), energy adjusted
pyridoxine (1.48 vs. 1.42 mg, p = 0.65) and energy adjusted Vitamin
B12 (3.22 vs. 3.77 μg, p = 0.30).
There was no significant correlation (r2 = 0.01, p = 0.31) between
baseline AA plaque thickness on initial TEE and fasting plasma
homocysteine level. Also, a significant correlation (r2 = 0.01,
nutrient intake using values from the USDA Nutrient Database for
Standard. The Block 98 is an eight-page, scannable, quantitative
instrument that includes 109 food and beverage items (including
alcohol) and three multiple and nine single vitamin and mineral
supplement items; We chose to examine intake of folic acid, vitamin
B12, and pyridoxine in this analysis because of their importance in
homocysteine metabolism.
statIstIcal analysIs
Continuous variables describing demographic characteristics and bio-
chemical parameters were expressed as mean ± standard deviation.
Univariate analysis using the Chi square test and Risk Ratio (RR) anal-
ysis investigated the association between each stroke risk factor and
progression of AA atheroma. Subsequently, multiple logistic regres-
sion and adjusted Relative Risk (adj. RR) analysis explored the associa-
tion between AA atheroma progression and all stroke risk factors using
methods described by Zhang and Yu (1998). This allows assessment
of whether stroke risk factors independently increased the chance of
detecting progression of AA atheroma by TEE. Kolmogorov–Smirnov
(K–S) test was used to assess normality of distribution of continu-
ous variables. The variables that deviated from normal distribution
were log-transformed prior to conducting tests applicable to normally
distributed variables. Linear regression analysis was used to test the
association between tHcy and interval change in plaque thickness as
well as cross-sectional plaque area, measured on the sequential TEEs.
Multiple linear regression analysis was used to test if the association
between tHcy and AA atheroma progression was independent of
determinants of tHcy including age, intake of vitamin B12, folic acid
levels, and genetic MTHFR polymorphism. Statistical analysis was
performed using SAS version 9.1.3 (Cary, NC, USA).
The characteristics of the 118 patients who had a protocol- mandated
follow-up TEE are described in Table 1. They had a mean age of
65 ± 12 years; 53% were males and 25% were black. The majority
had a history of hypertension or elevated cholesterol, while smaller
proportions had diabetes mellitus, history of recent tobacco use, or
elevated homocysteine levels. On the baseline study, the largest lesion
was mild in 8 (7%), moderate in 72 (61%) and severe in 38 (32%).
Of these 118 patients, 33 (28%) showed progression and 16 (14%)
had regression of their index lesion at 1 year. Among the 85 patients
who did not progress, there were no significant differences between
the sub-group of patients who regressed (N = 16) and those who did
not (N = 69) in stroke risk factors including lipid profiles and fasting
homocysteine levels. Hence this entire group (N = 85) is justifiably
compared with the progression group (N = 33). Laboratory param-
eters including tHcy were assessed at similar time intervals (p = 0.91)
from the index event among the progression group (2.8 ± 7.3 days)
and the no-progression group (3.0 ± 7.2 days). Among the stroke
risk factors, age 65 years, hypertension, diabetes, high cholesterol
and smoking were not associated with atherosclerotic progression
(Figure 1). Only tHcy (14.0 μmol/l) was significantly associated
with progression on both univariable (RR = 3.4, 95% CI 2.0–5.8)
and multivariable analysis (RR = 3.6, 95% CI 2.2–4.6, adjusted
for the vascular risk factors). The change in plaque thickness over
12 months was higher (p < 0.0001) in patients with homocysteine
level 14.0 mcm/l (0.90 ± 0.22 mm) than those with homocysteine
Table 1 | Baseline clinical characteristics of stroke/TIA patients (N = 118,
79 strokes and 39 TIAs) assessed for progression of aortic arch
Risk factors Stroke/TIA patients
(N = 118)
Age 65 ± 12
Blacks 29 (25%)
Males 63 (53%)
Hypertension 94 (80%)
Diabetes 31 (26%)
Hypercholesterolemia 79 (67%)
Total cholesterol (mg/dl) 185 ± 40
LDL (mg/dl) 106 ± 38
HDL (mg/dl) 53 ± 17
Triglycerides (mg/dl) 151 ± 97
Smokers 27 (23%)
Alcohol use 23 (20%)
CAD 37 (31%)
Atrial fibrillation 12 (10%)
PVD 20 (17%)
Hyperhomocysteinemia 29 (25%)
Homocysteine level (mcm/l) 11.1 ± 5.4
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Sen et al. Hyperhomocysteinemia and aortic atheroma progression
FIGURE 1 | Results of uni- and multivariable analysis investigating the contribution of vascular risk factors to AA plaque progression (1 grade over a
period of 12 months) in patients with stroke and TIA.
