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ORIGINAL ARTICLE

Elevation of plasma homocysteine levels associated

with acute myocardial infarction
Manohara P.J. Senaratne, MB BS, PhD
Jo Griffiths, BScN
Jayan Nagendran, BSc

Dr. Senaratne, Ms. Griffiths and Mr. Nagendran are from

the Division of Cardiac Sciences, Grey Nuns Hospital,
Edmonton, Alta.
Medical subject headings: coronary disease; homocysteine;
myocardial infarction; risk factors
(Original manuscript submitted Mar. 22, 2000; received in
revised form May 30, 2000; accepted June 7, 2000.)
Clin Invest Med 2000;23(4):220-6.
2000 Canadian Medical Association

Abstract

Rsum

Objective: To study the effect of acute myocardial

infarction (AMI) on plasma homocystein (Hcy) levels, to
determine the optimal time to measure this risk factor for
coronary artery disease.
Design: A prospective case study.
Setting: The Division of Cardiac Sciences, Grey Nuns
Hospital in Edmonton.
Patients: Sixty-two patients (40 men, 22 women) admitted to hospital with AMI.
Intervention: Measurement of Hcy levels within 48 to
72 hours of admission and at 6 weeks after discharge
from the Coronary Care Unit. In a second group of 15
patients, the Hcy levels were measured on hospital days
1 and 3.
Main outcome measure: Comparison of the Hcy levels
measured at the time of AMI and after discharge.
Results: Mean (and standard error of the mean) Hcy
level measured during the AMI (13.6 [0.98] mol/L) was
significantly higher (p < 0.05) than at 6 weeks (12.1
[1.01] mol/L). Based on the 48- to 72-hour and 6-week
determinations, 31 and 21 patients, respectively, had
abnormal Hcy levels (greater than 12 mol/L) (p <
0.001). In the separate group of 15 patients, the Hcy level
measured on day 3 (9.7 [0.6] mol/L) was noted to be
significantly higher (p < 0.01) than on day 1 (7.7 [0.8]
mol/L).
Conclusions: There is an elevation of Hcy during AMI
that may be related to an increase in the acute-phase reactant proteins. Thus, Hcy measurement should be deferred
for 6 weeks in order to determine the true baseline level.

Objectif : tudier leffet de linfarctus aigu du myocarde

(IAM) sur les taux plasmatiques dhomocystine (Hcy)
afin de dterminer le moment optimal pour mesurer ce
facteur de risque de coronaropathie.
Conception : tude de cas prospective.
Contexte : La Division de cardiologie de lhpital Grey
Nuns, Edmonton.
Patients : Soixante-deux patients (40 hommes, 22
femmes) hospitaliss la suite dun IAM.
Intervention : Mesure des taux de Hcy dans les 48 72
heures suivant ladmission et six semaines aprs que le
patient ait reu son cong de lunit des soins coronariens. Dans un deuxime groupe de 15 patients, on a
mesur les taux de Hcy les premier et troisime jours de
lhospitalisation.
Principales mesures de rsultats : Comparaison des taux
de Hcy mesurs au moment de lIAM et aprs le cong.
Rsultats : Le taux moyen (et erreur type de la moyenne)
de Hcy mesur au cours de lIAM (13,6 [0,98] mol/L)
tait beaucoup plus lev (p < 0,05) qu six semaines
(12,1 [1,01] mol/L). Si lon se fonde sur la dtermination tablie de 48 72 heures et six semaines aprs lincident, 31 et 21 patients respectivement prsentaient des
taux anormaux de Hcy (suprieurs 12 mol/L) (p <
0,001). Dans lautre groupe de 15 patients, on a constat
que le taux de Hcy mesur le troisime jour (9,7 [0,6]
mol/L) tait beaucoup plus lev (p < 0,01) que le premier jour (7,7 [0,8] mol/L).
Conclusions : Il se produit, pendant un IAM, une lvation du taux de Hcy qui peut tre lie une augmentation
des protines ractantes en phase aigu. Cest pourquoi il
faudrait retarder de six semaines la mesure du taux de
Hcy afin de dterminer le niveau de rfrence rel.

