(Circulation. 1995;92:2825-2830.)
© 1995 American Heart Association, Inc.
Articles |
Hyperhomocysteinemia and Low Pyridoxal Phosphate
Common and Independent Reversible Risk Factors for Coronary Artery Disease
From the Departments of Cardiology (K.R., E.L.M., S.E.N., E.J.T.), Internal Medicine (A.G.), Biostatistics and Epidemiology (D.P.M., M.K.), Clinical Pathology (R.G., K.K.-M., F.v.L.), and Cell Biology (S.R.S., D.W.J.), Cleveland Clinic Foundation, Cleveland, Ohio; and Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (J.S.), Boston, Mass.
Correspondence to Killian Robinson, MD, Desk F15, Department of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
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Abstract |
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Background High plasma homocysteine is associated with premature coronary artery disease in men, but the threshold concentration defining this risk and its importance in women and the elderly are unknown. Furthermore, although low B vitamin status increases homocysteine, the link between these vitamins and coronary disease is unclear.
Methods and Results We compared 304 patients with coronary disease with 231 control subjects. Risk factors and concentrations of plasma homocysteine, folate, vitamin B12, and pyridoxal 5'-phosphate were documented. A homocysteine concentration of 14 µmol/L conferred an odds ratio of coronary disease of 4.8 (P<.001), and 5-µmol/L increments across the range of homocysteine conferred an odds ratio of 2.4 (P<.001). Odds ratios of 3.5 in women and of 2.9 in those 65 years or older were seen (P<.05). Homocysteine correlated negatively with all vitamins. Low pyridoxal 5'-phosphate (<20 nmol/L) was seen in 10% of patients but in only 2% of control subjects (P<.01), yielding an odds ratio of coronary disease adjusted for all risk factors, including high homocysteine, of 4.3 (P<.05).
Conclusions Within the range currently considered to be normal, the risk for coronary disease rises with increasing plasma homocysteine regardless of age and sex, with no threshold effect. In addition to a link with homocysteine, low pyridoxal-5'-phosphate confers an independent risk for coronary artery disease.
Key Words: coronary disease • vitamins
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Introduction |
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Coronary heart disease is a major public health problem in the Western world. Identifiable risk factors include hypercholesterolemia, hypertension, cigarette smoking, and diabetes mellitus. An increase in plasma homocysteine concentration has also been associated with premature arterial disease,1 2 3 4 5 6 7 8 9 10 11 12 13 possibly related to a deficiency in the enzyme cystathionine ß-synthase.3 5 This enzyme is deficient in homocystinuria, a rare disorder characterized by high homocysteine concentrations and early, aggressive occlusive arterial disease.14 Abnormalities of the enzyme methylenetetrahydrofolate reductase, also required for homocysteine metabolism, may also play a role.15 Other essential biochemical modulators of homocysteine include folic acid,16 vitamin B12,17 and vitamin B618 deficiencies, which are associated with increased plasma homocysteine concentrations.
Although elevated plasma homocysteine is associated with coronary artery disease, the precise level associated with increased risk is unknown. The potential for an increased risk of coronary disease in women and in older hyperhomocysteinemic subjects has not been previously explored. Finally, the relation between homocysteine concentrations and B group vitamins in patients with coronary artery disease has been incompletely defined. The present study was undertaken to explore the level of homocysteine associated with an increased coronary risk and to detect a similar effect, if any, in women and the elderly. The interrelations among plasma homocysteine, essential B group vitamin concentrations, and coronary disease were also studied.
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Methods |
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Patients
Three hundred four patients (201 men and 103 women; mean age, 62±11 years) with established coronary artery disease were studied. The baseline demographic, laboratory, and angiographic features of both cases and controls are summarized in Table 1
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Control Subjects
Consecutive subjects attending an executive health screening
program at The Cleveland Clinic Foundation served as control subjects.
There was no clinical or ECG evidence of coronary artery
disease in any of these individuals.
Diagnosis of Coronary Artery Disease
All patients had angiographic documentation of stenosis
of 
70% of at least one major epicardial coronary vessel
diagnosed at the time of coronary angiography carried out in
standard manner.
Risk Factors
Hypercholesterolemia (elevated total
serum cholesterol) was defined as a total serum
cholesterol concentration of 200 mg/dL or a history of
medication for hypercholesterolemia. Cigarette
smokers were categorized as either nonsmokers (those who had never
smoked) or ever smokers (current smokers or those who had stopped).