p = 0.29) was not noted between baseline AA plaque area and fast-
ing plasma homocysteine level. However, a correlation (r2 = 0.11;
p < 0.001) between baseline fasting homocysteine levels and the
change () in AA plaque thickness was observed, as shown in
Figure 2A. Likewise, there was a correlation (r2 = 0.08; p = 0.002)
between baseline fasting homocysteine levels and the change ()
in AA plaque area, as shown in Figure 2B. Plasma tHcy was associ-
ated with change in plaque thickness over 12 months, independent
of age, dietary factors, renal function and MTHFR polymorphism
(Standardized β-coefficient 0.335, p = 0.02) as noted in Table 2.
This 12-month study indicates that AA atheroma is a dynamic
process: 28% of stroke/TIA patients showed plaque progression
and 14% experienced regression. It confirms our prior finding
that progression of AA atheroma is associated with hyperhomo-
cysteinemia (14.0 μmol/l) and that these changes were not influ-
enced by traditional vascular stroke risk factors. In that study, we
reported a higher rate of progression (37%) and regression (22%);
however, a composite of changes were measured in the ascending,
arch, and descending thoracic aorta. When patients with changes
only in the arch were selected, progression was noted in 29% and
regression in 9%, similar to the present study. The present study
has the advantage of a prospective design utilizing methodologi-
cal details discussed earlier, aimed at improving the accuracy of
measurement of aortic plaque.
Montgomery et al. prospectively re-evaluated 30 patients with
moderate to severe aortic plaque noted on initial biplanar or
multiplanar TEE (obtained as part of a workup for cardiac disease
or an embolic event). Over an average of a 1-year period, progres-
sion was reported in 23% and regression in 10% (Montgomery
et al., 1996). In a small group of 16 patients with familial hyper-
cholesterolemia taking pravastatin, Pistavos et al. (1998) using
monoplanar TEE noted a rate of progression of 19% and a rate
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Sen et al. Hyperhomocysteinemia and aortic atheroma progression
and electron-beam CT (EBCT) have been shown to be promis-
ing approaches to measure AA progression (Rumberger, 2001;
Takahashi and Stanford, 2005; Corti, 2006). Several studies testing
the effect of statins and lipid lowering agents have used MRI to
image changes in the thoracic aorta (Pistavos et al., 1998; Corti
et al., 2005; Yonemura et al., 2005). Yet, none of these studies have
reported the association of AA progression with tHcy.
Nevertheless, all prior studies utilizing transesophageal imag-
ing to evaluate AA atheroma suffer from similar limitations. Use
of a grading system may limit the ability to detect progression or
regression of AA atheroma due to a “ceiling effect.For example, an
aortic plaque of 4.6 mm thickness progressing to a thickness of 7
or 8 mm may be graded as severe in both instances and hence may
be incorrectly regarded as not to have progressed. Secondly, use of
thickness as the only variable does not consider the effect of aortic
remodeling that is associated with atherosclerosis. Age related loss
of elasticity frequently results in distention and unfolding of the
AA and accompanies aortic atherosclerosis (Shimojo et al., 1991).
Hence, use of plaque area may be a better means of quantification
compared to IMT in terms of capturing these modeling changes.
The current study has a few limitations that merit com-
ment. First, generalizability may be limited by the requirement
that individuals with stroke/TIA have evidence of 1 mm aortic
atheroma on initial TEE and agree to a follow-up TEE, 12 months
later. Second, as TEE is a semi-invasive test, measurements of AA
atheroma were not performed at intermediate time points. Third,
the lack of association between traditional risk factors and change
in plaque thickness may indicate a lack of sufficient power to detect
such relationships. Alternatively, treatment of hypertension, dia-
betes and hypercholesterolemia may have modified the impact of
these risk factors. Finally, multivariable logistic regression models
can generally handle 1 predictor for every 8–10 outcome events.