220

Clin Invest Med Vol 23, no 4, aot 2000

Homocysteine in myocardial infarction

Introduction
In the natural history of coronary artery disease
(CAD) an acute myocardial infarction (AMI) is often
its first clinical presentation. An AMI results in early
and late morbidity and mortality.1,2 Thus, an assessment of the risk factors for CAD is done at the time
of an AMI, because favourable modification of these
factors may minimize future coronary events, including repeat infarction and death. Unavoidably, there is
much controversy in the search for risk factors for
CAD, where the relative influence of independent
risk factors is often confounded.35 Also, the traditional risk factors of smoking, hypertension, diabetes,
dyslipidemia and a family history of premature CAD
are believed to account for only 30% to 40% of the
causes of atherosclerosis. An elevated plasma homocysteine (Hcy) level has recently been indicated as an
independent risk factor for CAD,68 although there is
no universal agreement regarding the pathogenetic
role of homocysteine in the development of atherosclerosis.9,10 Further, there is debate regarding what
value should be considered as the upper limit of normal for Hcy, similar to the controversy associated
with serum cholesterol levels. It has been shown that
AMI is associated with a decrease in serum cholesterol levels.11 Thus, cholesterol measurements are
usually deferred for about 6 weeks after an AMI,
although a measurement taken within the first 24
hours after the onset of an AMI may approximate the
baseline level. In light of these changes in serum cholesterol, we planned to study the effect of an AMI on
Hcy levels in order to determine the optimal time for
measuring Hcy after an AMI.

Methods
We prospectively examined 62 consecutive patients
(40 men, 22 women, mean [and standard error of the
mean] age 63.3 [1.5] years) admitted during a 3month period with an AMI to the Coronary Care Unit
of Grey Nuns Hospital in Edmonton. The diagnosis
of AMI was based on the presence of at least 2 of the
3 following criteria: (1) chest pain suggestive of
myocardial ischemia lasting 30 minutes or longer; (2)
enzymatic evidence of acute myocardial necrosis, as
demonstrated by a rise in creatine kinase levels above
Clin Invest Med Vol 23, no 4, August 2000

the upper limit of normal (greater than 170 U/L with

the CK-MB fraction being greater than 5%; (3) new
electrocardiographic changes that included development of new Q waves or ST-T changes (defined as
new or presumed new ST segment depression greater
than 1.0 mm or new T-wave inversion greater than
2.0 mm in depth, or both) lasting 48 hours or longer.
Informed consent was obtained from each patient.
Measurement of Hcy levels
The Hcy concentration was measured after an
overnight fast of 12 hours, with the first sample taken
48 to 72 hours after admission. The delay of 48 to 72
hours was used to allow for the biologic changes
associated with an AMI to manifest themselves. The
blood was drawn in pre-cooled test tubes containing
ethylenediaminetetraacetic acid with the plasma separated within 10 minutes and stored at 20 C until
analysis. The plasma was analysed for homocysteine
levels by an enzyme immunoassay,12 which allowed
total plasma homocysteine levels to be measured.
Repeat fasting Hcy samples were measured by the
same procedure, 6 weeks after discharge from the
Coronary Care Unit.
Based on the results of the first part of the study, we
decided to investigate prospectively the change in
Hcy between day 1 and day 3 after an AMI. In a separate group of 15 consecutive patients admitted with
an AMI, a fasting Hcy was obtained within 24 hours
of admission and repeated after 72 hours.
Statistical analysis
The Hcy levels together with demographic, clinical
and investigational variables were put into a database
within the SPSS data management system and
analysed with use of the system.13 The Hcy level at
the time of the AMI for each patient was compared
with the level determined 6 weeks after discharge
from the Coronary Care Unit by a paired t-test. The
Hcy level at 6 weeks was further categorized into 2
groups: patients with abnormal and normal Hcy levels. The upper limit of normal for Hcy (as established
in the University of Alberta hospital laboratory,
which does Hcy assays for all hospitals in Edmonton)
was 12.0 mol/L. Variables obtained from the med221

Senaratne et al

ical history, clinical course and complications in the

Coronary Care Unit, and investigative data were
evaluated against the Hcy level. Discrete variables
were categorized to ensure that responses would fall
into mutually exclusive categories. The cross-tabulations were done on discrete variables using a 2 test.
Analyses between abnormal and normal Hcy groups
for continuous variables were made using an
unpaired t-test. The Hcy levels between day 1 and
day 3 in the second part of the study were compared
with a paired t-test. For continuous variables, mean
(and standard errors of the mean [SEM]) are quoted.
A p value less than 0.05 was considered as significant
in all analyses.