Hypertension was diagnosed if the blood pressure was more than 150/90
mm Hg or, in the presence of a history of hypertension, if the patient
was taking antihypertensive medications. Diabetes mellitus was
diagnosed if the fasting glucose concentration was more than 140 mg%
or if the patient was taking insulin or oral hypoglycemic therapy.
Measurements of Total Plasma Homocysteine
Total fasting plasma homocysteine was measured according to the
method of Jacobsen et al.19 In this assay, all forms of
plasma homocysteine are determined, including reduced and oxidized
forms (homocystine, homocysteine-cysteine mixed disulfide, and
protein-bound mixed disulfide).
Vitamin Concentrations and Other Assays
Concentrations of folic acid and of vitamin
B12 were measured using a commercial
radioligand binding technique (Simultrac; Becton
Dickinson). Pyridoxal 5'-phosphate concentrations were measured
according to the technique of Camp et al.20 Vitamin
B12 deficiency was defined as a plasma concentration of
less 125 pmol/L. Folate deficiency was defined as a concentration of
less than 6.4 nmol/L. Pyridoxal 5'-phosphate deficiency was defined as
a level of less than 20 nmol/L.
Statistical Analysis
Percentages are computed as a function of nonmissing data.
Mean age is reported ±1 SD. Homocysteine and continuous variables
other than age are reported as mean and median values. Percentages were
compared using Pearson's 
2 test or Fisher's
exact test depending on the factor prevalences. Ages were compared
using Student's t test, and other continuous variables
were compared using a Wilcoxon rank-sum test. Correlations
presented here are Spearman correlations. For the full sample,
odds ratios and 95% confidence intervals (CI) were computed based on
the parametric estimates and standard errors from a multiple
logistic regression. Diabetes, hypertension, smoking history, and
hypercholesterolemia were all considered as
potential covariates. Hypercholesterolemia
showed no association with coronary artery disease in this
sample, perhaps because of behavior modification, so it was not used as
a covariate. Age and sex were used as covariates in all logistic
regression models. The coronary disease covariates were not,
however, included in subset models. No positive association between any
of the risk factors and homocysteine concentration or high homocysteine
was detected. To have adequate power to assess the odds ratio for
coronary artery disease conferred by hyperhomocysteinemia, only
age and sex were used as covariates in the subset models.
Creatinine was not used as a covariate, but patients with a
history of renal failure were excluded from the study to protect
against the possibility that high creatinine values are a
confounder in the relation between hyperhomocysteinemia and
coronary artery disease. The 80th percentile values of plasma
homocysteine concentration were arbitrarily selected to allow the
calculation of prevalences of higher homocysteine concentrations and
odds ratios in different patient groups. This value permitted the
comparison of levels of essential B group vitamins in individuals with
higher and lower plasma homocysteine concentrations and yielded larger
sample sizes than if higher percentile values had been chosen.
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Results |
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Distribution of Plasma Homocysteine Concentrations
Homocysteine concentrations were higher (14.4± 15.4 versus 10.9±3.4 µmol/L, P<.001) in patients than in control subjects (Tables 2
and 3),
and values for patients were shifted and skewed to the right. A
correlation was observed between homocysteine and
creatinine that persisted when adjusted for age and sex
(r=.29, P<.001).
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Definitions of Hyperhomocysteinemia and Relation of Odds Ratios to
Plasma Homocysteine Concentration
All Patients
Alternate models of high homocysteine concentration were applied.
First, with an absolute plasma homocysteine concentration of 8 µmol/L
as a cutoff point, an odds ratio of 4.6 (CI, 1.8 to 11.6;
P=.001) was seen. Odds ratios of 2.9 (CI, 1.6 to 5.1;
P<.001) and 2.8 (CI, 1.6 to 4.6; P<.001) were
observed with cutoff points of 10 and 12 µmol/L, respectively. A
concentration of 14 µmol/L conferred an odds ratio of 4.8 (CI, 2.6 to
8.9; P<.001). Second, with increments of 5 µmol/L in
absolute plasma homocysteine concentrations, odds ratios of 2.4 (CI,
1.7 to 3.5; P<.001) were seen. These models are shown in
the Figure. An odds ratio of 2.3 was seen for the second
tertile of plasma homocysteine compared with the first
(P<.05). A further increase of 2.1 was seen for the third
tertile compared with the second (P<.05).
