(Circulation. 2000;102:1227.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Plasma Homocysteine Predicts Mortality Independently of Traditional Risk Factors and C-Reactive Protein in Patients With Angiographically Defined Coronary Artery Disease
From the Department of Medicine, Division of Cardiology, LDS Hospital, University of Utah, Salt Lake City.
Correspondence to Jeffrey L. Anderson, MD, Division of Cardiology, University of Utah School of Medicine, 50 North Medical Dr, Salt Lake City, UT 84132.
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Abstract |
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Background—Plasma homocysteine (tHCY) has been associated with coronary artery disease (CAD). We tested whether tHCY also increases secondary risk, after initial CAD diagnosis, and whether it is independent of traditional risk factors, C-reactive protein (CRP), and methylenetetrahydrofolate reductase (MTHFR) genotype.
Methods and Results—Blood samples were collected from 1412
patients with severe angiographically defined CAD (stenosis
70%). Plasma tHCY was measured by fluorescence polarization
immunoassay. The study cohort was evaluated for survival after a mean
of 3.0±1.0 years of follow-up (minimum 1.5 years, maximum 5.0 years).
The average age of the patients was 65±11 years, 77% were males, and
166 died during follow-up. Mortality was greater in patients with tHCY
in tertile 3 than in tertiles 1 and 2 (mortality 15.7% versus 9.6%,
P=0.001 [log-rank test], hazard ratio [HR] 1.63).
The relative hazard increased 16% for each 5-µmol/L increase in tHCY
(P<0.001). In multivariate Cox
regression analysis, controlling for univariate
clinical and laboratory predictors, elevated tHCY remained predictive
of mortality (HR 1.64, P=0.009), together with age (HR
1.72 per 10-year increment, P<0.0001), ejection
fraction (HR 0.84 per 10% increment, P=0.0001),
diabetes (HR 1.98, P=0.001), CRP (HR 1.42 per tertile,
P=0.004), and hyperlipidemia.
Homozygosity for the MTHFR variant was weakly predictive
of tHCY levels but not mortality.
Conclusions—In patients with angiographically defined CAD, tHCY is a significant predictor of mortality, independent of traditional risk factors, CRP, and MTHFR genotype. These findings increase interest in tHCY as a secondary risk marker and in secondary prevention trials (ie, with folate/B vitamins) to determine whether reduction in tHCY will reduce risk.
Key Words: coronary disease • amino acids • genes • risk factors • inflammation
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Introduction |
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One third to one half of the variation in vascular disease occurrence remains unexplained by traditional risk factors.1 2 Epidemiological and experimental evidence suggests that homocysteine may be an additional risk factor.2 3 4
Homocysteine is produced by catabolism of methionine, an essential amino acid, and is further metabolized by transsulfuration (when methionine is in excess) or by remethylation (when methionine is deficient).2 Approximately 70% of the total plasma pool of homocysteine (tHCY) is protein bound, and 25% circulates as the dimer, homocystine.2 5 Severe elevation of tHCY, caused by homozygous defects of homocysteine metabolism, results in vascular injury and premature atherothrombosis but is rare.2 6 7 In contrast, mild to moderate elevation of tHCY is common, but its causes are less well defined. Genetically determined but milder metabolic deficiencies (eg, the thermolabile methylenetetrahydrofolate [MTHFR] gene polymorphism) merit further evaluation.2 8 9 10 Deficiencies of folic acid and vitamin B6 may play a role through their association with increased tHCY.11 12 13 If mild to moderate elevations of tHCY accelerate the progression of coronary artery disease (CAD), these common nutritional and genetic deficiencies, together with other factors, could have substantial impact on risk at a population level.
Epidemiological studies have associated mild to moderate elevations of tHCY with primary cardiovascular risk and have suggested a graded relationship extending into the "normal" range (<15 µmol/L).2 However, the fewer data from prospective longitudinal cohort studies, which provide better tests of risk association, are less consistent,2 and only one study has evaluated secondary risk, after CAD diagnosis.14 We endeavored to further evaluate tHCY and MTHFR polymorphism as secondary risk predictors.
