CLIN.CHEM.

40/6, 857-858 (1994)

Role of Plasma Homocyst(e)ine in Arterial Occlusive Diseases

Children with homocystinuria, a rare genetic disorder, A study of 287 pairs of individuals asymptomatic for
have severe hyperhomocyst(e)inemia and often have clinical atherosclerosis measured intimal-medial thick-
myocardial infarction and stroke at an early age (3). Ini- ness of the carotid wall by B-mode ultrasound (13). Sub-
tially, homocyst(e)ine was considered to be absent in the jects with thickened carotid walls (cases) had higher
blood of nonhomocystinuric individuals. However, techni- plasma concentrations of homocyst(e)ine than controls.
cal advances and the demonstration that most plasma Logistic regression analysis showed that the odds ratio
homocyst(e)ine is bound to proteins (4) resulted in several for having carotid artery thickening increased monoton-
methods now capable of measurmg basal concentrations of ically with increasing homocyst(e)ine content; odds ratios
homocyst(e)ine in large numbers of plasma/serum sam- >1 were obtained after adjusting for several risk factors
ples per day (5). In this issue, Jacobsen et al. describe an for atherosclerosis. These data suggest that homocys-
HPLC method with a relatively simple procedure for sam- t(e)inemia is a risk factor for carotid atherosclerosis
ple preparation (6); their method can process -80 samples among subjects free of clinical atherosclerotic disease.
per day with small intra- and interassay CVs. In addition, Retrospective studies cannot determine whether in-
they confirmed earlier findings that men have higher ho- creases in homocyst(e)ine are the cause or the result of
mocyst(e)ine concentrations than women (7). arterial occlusive diseases. Prospective studies, though, do
Accurate assessment of low concentrations of homocys- not have this limitation. Thus, as part of the Physicians
t(e)inemia is important because various retrospective Health Study trial of aspirin and a-carotene, 14916 par-
case-control studies have found moderate increases of ticipants with no history of myocardial infarction or stroke
homocyst(e)ine in 12-42% of patients with coronary,
sent blood samples prior to randomization in the trial.
cerebrovascular, or peripheral arterial diseases (8, 9).
After as long as 5 years of follow-up, 271 cases of new
For example, one study of 176 men with premature cor-
myocardial infarctions were confirmed. Each case was
onary artery disease (CAD) found that cases had higher
matched to one control who was free from myocardial
concentrations of homocyst(e)ine than controls (10). Sta-
infarction at the time of the cases diagnosis. Controls were
tistical adjustment for a wide variety of coronary risk
randomly selected from participants who met the match-
factors suggested that homocyst(e)inemia is an indepen-
ing criteria of age, smoking habit, and time from random-
dent risk factor for CAD.
ization (14). The cases had a slightly, but statistically
Cross-sectional studies have correlated concentrations
significant, higher mean concentration of homocyst(e)ine
of plasma homocyst(e)ine with the extent of coronary dis-
than the noncases, i.e., 11.1 vs 10.5 imoI/L, respectively.
ease determined by coronary angiography. Ubbink et al.
Most of this difference was attributable to an excess of
studied 163 male Caucasian patients with typical angina
high values among the cases,but statistical power was not
without previous myocardial infarction (11). Hyperhomo-
sufficient to rule out a graded distribution of risk. Men
cyst(e)inemia was present in a large proportion of angina
with values of homocyst(e)ine above the 95th percentile
patients without apparent coronary artery stenosis; fur-
(15.8 prnol/L) had a relative risk of 3.1 (95% confidence
thermore, there was a linear trend of increased prevalence
interval, 1.4-6.9, P = 0.005), compared with men who had
of hyperhomocyst(e)inemia associated with the number of
normal concentrations (90th percentile or less). This in-
coronary arteries with significant stenosis. In a similar
creased risk was essentially unchanged after adjustment
study of 199 CAD patients, the number of main coronary
arteries with >50% stenosis increased with higher home-
for various risk factors for CAD by multivariate analysis.
Prospective data are also available from >21 000 indi-
cyst(e)inemia (12). Thus, both observations suggested that
viduals with blood samples collected in 1986-87(15); 123
the extent of coronary artery disease was positively corre-
lated with the concentrations of homocyst(e)ine.
new cases of myocardial infarction in this group had been
confirmed by the end of 1990. Each case was matched to
four controls by sex, age, and time since last meal. The
1 Plasma/serum homocyst(e)une [H(e)] is the sum of the thiol- mean concentration of homocyst(e)ine among cases was
containing amino acid homocysteine and the homocysteinyl moi- 12.7 nno]/L, compared with 11.3 j.imol/L in the controls
ety of the disullides homocystune and cysteune-homocysteine, (P = 0.0002). The distribution of values was shifted to-
whether free or bound to proteins. Homocyst(e)inernia relates to
the amount of homocyst(e)ine in blood, plasma, or serum; hyper- ward higher concentrations among cases across the en-
homocyst(efinemia is a term introduced by Malunow et al. (1), tire distribution of values of homocyst(e)ine. By multiple
indicating above-normal concentrations of H(e) (i.e., about >16 logistic regression analyses, adjustment for a wide range
mol/L). Moderate, intermediate, and severe hyperhomocys- of CAD risk factors only slightly attenuated the relative
t(e)inemia refer to concentrations between 16 and 30, between 31
and 100, and >100 moI/L, respectively. Thus, homocystinuria is risk, which remained statistically significant. There was
also called severe hyperhomocyst(e)inemia (2). a trend, as in the Physicians Health Study, for greater