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Effects of Sex
Homocysteine levels were higher in male than female control
subjects (11.2±2.9 versus 10.1±4.7 µmol/L, P=.004) and
were higher in male patients than in male control subjects (13.9±4.5
versus 11.2±2.9 µmol/L, P<.001) (Tables 2
and 4). A sex-adjusted 80th percentile cutoff point of
plasma homocysteine concentration (13.5 µmol/L) resulted in a
prevalence of hyperhomocysteinemia of 45% in male patients (Table 4,
P<.01). A plasma homocysteine at this concentration
conferred an odds ratio of 2.9 (CI, 1.7 to 4.7) in men, adjusted for
all other risk factors (P<.001).
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Mean homocysteine concentrations were higher in female patients than in
their control subjects (15.3±25.7 versus 10.1±4.7 µmol/L), although
the standard deviation was high due to one folate-deficient patient
(plasma folate 3.1 nmol/L) with a homocysteine concentration of more
than 250 µmol/L. Nevertheless, the median homocysteine value for
female patients was higher than that for the female control group (12.1
versus 9.5 µmol/L, P<.01). A sex-adjusted 80th
percentile cutoff point of plasma homocysteine concentration (11.8
µmol/L) resulted in a prevalence of hyperhomocysteinemia of 56% in
female patients (Table 4, P<.001), significantly higher
than the prevalence of 45% for male patients (P<.05). A
plasma homocysteine at this concentration conferred an odds ratio of
3.4 (CI, 1.4 to 8.5) in women (P<.05).
Effects of Age
Overall, homocysteine concentrations correlated with age
(r=.27, P=.001) (Tables 3 and 4). In patients
less than 65 years old, mean homocysteine concentrations were higher
than in control subjects (14.2±20.4 versus 10.8±3.4 µmol/L,
P<.001). A sex-adjusted 80th percentile cutoff point of
plasma homocysteine concentration for control subjects resulted in a
42% prevalence of hyperhomocysteinemia among patients less than 65
years old (Table 4, P<.001). A plasma homocysteine at this
concentration conferred an odds ratio 2.9 (CI, 1.8 to 4.6;
P<.001) for those less than 65 years old.
In patients 65 years or older, mean homocysteine concentrations were
higher than in both control subjects (14.5±5.1 versus 11.9±3.5
µmol/L, P=.016) and patients less than 65 years old
(median, 13.4 versus 12.1 µmol/L; P=.002; Table 3). A
sex-adjusted 80th percentile cutoff point of plasma homocysteine
concentration resulted in a 58% prevalence of hyperhomocysteinemia
among patients 65 years of age or older (P<.05, Table 4). A
plasma homocysteine at this concentration conferred an odds ratio of
3.2 (CI, 1.2 to 8.4; P<.05) for those 65 years of age or
older.
Relation Between Concentrations of Vitamin Cofactors and
Plasma Homocysteine
Significant negative correlations were seen between homocysteine
and folate in both patients and control subjects (r=-.29
and -.41, respectively; P<.001). In both patients and
control subjects, similar correlations between homocysteine and vitamin
B12 (r=-.39 and -.38, P<.001) and
pyridoxal 5'-phosphate (r=-.19 and -.28,
P<.01) were observed.
Overall, folate values were higher in patients (mean, 22.6±12.4
nmol/L; median, 19.2 nmol/L) than in control subjects (mean, 17.9±9.4
nmol/L; median, 15.4 nmol/L; P<.001). Folate levels were
lower in those with homocysteine levels of more than 14 µmol/L (mean,
19.4±11.3 nmol/L; median, 14.0 nmol/L) compared with those with
homocysteine concentrations of less than this value (mean, 23.5±12.1
nmol/L; median, 18.1 nmol/L; P=.006). Similar findings were
seen in relation to vitamin B12 (230±113 versus 310±150
pmol/L, P<.001) and pyridoxal 5'-phosphate levels (55±52
versus 83±74 nmol/L, P<.001, Table 5).