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Methods |
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Study Objectives
We prospectively tested whether (1) tHCY predicts all-cause mortality, independent of standard risk factors and C-reactive protein (CRP), in patients with angiographic CAD and (2) homozygosity for the MTHFR C677T polymorphism predicts tHCY levels and mortality.15 16
Study Population
The present study consisted of a cohort of 1412 consecutive
patients that underwent coronary angiography from August 1994
through August 1997, had severe CAD, consented for the study (approved
by the hospital’s institutional review board), had blood drawn at
angiography and tHCY measured, and survived hospitalization. Patient
information was entered into a computerized database as previously
described.17 Subjects from our referral area are primarily
of European extraction and are genetically similar to other US
white individuals.18
Angiographic CAD
Severe CAD, defined as 1 stenosis of 70% diameter
in 1 coronary artery, was identified by the patient’s
attending cardiologist, who was unaware of tHCY level or
MTHFR genotype.
Assessment of Outcomes
Subjects were followed until death or August 1999 (mean cohort
follow-up 3.0±1.0 years, range 1.5 to 5.0 years). Study subject status
was determined by a telephone survey and by a search of a national
Social Security database, which was completed on all study subjects by
August 20, 1999.
Laboratory Testing
At the time of angiography, blood samples were collected in EDTA
and refrigerated at 4°C. Within 24 hours, samples were
centrifuged, and plasma and DNA were separated and stored
cryogenically. Plasma tHCY was measured by a fluorescence
polarization immunoassay (Abbott Diagnostics). In a
subgroup of 526 patients, genotyping for the MTHFR point
polymorphism C677T was performed by polymerase chain
reaction amplification of a 198-bp segment that brackets
nucleotide 677.9 The amplicon was
digested with the HinfI restriction enzyme, and
genotypes were determined after electrophoresis in 1.5%
agarose.9
CRP was initially assayed by a fluorescence polarization immunoassay (Abbott Diagnostics) with use of a high-sensitivity (0.5-mg/dL) low-range (0- to 6.5-mg/dL) CRP protocol.19 Samples exceeding that range were reanalyzed by a lower sensitivity (1.5-mg/dL) high-range (0- to 26-mg/dL) protocol; 95% of healthy individuals have CRP levels <0.5 mg/dL, and 98% have levels <1.0 mg/dL.20 21
Lipid panel assays were performed on a Vitros 950 instrument (Johnson & Johnson Clinical Diagnostics). Total cholesterol,22 triglyceride,23 and HDL cholesterol concentrations were determined by enzymatic methods. LDL cholesterol was calculated by an indirect method.
Risk Factors and Definitions
Ten clinical factors were assessed: age, sex, diabetes, history
of hypertension, history of hyperlipidemia, family
history of CAD, smoking status (current or >10 pack years), disease
presentation at index hospitalization, index treatment, and
renal failure. Age was analyzed as a continuous variable.
Diabetes was defined as fasting blood sugar >126 mg/dL, glycosylated
hemoglobin >7.5%, or antidiabetic therapy. Hypertension was defined
as a history of systolic blood pressure >160 mm Hg,
diastolic blood pressure >90 mm Hg, or
antihypertensive therapy. Family history was positive if clinical CAD
appeared in a first-order relative before the age of 65 years. At index
hospitalization, clinical presentation was categorized as
stable angina, unstable angina, or myocardial infarction, and clinical
treatment was categorized as medical therapy (only),
percutaneous coronary intervention, or
CABG.
Eight laboratory risk factors were analyzed in addition to tHCY and MTHFR genotype: left ventricular ejection fraction (contrast method or another, if unavailable), systolic and diastolic blood pressures, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and CRP.