CLINICAL CHEMISTRY, Vol. 40. No. 6, 1994 857

association among younger, as opposed to older, subjects.
The data provide important new evidence supporting the
hypothesis that increased homocyst(e)ine is an indepen-
dent risk factor for coronary disease. The data from this
prospective study are generally compatible with those
observed among the US physicians.
The importance of genetic factors in the control of ho-
mocyst(e)inemia has been clearly demonstrated in a re-
cent paper in Clinical Chemistry: Wu et al. (16) found
concordant high homocyst(e)inemia in at least 12% of 85
families with two or more siblings affected by early CAD.
Previous studies also suggested such a genetic control in
observations on two large series of monozygotic twins (17,
18), as well as in a smaller series of patients with CAD
(19). Moreover, the term familial hyperhomocyst(e)inemia
was introduced in the literature after analysis of data
obtained in a study on relatives of patients with prema-
ture CAD (20). These observations demonstrated that 14%
of CAD patients had familial hyperhomocyst(e)inemia,
condusion similar to that of Wu et al. (16).
Homocyst(e)ine concentrations are affected by both
genetics and diet (17-23). The observations of Jacobsen
et al. (6) and Wu et al. (16) confirm those earlier studies
and provide additional information to reports showing
that concentrations of homocyst(e)ine are decreased by
the administration of folic acid, pyridoxine, vitamin B12,
or bet.aine, singly or in combination (24-26).
In summary, increased hyperhomocyst(e)inemia is
common in patients with coronary, cerebrovascular, or
peripheral arterial diseases. Data suggest that hyperho-
mocyst(e)inemia is an independent risk factor for clinical
and subclinical atherosclerosis. Although supplementary
B vitamins readily reduce plasma concentrations of ho-
mocyst(e)ine, whether such therapy alters the evolution
of arterial occlusive diseases needs to be established by
appropriate clinical trials.
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M. R. Malinow
Oregon Regional Primate Research Center
505 NW 185th Ave.
Beaverton, OR (address for correspondence; fax
503-690-5563)
and The Oregon Health Sciences University
St. Vincent Hospital and Medical Center
Portland, OR 97006
M. J. Stampfer
Dept. of Epidemiology, Harvard School of Public Health
Channing Laboratory, Harvard Medical School
Brigham and Womens Hospital
Boston, MA 02115