Findings
Demographic and investigational data
Of the 62 patients, 56 had their fasting Hcy repeated
at 6 weeks; 5 patients had died in the interim and 1
patient refused follow-up. The clinical and investigative characteristics for these 56 patients are outlined
in Table 1. There were 36 men (64%) and 20 women
(36%), with a mean age of 62.3 (1.6) years (range
from 38 to 83 years). Eight patients (14%) had a history of AMI. The frequency of independent risk factors for AMI was as follows: hypertension, 26 (46%);
known dyslipidemia, 25 (45%); current smokers, 20
(36%); family history of CAD (defined as CAD in a
first-degree male relative younger than 55 years or a
first-degree female relative younger than 65 years
old), 18 (32%); and diabetes, 10 (18%). The locations
of the AMIs were: anteroseptal, 18 (32%); inferior or
posterior, or both, 33 (59%); lateral, 3 (5%); indeterminate, 2 (4%). The AMIs were Q wave in type in 31
(55%) patients. Twenty-seven patients (48%)
received thrombolytic therapy. The highest creatine
kinase levels had a mean of 1256 (166) U/L. The
mean creatinine level for the group was 100.5 (4.4)
mol/L.
Hcy measurements
The Hcy levels measured 48 to 72 hours after admission and at 6 weeks in the 56 patients were 13.6
(0.98) mol/L (range from 5.0 to 50.0 mol/L) and
222

12.1 (1.01) mol/L (range from 5.8 to 60.0 mol/L)

respectively (p = 0.009 by a paired t-test). By assessment of the 48- to 72-hour measurement, 31 patients
(50%) had an abnormal Hcy level (greater than 12.0
mol/L). In contrast, evaluation of the Hcy at 6
weeks revealed that 21 patients (38%) had abnormal
levels. A cross-tabulation analysis of normal versus
abnormal Hcy between the 48- to 72-hour and 6week levels demonstrated a significant difference (p
< 0.001). The magnitude of the change in the plasma
homocysteine levels between first and second measurements varied from 10.0 to 18.0 mol/L. Fourteen
patients (25%) demonstrated an increase in the Hcy
level during the 6-week period.
Analysis for differences between patients who
demonstrated an increase in the Hcy levels and
patients who demonstrated a decrease during the 6week period found that the only significant variable
(of 23 evaluated) was a lower prevalence of a history
Table 1: Clinical and investigative characteristics of the
56 patients who had acute myocardial infarction (AMI)
Characteristic
Mean (and SEM) age, yr
Age group (yr), no. (%)
< 50
5070
> 70
Range
Smoking, no. (%)
Ever
Within last year
Diabetes, no. (%)

Male,
n = 36

Female,
n = 20

61.7 (2.1)

63.4 (2.4)

9 (25)
15 (42)
12 (33)
3883

3 (15)
9 (45)
8 (40)
4378

31 (86)
13 (36)

13 (65)
7 (35)

7 (19)

3 (15)

Hypertension, no. (%)

16 (44)

10 (50)

Known dyslipidemia, no. (%)

19 (53)

6 (30)

Family history of coronary

artery disease, no. (%)

10 (28)

8 (40)

Mean (and SEM) maximum

creatine kinase, U/L

1381
(219)

1011
(236)

108 (4.7)

86.9 (8.4)

Location of AMI, no. (%)

Anteroseptal
Inferior and/or posterior
Lateral
Indeterminate

10 (28)
22 (61)
2 (6)
2 (6)

8 (40)
11 (55)
1 (5)
0

Type of AMI, no. (%)

Q wave
Non-Q wave

19 (53)
17 (47)

12 (60)
8 (40)