Statistical Considerations
Highest versus lower tertile tHCY groups were compared at
baseline by Pearson 
2 (categorical
variables) or Student t test (continuous variables),
and survival was assessed by the Kaplan-Meier method (log-rank
statistic) and Cox regression. Other univariate and
multivariate survival analyses were performed
by using Cox regression (SPSS, version 9.0); a backward stepwise
logistic regression approach was taken for the
multivariate analyses, with P=0.10
as the critical value for entering and excluding variables in the
model. Hazard ratios (HRs) and 95% CIs are reported with 2-tailed
probability values; P<0.05 was taken to be nominally
significant.
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Results |
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Patient Characteristics
Table 1
shows patient
characteristics. The average age of patients was 65±11 years, 77%
were males, and 166 (11.8%) died after a mean of 1.4 years (range 0 to
4.8 years). Those with higher tHCY levels (tertile 3) were similar in
age, sex, and most other risk factors. They had a less-frequent history
of hyperlipidemia, and some differences were noted in
lipid fractions; however, total cholesterol levels were
similar.
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Mortality by Baseline tHCY Level
Mortality over follow-up was significantly greater in patients
with tHCY in the highest versus the lower 2 tertiles (mortality 15.7%
versus 9.6%), as shown in the Figure
(log-rank statistic 10.1, P=0.0014) and Table 2 (HR 1.63, 95% CI 1.20 to 2.22).
Absolute tHCY concentration increments also strongly predicted risk
(eg, HR 1.16 per 5-µmol/L increment, P=0.0007) (Table
2).
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Other Univariate Predictors
CRP was strongly associated with mortality (HR 1.46 per tertile,
P=0.0001). Other univariate predictors were age,
ejection fraction, diabetes, and number of diseased vessels and lesions
(Table 2). A diagnosis of hyperlipidemia
paradoxically predicted lower risk after CAD diagnosis, in part because
of its correlation with prescription of a statin and younger age.
Initial treatment and diastolic blood pressure were
marginal predictors. HDL cholesterol (which correlated with
female sex and older age) weakly predicted increased risk; total
cholesterol (P=0.38), LDL
cholesterol (P=0.48), and
triglycerides (P=0.14) were not predictors of
secondary risk.
Multivariate Predictive Models
The 13 clinical and laboratory variables that predicted
(P
0.10) univariate risk were entered into
multivariate Cox regression analyses.
Third-tertile tHCY (HR 1.64, P=0.009) was selected as an
independent predictor of mortality, together with age (HR 1.72 per
10-year increment, P<0.0001), ejection fraction (HR 0.84
per 10% increment, P=0.001), diabetes (HR 1.98,
P=0.001), CRP (HR 1.42 per tertile, P=0.004),
history of hyperlipidemia (protective), and,
marginally, less invasive treatment (Table 3). As a continuous variable, tHCY
also was a strong independent predictor (HR 1.16 per 5-µmol/L
increment, P<0.005) (Table 4).
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tHCY and Mortality by MTHFR Genotype
Neither the presence of an MTHFR mutant allele (HR
1.01, 95% CI 0.65 to 1.57; P=0.96) nor C677T
homozygosity (mortality 11.7% for homozygous genotype versus
15.9% for wild-type or heterozygous genotype, HR 0.74, 95% CI
0.34 to 1.62) was associated with increased mortality (Table 5). However, homozygosity was associated
weakly with tHCY (Pearson correlation coefficient 0.145,
P0.001; mean 18.5 µmol/L, 95% CI 15.7 to
21.3, and median 14.5 µmol/L for homozygous genotype
versus mean 14.9 µmol/L, 95% CI 14.2 to 15.5, and median
12.9 µmol/L, for wild-type or heterozygous genotype;
P=0.015 [t test]). MTHFR
homozygosity was weakly predicted by absolute tHCY levels (odds ratio
[OR] 1.25 per 5-µmol/L increment, P=0.0013) but less so
by third-tertile tHCY (OR 1.69, P=0.059 [logistic
regression]).