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Prevalence of Vitamin Deficiencies
Deficiency of folate (defined as less than 6.4 nmol/L) was seen in
2 patients (1%) and 2 control subjects (1%). Deficiency of vitamin
B12 (defined as less than 125 pmol/L) was seen in 22
patients (7.8%) and 12 control subjects (5.3%; P=NS).
Deficiency of pyridoxal 5'-phosphate (defined as less than 20 nmol/L)
was seen in 22 patients but only 5 control subjects (10% versus 2%,
P<.01).
Relation of Vitamin Deficiencies to Coronary Artery
Disease
The odds ratios for coronary disease in those with folate
or vitamin B12 deficiency were 0.7 (CI, 0.1 to 11.4) and
1.6 (CI, 0.5 to 5.0) respectively (P=NS for both).
In contrast, the odds ratio for coronary disease in those with low pyridoxal 5'-phosphate adjusted for all traditional risk factors was 3.8 (CI, 1.1 to 13.7; P=.04). When hyperhomocysteinemia was included in a multivariate analysis, an odds ratio of 4.3 (CI, 1.1 to 16.9) persisted for coronary disease in those with low pyridoxal (P=.04). Furthermore, when patients with coronary disease and coexisting vitamin deficiency were excluded, homocysteine concentrations remained higher than in control subjects (13.3±4.0 versus 10.8±3.3 µmol/L, P<.001). The odds ratio for coronary heart disease in those in whom all vitamin deficiencies had been excluded also remained high (3.8; CI, 2.1 to 7.0; P<.001).
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Discussion |
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The rare syndrome of homocystinuria21 is characterized by excessively high homocysteine concentrations and vascular disease with a 50% risk of such an episode before age 30.14 Many studies have confirmed that milder elevations of homocysteine also confer an independent risk of stroke, coronary disease, and peripheral vascular disease.1 2 3 4 5 6 7 8 9 10 11 12 13 The results of the present study broaden the definition of hyperhomocysteinemia to include many individuals currently categorized as falling within a "normal" range and demonstrates the absence of a threshold phenomenon. Furthermore, the increased risk associated with high homocysteine has been extended to include women and the elderly. Highly significant negative correlations have been shown between all essential B group nutrients studied and homocysteine. In the evaluation of the relation between pyridoxal phosphate and homocysteine concentrations, an independent association between low concentrations of this cofactor and coronary disease has been revealed. Even when all patients with vitamin deficiency are excluded, however, high homocysteine concentrations are still associated with an increased risk of coronary artery disease.
The precise level, if any, of plasma homocysteine at which an increased risk of vascular disease may begin has not been clearly defined. Many studies have used arbitrary definitions of abnormality based on homocysteine concentrations of more than 2 SD above the mean for controls3 4 7 8 9 or more than the 95th percentile for normal control subjects.10 12 Others have used simple comparisons of mean values for patients and control subjects2 or other techniques.1 5 6 13 Plasma homocysteine concentrations are not normally distributed, and these arbitrary definitions of hyperhomocysteinemia may not be appropriate. Furthermore, because gender influences plasma homocysteine significantly, definitions of hyperhomocysteinemia using mixed-sex control group may also be unsuitable for definitions of normality. To circumvent the various biological variations, we explored a number of different models of "high" plasma homocysteine concentrations and used sex-specific definitions as well as log-transformed data. The results show that homocysteine concentrations now widely accepted as normal are associated with an increased likelihood of coronary artery disease and that this risk increases with rising homocysteine concentrations.
In both men and women, higher homocysteine concentrations were associated with increased odds ratios of coronary disease. The prevalence of hyperhomocysteinemia in women was greater than in men, although the numbers were too small to establish any statistically significant sex differences in odds ratios for coronary heart disease. Little attention has been given to the risk of coronary disease conferred by high homocysteine concentrations in women, although higher levels have been reported in women with vascular disease.2 7 9 It is now clear, however, that hyperhomocysteinemia also increases the risk for coronary disease in women.
Most studies of patients with coronary disease have focused on subjects 65 years of age or younger,1 3 5 6 11 12 13 although some studies of stroke and peripheral vascular disease have included older patients.7 8 9 Older patients, who form a large proportion of the coronary population, have received little attention. Our study extends the coronary risk associated with hyperhomocysteinemia to these patients. The mechanisms for the increased homocysteine concentrations in this age group may relate to prerenal factors,9 inadequate nutrient intake,22 or even age-related decreases in the activity of enzymes responsible for the metabolism of homocysteine.23 Regardless of mechanism, increased plasma homocysteine is a common risk factor for coronary disease in older people: more than 50% of our older patients were hyperhomocysteinemic (based on an 80th percentile definition). Homocysteine concentrations correlate negatively with folate4 9 12 13 19 22 as well as vitamins B124 12 13 19 22 and B6.9 12 22 Our study confirms this in both patients and control subjects.