With only 33 patients demonstrating progression of AA atheroma
and inclusion of six covariates in the model, there may be a concern
about over-fitting. This is unlikely as using fewer (4) covariates in
of regression of 38% over 2 years. More recently Geraci and
Weinberger (2000), using supraclavicular B-mode ultrasonog-
raphy of the proximal AA in 89 patients evaluated for transient
neurological symptoms or dizziness, noted a progression rate of
19% and a regression rate of 18% over an average of 7.7 months
(range 3–18 months). Compared to these studies, we report a
similar rate of progression (28%). Parenthetically, in the extrac-
ranial carotid arteries, atheroma appears to progress at a lesser
rate over longer follow-up. Thus, in the internal carotid artery a
progression rate of 15–19% has been reported over 1.5–3.0 years
(Olin et al., 1998; Liapis et al., 2000; Schminke et al., 2000). These
studies do not report regression of carotid atheroma. The risk fac-
tors associated with atheroma progression were not investigated
in any of these reports. Our rate of regression of AA atheroma
noted on TEE (14%) is similar to that reported in the initial
TEE series (10%) (Montgomery et al., 1996), but is lower than
that reported in patients on statins (Pistavos et al., 1998). Newer
imaging modalities including MRI, Multi-detector CT (MDCT)
FIGURE 2 | (A) A correlation (r2 = 0.11, p < 0.001) was noted between the change () in AA plaque thickness over a 12-month interval and fasting plasma homocysteine
level (log-transformed), depicted in a semi-log scatter plot. (B) A correlation (r2 = 0.08, p = 0.002) was noted between the change () in AA plaque area over a 12-month
interval and fasting plasma homocysteine level (log-transformed), depicted in a semi-log scatter plot.
Table 2 | Covariates which may influence tHcy and its association with
the change in AA plaque thickness over 12 months (dependent
variable), tested using multiple linear regression analysis.
Variables Standardized p-Value
Age 0.019 0.890
BUNa 0.178 0.327
Creatininea 0.142 0.452
Dietary B12 intakea 0.046 0.805
Dietary folate intake 0.074 0.792
Dietary pyridoxine intake 0.227 0.415
MTHFR genotype (677 TT) 0.151 0.228
Homocysteinea 0.335 0.022
Frontiers in Neurology | Neurocritical and Neurohospitalist Care November 2010 | Volume 1 | Article 131 | 6
Sen et al. Hyperhomocysteinemia and aortic atheroma progression
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Stroke Prevention) study followed patients for a 24-month period,
did not include a placebo-arm and did not show a reduction in
incidence of stroke or composite vascular events (Toole et al.,
2004). The NORVIT (Norwegian Vitamin Trial), despite a longer
follow-up, (median follow-up of 40 months) and a placebo-arm
did not reveal a decrease in composite vascular events (Bønaa et al.,
2006), but did show a non-significant 17% decrease in stroke. The
Heart Outcomes Prevention Evaluation-2 (HOPE-2) trial with the
strength of the longest follow-up of 60 months, the largest sample
size, and a placebo-arm showed a significant 25% reduction in
incidence of stroke (Lonn et al., 2006). In light of the results of
our study as well as the carotid IMT study (Hackam et al., 2000),
it appears that the effect of homocysteine on a surrogate outcome
such as atherosclerosis progression is more immediate and easily
detectable in a smaller sample size, compared to the recurrence of
vascular events.
Our study supports an independent correlation between tHcy
and atherosclerosis, and suggests that tHcy may serve as a media-
tor of aortic plaque progression. Thus, tHcy should be ascer-
tained in stroke and TIA patients with AA atheroma. If elevated,
progression may be amenable to vitamin therapy. The results
neither establish a causal relationship between homocysteine and
cardiovascular risk, nor if tHcy is a marker of existing disease
burden. Further studies are needed to elucidate the role of tHcy
in atherogenesis.
Funding for the study was provided by PHS grant 1K23NS02117
and in part by grants M01RR00046 and UL1RR025747 from the
National Center of Research Resources.
a step-wise logistic regression model, yielded similar independent
association between hyperhomocysteinemia and progression of
AA atheroma.