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Entry of the MTHFR genotype into Cox bivariate regression analysis did not diminish the predictive value of elevated (top tertile) tHCY (HR 1.84, 95% CI 1.19 to 2.85; P=0.006; n=526). Also, the MTHFR genotype was not retained when forced into multivariate risk analyses.
tHCY and Lipids
Patients in tHCY tertile 3 had somewhat lower
triglyceride levels (Table 1), carried a diagnosis
of hyperlipidemia less frequently (45% versus 54%,
Table 1), and tended to be treated less often with
lipid-lowering medication (9.5% versus 13.6%) than those in tHCY
tertiles 1 and 2. In contrast, they had somewhat higher LDL and
slightly lower HDL levels (Table 1). These differences did not
affect the independent predictive value of tHCY (Tables 3 and 4).
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Discussion |
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Summary of Study Findings
In this large prospective study of patients with angiographically documented CAD, tHCY was strongly predictive of all-cause mortality. The predictive value of tHCY was independent of traditional risk factors, CRP, and MTHFR genotype and was robust, being present consistently in all primary and supplemental analyses and undiminished when adjusted for multiple other predictive variables. The magnitude of tHCY risk (HR 1.64 per third tertile) approached that of a 10-year increase in age or of diabetes. In contrast, the MTHFR genotype was not associated with mortality, although mutant homozygosity was weakly related to increased tHCY.
Comparison With Previous Studies
An overview of cross-sectional and case-control observational
studies (n=4000+ subjects, 27 studies) suggested an association between
elevated (>90th percentile) plasma tHCY levels and occurrence of
coronary events (OR 1.7), carotid or cerebrovascular
atherosclerosis (OR 2.5), peripheral
vascular disease (OR 6.8), and aortic
atherosclerosis.2 In contrast, prospective
cohort studies have been fewer, and results have been more
variable. Eight reports found significant positive associations of
tHCY and vascular risk, whereas 6 did not.2 Most
observations were in subjects without evident vascular disease at
entry. Because of lack of consistency in the database and
measurement standardization, tHCY is not yet recommended for routine
risk assessment in primary prevention.1
Much less information is available on tHCY as a risk factor in secondary prevention. Only Nygard et al14 have studied mortality in patients with angiographically demonstrated CAD, reporting a graded relation between plasma tHCY levels and mortality (P=0.02). The mortality ratio was 4.5 for persons with the highest (>20 µmol/L) compared with the lowest (<9 µmol/L) concentration bracket, and tHCY remained predictive after adjustment for traditional risk factors.
Our findings confirm and extend the observations of Nygard et
al.14 The present study was larger (by 2- to 3-fold),
had greater power, and yielded a highly significant result
(P0.001). Adjustment was made for multiple traditional
clinical factors as well as laboratory variables (lipid levels,
number of diseased vessels, and number of coronary lesions).
Multivariate analyses also included newer
factors (ie, CRP, an inflammatory marker, and MTHFR
genotype, a determinant of homocysteine
metabolism). In the fully adjusted model, the predictive
value of tHCY was undiminished. The projected increase in relative
hazard (1.64 for levels >16 µmol/L), although substantial,
appears to be less than that reported by Nygard et al but may be
quantitatively more accurate.
MTHFR and Risk
MTHFR plays a critical role in homocysteine
metabolism. The C677T gene variant has received
attention because it specifies a thermolabile enzyme with reduced
enzymatic activity and is common (53% of our patients were carriers;
11% were homozygotes). Kluijtmans et al8 reported
this variant to be a genetic risk factor for
cardiovascular disease, but we and others did not find
an association with angiographic CAD in cross-sectional
studies.9 10
In the present study, MTHFR polymorphism was not
associated with secondary risk (progression to death) in patients with
established CAD. However, the analysis is limited by modest
statistical power: the 95% CIs allow exclusion of an adverse relative
risk of mortality no smaller than 
50%. Our HR of 1.03 for each
1-µmol/L increase in tHCY projects to a relative hazard of
only 1.1 for the average increment in homozygotes of 3
µmol/L. Thus, the apparent null finding for MTHFR
homozygosity is not surprising. However, even if present, the risk
must be small. Also, tHCY values substantially vary within and overlap
between genotype groups. Thus, it seems clear that the
measurement of tHCY will be more informative in individual risk
assessment than will the determination of MTHFR
genotype.