Frank folate or vitamin B12 deficiency was, however, rare and was not associated with an increased risk of coronary disease. There was no evidence that the increased homocysteine concentrations in patients in the present study were due to poorer nutrition compared with control subjects. In this study, folate levels were actually higher in patients.
Vitamin B6 deficiency (pyridoxal-5'-phosphate levels of less than 20 nmol/L) was more frequent in our patients than control subjects. An independent increased risk of coronary disease was seen in these patients even when an allowance was made for hyperhomocysteinemia. Vascular lesions have been seen in animals deficient in pyridoxine,24 and Selhub et al25 reported an association between inadequate pyridoxal status and carotid arteriosclerosis, although this diminished after adjustment for homocysteine. An increase in antithrombin III activity has been shown after administration of vitamin B6,26 and the activated form, pyridoxal 5'-phosphate, inhibits platelet aggregation.27 Furthermore, plasma homocysteine levels may also be reduced by essential vitamins, including folic acid4 28 29 31 and vitamin B6.3 4 30 In two studies of patients with coronary disease, homocysteine concentrations were reduced with combinations of vitamins B6 and folic acid31 or vitamin B12,32 which is also consistent with correction of an underlying deficiency.
Conversely, the elevated homocysteine in our patients was not entirely
explained by low vitamin concentrations as both high homocysteine
concentrations and an increased odds ratio of coronary disease
persisted when such patients were excluded. Although heterozygosity for
cystathionine ß-synthase deficiency3 5 could be
responsible for hyperhomocysteinemia in some patients with
coronary artery disease, the gene frequency of this condition
is too low to account for the large number of hyperhomocysteinemic
patients seen in everyday clinical practice.33 Recently,
the cDNA for the gene coding for
methylenetetrahydrofolate reductase was
isolated,34 and nine mutations were described in patients
with severe methylenetetrahydrofolate
reductase deficiency.34 35 A C
T substitution at
nucleotide 677, resulting in the conversion of an alanine
to a valine residue, has also been reported36 in
association with thermolabile
methylenetetrahydrofolate reductase.
This has important implications for studies of patients with vascular
disease as, in the study of Frosst et al,36 the
substitution occurred at a frequency of 
38% of unselected
chromosomes and was associated with homocysteine concentrations well
within the range associated with vascular disease. The relation of this
to underlying nutrient disturbances in patients with vascular
disease requires further study.
In summary, high homocysteine concentrations and low pyridoxal 5'-phosphate are independent risk factors for coronary artery disease. The risk associated with homocysteine rises with increasing concentrations, has no threshold, and is evident in women and the elderly.
Statistical Footnote
The estimated homocysteine effect from three different logistic
regression models is shown in the Figure. The threshold model is the
maximum likelihood estimate (MLE) based on the constraint that all
persons with a value less than this are equal and that all those with a
value greater than this are equal. In this model, the odds of
developing coronary disease increase only when the threshold of
14 µmol/L is passed. The basic logistic regression model is the MLE
based on the constraint that an increase of n µmol/L will
have the same impact on the odds of coronary disease regardless
of the baseline value. The generalized additive model is constrained
only by local smoothing, and the fit of this model appears to validate
the absence of a threshold effect. It shows that persons at the upper
end of the "normal" range may have odds of coronary
disease three to four times higher than persons at the lower end of the
range.
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Acknowledgments |
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This work was funded in part by The Cleveland Clinic Foundation (RPC 4425) and the National Institutes of Health (HL-52234 to Dr Jacobsen). We acknowledge the secretarial assistance of Marie Scott; the constructive biostatistical advice offered by Dr Paul Jacques of Tufts University, Boston; and the assistance of Dr Richard Lang of the Section of Preventive Medicine, The Cleveland Clinic Foundation, for permission to study patients under his care.
Received April 27, 1995; revision received May 31, 1995; accepted June 23, 1995.
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