We report that elevated homocysteine levels (14.0 μmol/l) are
significantly associated with progression of AA atheroma independ-
ent of the selected determinants of tHcy. Though, admission tHcy
is known to be elevated as an acute phase reactant after a stroke
(Howard et al., 2000), this is an unlikely explanation for the associa-
tion between tHcy and aortic plaque progression. Admission tHcy
were performed at similar intervals from the index event in both the
progression and the no-progression group. Further, initial stroke
severity (measured by admission NIH stroke scale) did not influ-
ence the association between tHcy and plaque progression. Limited
data on convalescent tHcy although concordant with admission
tHcy in its association with plaque progression, did not reach sta-
tistical significance. It is possible that homocysteine may mediate
endothelial dysfunction resulting in plaque progression (Coppola
et al., 2000). Alternatively, hyperhomocysteinemia may produce a
hypercoagulable state that may result in thrombus deposition on
the atheromatous plaque (Coppola et al., 2000). Since hyperho-
mocysteinemia can be treated with vitamin therapy (Folic acid, B6
and B12), it can be speculated that such treatment may prevent the
progression of AA atheroma. Indeed, a recent study has indicated
that progression of carotid intima-media thickness may be arrested
and regression promoted by treating hyperhomocysteinemia with
folic acid 2.5 mg, pyridoxine 25 mg and cyanocobalamin 250 μg
daily (Hackam et al., 2000). Three recent large, multicenter, double-
blind, randomized studies have evaluated the impact of homo-
cysteine lowering therapy for secondary prevention of stroke and
MI in high-risk individuals. The VISP (Vitamin Intervention for
www.frontiersin.org November 2010 | Volume 1 | Article 131 | 7
Sen et al. Hyperhomocysteinemia and aortic atheroma progression
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Confl ict of Interes t S tatement: T he
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential conflict
of interest.
Received: 18 April 2010; paper pend-
ing published: 17 August 2010; accepted:
13 September 2010; published online: 26
November 2010.
Citation: Sen S, Reddy PL, Grewal RP,
Busby M, Chang P and Hinderliter A (2010)
Hyperhomocysteinemia is associated with
aortic atheroma progression in stroke/TIA
Patients. Front. Neur. 1:131. doi: 10.3389/
This article was submitted to Frontiers in
Neurocritical and Neurohospitalist Care, a
specialty of Frontiers in Neurology.
Copyright © 2010 Sen, Reddy, Grewal,
Busby, Chang and Hinderliter. This is an
open-access article subject to an exclusive
license agreement between the authors and
the Frontiers Research Foundation, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the
original authors and source are credited.
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    • "По некоторым данным, влияние мутации в гене, кодирующем фермент метилентетрагидрофолатредуктазу , на уровень гомоцистеина в сыворотке крови наиболее значительно при сопутствующем дефиците витамина В 12 и рибофлавина [19]. Было показано, что повышение концентрации гомоцистеина ассоциировано с более быстрым прогрессированием стенозирующего поражения крупных артерий и увеличением размеров атеросклеротической бляшки [20] . Соответственно, у пациентов с атеросклеротическим поражением дуги аорты и ее ветвей существенно повышен риск развития транзиторной ишемической атаки (ТИА) и ишемического инсульта, в первую очередь атеротромботического подтипа. "
    [Show abstract] [Hide abstract] ABSTRACT: Vitamin metabolic disorders can cause diverse dysfunctions of both the peripheral and central nervous systems. There is conclusive evidence that cyanocobalamin (vitamin B12) and folic acid deficiencies may lead to diminished cognitive functions even to the extent of developing dementia. Cognitive impairments may be accompanied by involvement of other regions of the central nervous system, the corticospinal tract in particular, less frequently by brainstem and cerebellar disorders. Changes in nervous system functions in the presence of cyanocobalamin deficiency may predominate in the clinical picture, ahead of the occurrence of hematological changes. The paper considers the possible mechanisms for involvement of brain neurons in deficiency of cyanocobalamin and in that of folic acid in particular in patients with hyperhomocysteinemia. The low serum concentration of folic acid or cyanocobalamin in the elderly raises the risk of developing Alzheimer’s disease in future (by almost twice) and vascular dementia. The authors give the results of randomized clinical trials evaluating the efficacy of the vitamins used in patients with cognitive impairments. Thus, there are data that the use of cyanocobalamin in patients with lacunar infarcts and moderate cognitive impairments may give rise to their complete recovery and reduce the risk of depressive disorders. Intramuscular cyanocobalamin used in a daily dose of 1000 μg for 5 days, then 1000 μg once monthly is demonstrated to be efficacious. This therapy may be effective in patients with different types of dementia and cognitive diminution, primarily in those with these conditions and its serum concentration of less 150 pmol/l. Among the side effects while taking folic acid, there may be higher incidence rates of convulsive attacks. A number of trials have shown the efficacy of cyanocobalamin, pyridoxine, and folic acid in preventing acute cerebral ischemic episodes; however, not all the investigations could confirm this relationship. This may be related to patients’ age, therapy duration, blood inflammatory marker concentrations, and other factors.