CRP and Risk
Ridker et al15 showed that CRP, a nonspecific marker
of systemic inflammation, was a prospective predictor of
cardiovascular events in healthy US physicians. We
found CRP to be associated with CAD and a history of myocardial
infarction in a cross-sectional angiographic study.16 In
the present study, we demonstrate CRP to be independently
predictive of progression to a fatal outcome (secondary risk) in
patients with angiographic disease. Although the cause of relative CRP
elevation is unknown, it was unassociated with tHCY elevation
(correlation coefficient -0.06, P=0.04), suggesting that it
does not reflect tHCY-related vascular injury.
tHCY: Risk Potential and Pathophysiological Considerations
Boushey et al24 estimated an increase of 5
µmol/L in basal tHCY to be associated with a 60% increase in the
odds of coronary heart disease in men, an 80% increase in the
odds of coronary heart disease in women, and a 50% increase in
the relative risk of cerebrovascular disease. This magnitude of risk is
similar to that of a nearly 20-mg/dL increase in
cholesterol and could account for 10% of the risk of a
primary CAD event. Our data suggest that secondary risk attributable to
tHCY may be less than this but still highly significant.
Mild-to-moderate increases in tHCY levels in the general population may be related in part to dietary deficiencies of folic acid and vitamins B6 and B12.2 11 12 13 The role of common genetic factors, discussed above, remains unresolved.8 9 10 Perhaps MTHFR and other genetic variants act in concert, together with nutritional deficiencies and other as-yet-undetermined factors.
A causal relation between high tHCY levels and vascular disease is supported by observations from rare genetic diseases and experimental models2 : tHCY causes direct toxic damage to endothelial cells in both in vitro and in vivo models (including primates). As reviewed by Eikelboom et al,2 endothelial toxic damage may be caused by the generation of reactive oxygen species, impaired production of endothelium-derived NO, stimulation of smooth muscle cell proliferation, elevation of triglycerides and oxidation of LDL, and thrombogenicity associated with platelet adherence and coagulation factor activation.
In a recent study, oral methionine loading reduced flow-mediated brachial artery dilation (by 50%) in a time course paralleling increasing tHCY levels (from 8 to 23 µmol/L) in human subjects.25 In another study, methionine loading activated coagulation, modified adhesive properties of endothelium, and impaired vascular responses to L-arginine in association with moderate increases in tHCY (from 10.5 to 27 µmol/L).26 Pretreatment with vitamin E and ascorbic acid blocked these effects, suggesting an oxidative mechanism of vascular dysfunction.
Although folate with or without B vitamins is capable of decreasing tHCY levels,27 28 no well-designed studies have shown therapy to reduce vascular risk. Randomized clinical trials, currently under way, will better assess the causal role of tHCY in vascular disease and preventive strategies.2 29 30
Study Strengths and Limitations
The present study shares the limitations of nonrandomized
observational studies (ie, unsuspected selection biases and
confounding), but it has the advantage of being large and prospective
in design. The univariate association of tHCY with
mortality was adjusted for multiple potentially confounding
clinical and laboratory risk factors. Risk associations with tHCY were
maintained undiminished in these multivariate
analyses. Also, the presence and magnitude of associated risk
with tHCY are in keeping with epidemiological observations from
other2 or similar14 populations. The
MTHFR results also are supported by the majority of
association studies.9 10
Pathophysiological mechanisms cannot be directly
assessed in epidemiological studies but require separate basic and
clinical studies.
Conclusions
In patients with angiographically defined CAD, tHCY levels
prospectively predicted mortality independent of traditional risk
factors, CRP, and MTHFR genotype. This result
extends the association between homocysteine and CAD to include
mortality risk after CAD diagnosis, verifies the independent nature of
its predictive value, and supports the performance of secondary
intervention trials aimed at tHCY reduction.
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Acknowledgments |
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This study was supported in part by grants from the Deseret Foundation, Salt Lake City, Utah; Merck & Co, West Point, Pa; and Abbott Diagnostics, Abbott Park, Ill.