Mean (and SEM) serum

creatinine , mol/L

Clin Invest Med Vol 23, no 4, aot 2000

Homocysteine in myocardial infarction

of hypertension (24% versus 60%) in those with an

increase in Hcy level (p = 0.019). Some of the variables that did not demonstrate a significant difference
were age, weight, gender, peak creatine kinase level,
lipid subfractions, duration of hospital stay, history of
diabetes mellitus and history of smoking.
The 5 patients (3 men, 2 women) who died
between the sampling points had a mean (and SEM)
age of 75.8 (3.2) years (range from 67 to 86 years).
The infarctions were anteroseptal in 4 of these
patients; 2 patients had non-Q-wave AMIs. The maximum creatine kinase levels ranged from 555 to 3437
U/L, with the ejection fraction ranging from 0.25 to
0.4. The mean (and SEM) 48- to 72-hour Hcy level
in this group was 12.7 ( 2.1).
In the second part of the study 15 patients (13 men,
2 women; mean [and SEM] age 57.9 [3.2] years)
were investigated. The mean (and SEM) peak creatine kinase for the group was 1862 (485) U/L . The
AMI was Q wave in type in 69%. The locations of
the AMIs were as follows: anteroseptal, 25%; inferior or posterior, or both, 51%; lateral, 13%. The mean
(and SEM) Hcy levels on day 1 and day 3 following
the AMI in this group were 7.7 (0.8) mol/L and 9.7
(0.6) mol/L respectively. The mean Hcy value on
day 3 was significantly higher than on day 1 for the
whole group (p = 0.007 by the paired t-test). Thirteen
of the 15 patients demonstrated an increase in Hcy
levels from day 1 to day 3, ranging from 0.9 to 5.1
mol/L. Two patients demonstrated decreases in the
Hcy of 2.2 and 2.6 mol/L between day 1 and day 3.

cysteine levels. Although there is debate about the

cut-off point between normal and abnormal Hcy, this
difference between the 48- to 72-hour level and the 6week level would persist regardless of the exact value
accepted as the upper limit of normal. There was a
significant decrease in Hcy levels from the 48- to 72hour and the 6-week post-discharge measurements;
however, a considerable variation was noted, with
25% of the patients demonstrating an increase during
the time period. All blood samples were collected
approximately at the same time of the day (morning)
in pre-cooled test tubes, and the same assay technique was used for both samples. The intra-assay
coefficient of variation has been shown to be 2.0%,
with an inter-assay coefficient of variation of 5.1%.
This suggests that fluctuations in Hcy due to inconsistencies in the assay itself are unlikely to account
for the differences. The group who demonstrated an
increase in the Hcy level between the first and second
measurements (from 48 to 72 hours to 6 weeks) did
not show any appreciable difference in clinical and
investigational characteristics from the group who
demonstrated a decrease with only 1 of 23 variables
(history of hypertension), achieving a statistically
significant difference between the 2 groups.
Although the causes leading to an increase in the Hcy
level in some patients remains unclear, this type of
nonuniform directional change is not uncommon
with biologic variables.

Discussion

There are 3 possible explanations for the differences

in Hcy level noted in this study: (1) elevation of Hcy
is associated with an AMI, thus the true level is that
measured 6 weeks after discharge from the Coronary
Care Unit; (2) the true Hcy is the one measured at the
time of the AMI, with a possible decrease in Hcy
level 6 weeks after discharge resulting from
favourable modification of diet; and (3) an increase
in the protein-bound fraction of Hcy during an AMI.
Studies have shown that folic acid is effective in
lowering the Hcy level in patients after AMI.15 Thus,
it is possible that the dietary education given at the
time of an AMI, with emphasis on increased consumption of vegetables, may have resulted in a
decrease in the Hcy levels. However, this is contrary

Results and implications

Increased Hcy levels are an independent risk factor
for the development of atherosclerosis.6,8,14 In light of
the acceptance of this finding, an accurate measurement of the Hcy level is necessary. The present study
demonstrates that Hcy measurements taken 48 to 72
hours after the onset of an AMI appeared significantly different from those measured 6 weeks after discharge from the Coronary Care Unit. If this difference was not appreciated, it would result in misclassification of nearly 12% of patients with respect to
the normality or abnormality of their plasma homoClin Invest Med Vol 23, no 4, August 2000