    Full-text · Article · May 2015
    • "One major consequence of MD deficiency is a mild or moderate HHcy characterized by circulating total Hcy concentrations in the 15–30 or 31–100 μM range, respectively. This condition has long been associated with an elevated risk of chronic pathologies like atherosclerosis , ischemic heart disease and stroke in humans [5]. MD deficiency and subsequent HHcy can occur in individuals with increased requirement and/or inadequate intake of either MD, e.g. during pregnancy or aging [6]. "
    [Show abstract] [Hide abstract] ABSTRACT: Methyl donor (MD: folate, vitamin B12 and choline) deficiency causes hyperhomocysteinemia, a risk factor for cardiovascular diseases. However, the mechanisms of the association between MD deficiency, hyperhomocysteinemia, and cardiomyopathy remain unclear. Therefore, we performed a proteomic analysis of myocardium of pups from rat dams fed a MD-depleted diet to understand the impact of MD deficiency on heart at the protein level. Two-dimension gel electrophoresis and mass spectrometry-based analyses allowed us to identify 39 proteins with significantly altered abundance in MD-deficient myocardium. Ingenuity Pathway Analysis showed that 87% of them fitted to a single protein network associated with developmental disorder, cellular compromise and lipid metabolism. Concurrently increased protein carbonylation, the major oxidative post-translational protein modification, could contribute to the decreased abundance of many myocardial proteins after MD deficiency. To decipher the effect of MD deficiency on the abundance of specific proteins identified in vivo, we developed an in vitro model using the cardiomyoblast cell line H9c2. After a 4-day exposure to a MD-deprived (vs. complete) medium, cells were deficient of folate and vitamin B12, and released abnormal amounts of homocysteine. Western blot analyses of pup myocardium and H9c2 cells yielded similar findings for several proteins. Of specific interest is the result showing increased and decreased abundances of prohibitin and α-crystallin B, respectively, which underlines mitochondrial injury and endoplasmic reticulum stress within MD deficiency. The in vitro findings validate the MD-deficient H9c2 cells as a relevant model for studying mechanisms of the early metabolic changes occurring in cardiac cells after MD deprivation.
    Full-text · Article · Jan 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) enzyme is one of the most important enzymes with a pivotal role in the folate metabolism and DNA synthesis pathways. Single nucleotide polymorphism (SNPs) in the coding gene has been related to many medical diseases as well as diverse malignancies including the prostate cancer which is the leading cause of the cancer deaths in men and one of the major public health problems. The goal of this study is to determine the relationship between the MTHFR C677T SNP and the prostate adenocarcinoma in Iranian males attending to the Labbafi-nezhad hospital in Tehran. In this Case-control unmatched study, 67 and 75 paraffinized tissue samples were taken out of the specimens diagnosed previously as the prostatic adenocarcinoma and nodular prostatic hyperplasia for the case and control groups respectively. MTHFR C677T genotyping was done by the use of multiplex ARMS-PCR and frequencies of the alleles were compared between the case and control groups as well as calculating the deviation from Hardy-Weinberg equilibrium and Odds Ratio for the "T" allele regarding the prostatic carcinoma. The observed rates in the control group were not too different from that of expected from Hardy-Weinberg equilibrium (P=0.407). Frequencies of the possible genotypes were as follows: CC, 43.28% vs. 42.67%; CT, 49.25% vs. 52% and CT, 7.46% vs. 5.33% in the case and control groups respectively (P=0.85). 1.37 times increased risk was found for the homozygote carriers of C677T variant (OR: 1.37, 95% CI: 0.33-5.6; P=0.653) which is however statistically not significant. No association has been evident between the MTHFR 677C>T polymorphism and the risk of prostatic carcinoma in this study confirming the findings of some of the previous attempts; however, (OR: 1.37, 95% CI: 0.33-5.6) implies a slight effect of the homozygote on the carcinogenesis. Thus larger studies especially with a greater number of the smaples are recommended.
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