Received January 24, 2000; revision received April 6, 2000; accepted April 10, 2000.
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 G. Chwatko and H. Jakubowski Urinary Excretion of Homocysteine-Thiolactone in Humans Clin. Chem., February 1, 2005; 51(2): 408 - 415. [Abstract] [Full Text] [PDF]
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 C-K Wong, C J K Hammett, R The, J K French, W Gao, B J Webber, J M Elliott, A W Hamer, J A Ormiston, M W I Webster, et al. Lack of association between baseline plasma homocysteine concentrations and restenosis rates after a first elective percutaneous coronary intervention without stenting Heart, November 1, 2004; 90(11): 1299 - 1302. [Abstract] [Full Text] [PDF]
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 G. Vrentzos, J. A. Papadakis, N. Malliaraki, E. A. Zacharis, K. Katsogridakis, A. N. Margioris, P. E. Vardas, and E. S. Ganotakis Association of Serum Total Homocysteine with the Extent of Ischemic Heart Disease in a Mediterranean Cohort Angiology, September 1, 2004; 55(5): 517 - 524. [Abstract] [PDF]
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 Z. T. Bloomgarden Consequences of Diabetes: Cardiovascular disease Diabetes Care, July 1, 2004; 27(7): 1825 - 1831. [Full Text] [PDF]
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 A. Undas, J. Perla, M. Lacinski, W. Trzeciak, R. Kazmierski, and H. Jakubowski Autoantibodies Against N-Homocysteinylated Proteins in Humans: Implications for Atherosclerosis Stroke, June 1, 2004; 35(6): 1299 - 1304. [Abstract] [Full Text] [PDF]
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 R. Glowacki and H. Jakubowski Cross-talk between Cys34 and Lysine Residues in Human Serum Albumin Revealed by N-Homocysteinylation J. Biol. Chem., March 19, 2004; 279(12): 10864 - 10871. [Abstract] [Full Text] [PDF]
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 S. Matetzky, D. Freimark, S. Ben-Ami, I. Goldenberg, J. Leor, R. Doolman, I. Novikov, M. Eldar, and H. Hod Association of Elevated Homocysteine Levels With a Higher Risk of Recurrent Coronary Events and Mortality in Patients With Acute Myocardial Infarction Arch Intern Med, September 8, 2003; 163(16): 1933 - 1937. [Abstract] [Full Text] [PDF]
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 A. Liem, G. H. Reynierse-Buitenwerf, A. H. Zwinderman, J. W. Jukema, and D. J. van Veldhuisen Secondary prevention with folic acid: effects on clinical outcomes J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2105 - 2113. [Abstract] [Full Text] [PDF]
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 L. A. Bazzano, J. He, P. Muntner, S. Vupputuri, and P. K. Whelton Relationship between Cigarette Smoking and Novel Risk Factors for Cardiovascular Disease in the United States Ann Intern Med, June 3, 2003; 138(11): 891 - 897. [Abstract] [Full Text] [PDF]
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 J. L. Anderson, J. F. Carlquist, B. D. Home, and J. B. Muhlestein Cardiovascular Pharmacogenomics: Current Status, Future Prospects Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1): 71 - 83. [Abstract] [PDF]
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 M. Chandalia, N. Abate, A. V. Cabo-Chan Jr., S. Devaraj, I. Jialal, and S. M. Grundy Hyperhomocysteinemia in Asian Indians Living in the United States J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1089 - 1095. [Abstract] [Full Text] [PDF]
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D. Tanne, M. Haim, U. Goldbourt, V. Boyko, R. Doolman, Y. Adler, D. Brunner, S. Behar, and B.-A. Sela Prospective Study of Serum Homocysteine and Risk of Ischemic Stroke Among Patients With Preexisting Coronary Heart Disease Stroke, March 1, 2003; 34(3): 632 - 636. [Abstract] [Full Text] [PDF]
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 M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group MTHFR 677C->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis JAMA, October 23, 2002; 288(16): 2023 - 2031. [Abstract] [Full Text] [PDF]