Possible explanations

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Senaratne et al

to expectation, as pure dietary sources generally do

not provide a folic acid intake of more than 0.2 mg/d
(especially as the bioavailability of folic acid in foods
varies widely and is generally low), a level that is generally insufficient to reduce abnormal Hcy levels. This
conclusion is also supported by the observation that
diets containing cereals fortified with folic acid (at the
levels recommended by the United States Food and
Drug Administration) have not been shown to be efficacious in reducing Hcy levels.16 This study demonstrated only a 3.7% reduction in Hcy at the current
levels of folic acid supplementation of 127 g/d.
Evidence for the thesis that an increase in the Hcy
occurs at the time of an AMI is provided by the second part of the study. The results indicated a statistically significant increase in the Hcy between day 1
and day 3 following an AMI, with a mean difference
of 2.1 mol/L. Of the 15 patients in this part of the
study, 86.7% demonstrated an increase in the Hcy
from day 1 to day 3. The mean Hcy at day 3 in the
second part of the study (9.7 [0.6] mol/L) was lower
than the value at day 3 in the first part of the study
(13.6 [0.98] mol/L). The exact reason for this is
unclear but is likely due to the small sample size with
a wide range of Hcy levels obtained in the first part
of the study (2 patients had Hcy levels greater than 40
mol/L, resulting in an increase in the mean value for
the whole group). If there is a spurious increase in the
Hcy level after AMI, a mechanism must be elucidated to explain this transient change. Homocysteine
is a nonessential amino acid produced during the
metabolism of the essential amino acid methionine.
Homocysteine can either be re-methylated back to
methionine or undergo trans-sulfuration with the formation of cysteine. In this model, Hcy concentration
is believed to be in equilibrium with plasma methionine concentration. In contrast, the conversion to cysteine is believed to be an irreversible reaction. The
Hcy concentration is thus dependent on the cystathonine -synthase activity, the rate-limiting enzyme in
the formation of cysteine, as well as the state of equilibrium with methionine. The equilibrium of methionine is influenced by the activity of several enzymes
and the availability of their cofactors, such as folic
acid and vitamin B12.
It has been shown that the concentration of free
methionine increases during an AMI.17 This would
224

suggest that Hcy may also increase, in view of the

known state of equilibrium between methionine and
homocysteine. This conclusion is supported by the
previously noted increase in Hcy as a result of a
methionine-loading diets.18
Another explanation for the transient increase in
Hcy may be an enzymatic function, or a lack thereof.
In genetically caused homocystinuria, there is a
mutation in a gene that codes for cystathionine synthase, the enzyme that causes homocysteine to
condense with serine to form cystathionine. It is possible that the activity of cystathionine -synthase is
compromised during AMI as a result of previously
documented decreases in plasma serine concentrations.17 This decrease would in turn lead to an
increase in Hcy concentration owing to a lack of substrate, rather than to a deficient enzyme.
The third possible cause for the increase in Hcy at
the time of an AMI is an increase in the protein-bound
fraction of Hcy during an AMI. It has been demonstrated that there is an increase in acute-phase reactant
proteins at that time. This increase could lead to binding of the free homocysteine on the additional binding
sites available on the proteins. During this process, the
total concentration of Hcy would increase in proportion to the increase in plasma proteins, while the concentration of free homocysteine may be maintained
relatively constant through homeostasis.
In plasma, homocysteine exists in 3 forms: free
homocysteine; protein-bound homocysteine (the predominant fraction) with albumin being the major protein, although other proteins too are involved; and
cysteinehomocysteine mixed disulfide. Most
assays, including the one used in the present study,
measure the total homocysteine concentrations.
Therefore, the measured concentration of homocysteine would reflect and follow changes in plasma protein concentrations. Thus, in association with an AMI
with a rise in the concentration of acute-phase reactant proteins, Hcy could increase and return to baseline levels over the ensuing weeks with resolution of
the acute-phase reaction. For the hypothesis to be
true, homocysteine must bind to 1 or more of the
acute-phase reactant proteins (C-reactive protein, 1antitrypsin, haptoglobin, ceruloplasmin or 1-acid
glycoprotein), as the serum albumin level itself may
drop with an AMI.19
Clin Invest Med Vol 23, no 4, aot 2000

Homocysteine in myocardial infarction

Although 1 or more of the explanations given

above could account for an increase in the Hcy level
with an AMI, these explanations should be considered as speculative, requiring further elucidation.
Literature review
A literature review on this topic revealed only 2 articles that examined the timing of Hcy measurement
after an AMI. Egerton and associates20 concluded that
there was a decrease in the Hcy with an AMI, with
the levels determined on the first and third day being
lower than those determined on the seventh day. It
was suggested that the levels at day 7 or later would
accurately reflect the baseline level. As shown in figure 1 of their article, this conclusion appears unjust
since the levels measured at 21 days after the AMI as
well as on the first and third day appearedlower than
the level at day 7.20 The more plausible conclusion
would be that Hcy increases after an AMI (as the values on the first and third day were lower than on the
seventh day), reaches a maximum at day 7, and subsequently decreases, which is similar to the timecourse of events demonstrated in our study. However,
the study by Egerton and associates20 is limited
because only 14 patients completed the day 7 measurement.
A second study, by Landgren and associates,15
showed that the Hcy concentration 6 weeks after an
AMI were significantly higher than at 24 to 36 hours
after the onset of the infarction. It was suggested that
the difference in level may be due to a change in plasma protein content (due to hemoconcentration),
which is believed to be 9% higher in the standing
position than the supine position. It was hypothesized
that the difference in the Hcy level was owing to the
fact that the patients were supine during the in-hospital venipuncture but seated at the 6-week blood collection. However, there was no specified protocol in
the methodology to ensure that the subjects were
supine for a fixed time before blood sampling in the
hospital. The blood samples were collected up to 1200
hours during the hospital stay, making it unlikely that
patients would have been supine except at the time of
collection. The different results obtained in the study
of Landgren and associates compared with our study
and one by Egerton and associates,20 remains unclear.
Clin Invest Med Vol 23, no 4, August 2000

In our study, too, 25% of the patients demonstrated an

increase in the Hcy level from the time of the AMI to
6 weeks after discharge from the Coronary Care Unit,
although the entire group of patients demonstrated a
significant decrease in Hcy levels. Conversely, in the
study by Landgren and associates,15 5 of the 20
patients in their figure 1 showed a decrease in Hcy
levels. Thus, a bi-directional change in Hcy levels
during the recovery period after an AMI remains a
possibility, with patients who exhibited continued
coronary inflammation (at the atherosclerotic
plaques) demonstrating persistent increases in the
Hcy level. In recent years there has been considerable
interest in explaining the etiology and, more importantly, the precipitation of coronary events on the
basis of infection or inflammation, or both.21 In this
regard, it would be interesting to follow up those
patients who demonstrate an increase in the Hcy levels at 6 weeks (compared with the level at the time of
AMI) to assess for a higher incidence of future coronary events than those who demonstrated a decrease.
Nevertheless, during the acute phase of the AMI there
appears to be a more uniform increase in the Hcy levels, with 13 of our 15 patients demonstrating an
increase in the levels from day 1 to day 3.
Homocystinemia is not a single entity; a number of
different genetic mutations modified by environmental
influences determine the Hcy level for each patient.68
Further, the genetic mutations resulting in homocystinemia appear to be quite frequent although different ethnic groups demonstrate marked variations in
their frequency. Thus, the differences in the study by
Landgren and associates,15 done in Sweden, and our
study may be related to differences in the populations
studied. The population in Alberta is more diverse with
significant proportions of British, German and East
European origin, whereas those in Sweden may have
been of more uniform ethnic origin.

Conclusions
We have demonstrated an increase in Hcy level associated with an AMI, manifesting within 48 to 72
hours after admission to hospital. Therefore, the measurement of Hcy is best deferred for approximately 6
weeks after an AMI to obtain an accurate reflection
of the baseline level of homocysteine. Whether a Hcy
225

Senaratne et al

measurement taken within 24 hours of admission

would reflect the baseline level remains unclear. A
preliminary report of the present study has been
presented as an abstract.22

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Reprint requests to: Dr. Manohara P.J. Senaratne,

Associate Clinical Professor of Medicine, University
of Alberta. Director, Coronary Care Unit, Grey Nuns
Hospital, Rm. 2508, 1100 Youville Dr. W, Edmonton
AB T6L 5X8; fax 80 450 8359, [email protected]

Clin Invest Med Vol 23, no 4, aot 2000