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 O. Stanger, H.-J. Semmelrock, W. Wonisch, U. Bos, E. Pabst, and T. C. Wascher Effects of Folate Treatment and Homocysteine Lowering on Resistance Vessel Reactivity in Atherosclerotic Subjects J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 158 - 162. [Abstract] [Full Text] [PDF]
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N. Q. Hanson, J. H. Eckfeldt, K. Schwichtenberg, O. Aras, and M. Y. Tsai Interlaboratory Variation of Plasma Total Homocysteine Measurements: Results of Three Successive Homocysteine Proficiency Testing Surveys Clin. Chem., September 1, 2002; 48(9): 1539 - 1545. [Abstract] [Full Text] [PDF]
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H. Jakubowski Homocysteine Is a Protein Amino Acid in Humans. IMPLICATIONS FOR HOMOCYSTEINE-LINKED DISEASE J. Biol. Chem., August 16, 2002; 277(34): 30425 - 30428. [Abstract] [Full Text] [PDF]
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 N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
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A. K. Majors, S. Sengupta, B. Willard, M. T. Kinter, R. E. Pyeritz, and D. W. Jacobsen Homocysteine Binds to Human Plasma Fibronectin and Inhibits Its Interaction With Fibrin Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1354 - 1359. [Abstract] [Full Text] [PDF]
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 G.J. Blake and P.M. Ridker C-reactive protein and prognosis after percutaneous coronary intervention Eur. Heart J., June 2, 2002; 23(12): 923 - 925. [Full Text] [PDF]
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R.J. de Winter, G.S. Heyde, K.T. Koch, J. Fischer, J.P. van Straalen, M. Bax, C.E. Schotborgh, K.J. Mulder, G.T. Sanders, J.J. Piek, et al. The prognostic value of pre-procedural plasma C-reactive protein in patients undergoing elective coronary angioplasty Eur. Heart J., June 2, 2002; 23(12): 960 - 966. [Abstract] [Full Text] [PDF]
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M. Acevedo, G. L. Pearce, K. Kottke-Marchant, and D. L. Sprecher Elevated Fibrinogen and Homocysteine Levels Enhance the Risk of Mortality in Patients From a High-Risk Preventive Cardiology Clinic Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 1042 - 1045. [Abstract] [Full Text] [PDF]
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 S. N. Doshi, I. F.W. McDowell, S. J. Moat, N. Payne, H. J. Durrant, M. J. Lewis, and J. Goodfellow Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering Circulation, January 1, 2002; 105(1): 22 - 26. [Abstract] [Full Text] [PDF]
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J. W. Auer, R. Berent, B. Eber, S. Friso, P. F. Jacques, I. H. Rosenberg, J. Selhub, and P. W.F. Wilson Lack of Association of Increased C-Reactive Protein and Total Plasma Homocysteine Response Circulation, December 18, 2001; 104 (25): e164 - e164. [Full Text] [PDF]
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C. Fernandez-Miranda, M. Sanz, A. de la Calle, C. Loinaz, P. Gomez, P. Diaz-Rubio, A. G. de la Camara, and E. Moreno Determinants of Increased Plasma Homocysteine in 221 Stable Liver Transplant Patients Clin. Chem., November 1, 2001; 47(11): 2037 - 2040. [Full Text] [PDF]
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 L. Lavie, A. Perelman, and P. Lavie Plasma Homocysteine Levels in Obstructive Sleep Apnea : Association With Cardiovascular Morbidity Chest, September 1, 2001; 120(3): 900 - 908. [Abstract] [Full Text] [PDF]
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S. Friso, P. F. Jacques, P. W.F. Wilson, I. H. Rosenberg, and J. Selhub Low Circulating Vitamin B6 Is Associated With Elevation of the Inflammation Marker C-Reactive Protein Independently of Plasma Homocysteine Levels Circulation, June 12, 2001; 103(23): 2788 - 2791. [Abstract] [Full Text] [PDF]
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