Plasma homocysteine levels and mortality in patients with coronary artery
||Nygard O, Nordrehaug J, Refsum H, Ueland P, Farstad M, Vollset
||New England Journal of Medicine. 337:230-6. July
||University of Bergen and Haukeland University Hospital,
||Norwegian Council on Cardiovascular Diseases and the Norwegian
Homocystinuria, a disease characterized by very high levels of circulating
and urinary homocysteine, is associated with premature vascular disease.
There has been increasing interest in the role of moderately elevated homocysteine
levels in the pathogenesis of vascular and thrombotic diseases, in particular
coronary disease. There is evidence that homocysteine may be involved in
the pathogenesis of thrombotic events (which complicate atherosclerotic
disease), rather than in the development of atherosclerosis per se. In
order to investigate this hypothesis further, the authors looked at five-year
mortality in a cohort of patients with angiographically proven coronary
disease who had documented homocysteine levels at the time of angiography.
587 patients with angiographically documented coronary disease, studied
between February 1991 and June 1992.
Angiograms were interpreted blindly, and stenoses of at least 50% were
considered significant. CAD was scored as single, double or three vessel
disease, (left mainstem without RCA disease was scored as double vessel
disease). LV ejection fraction was also assessed.
History data collected
History of angina, hypertension, diabetes, family history of premature
coronary disease, other medical problems, medications, lipid-lowering diets,
smoking history and history of vascular events (myocardial infarction,
cerebrovascular disease, peripheral vascular disease).
At the time of angiography, blood was collected and analyzed for: plasma
total homocysteine, serum total cholesterol, HDL cholesterol, triglycerides,
serum apolipoproteins A-I and B and serum lipoprotein Lp(a). LDL cholesterol
Follow-up and causes of death
Deaths occurring between the time of angiography and April 30, 1996
were determined from the National Population Register, and causes of death
were obtained from death certificates.
Demographics: 478 men (81%), 109 women. Median age 62 years.
Predictors of homocysteine level
Clinical CAD: 22% had unstable angina; 57% had previous MI; 11%
had history of CABG.
Risk factors: Diabetes in 7% of patients; 27% had hypertension;
27% were smokers, 48% former smokers.
Medications: Aspirin 45%; beta-blocker 73%; calcium blocker 44%;
ACEI 9%; lipid-lowering medication 6%.
Angiographically documented CAD: single vessel disease in 16%
of patients; double vessel in 29%; three vessel disease in 55%. Ejection
fraction was below 50 in 13% of patients.
After angiography, 20% of patients were referred for PTCA, 54% for CABG,
13% were not accepted for revascularization, mainly because of diffuse
peripheral CAD and 12% had no indication for revascularization.
A number of clinical and biochemical factors were related to total homocysteine
Homocysteine levels and mortality
Sex: mean level was 11.4 umol/l in men, 10.5 umol/l in women
Age: increase with age (1.3 umol/l with each 20 years of age)
Prior MI: 1.0 umol/l higher
EF below 50%: 1.2 umol/l higher
Hypertensive therapy: 0.7 umol/l higher
After adjustment for age and sex, the strongest predictors were:
serum folate level (r=-0.36)
serum creatinine (r=0.30)
serum uric acid (r=0.17)
serum B12 (r=-0.15)
LV ejection fraction (r=0.13)
After median follow-up of 4.6 years, overall mortality was 11.1% among
men (53/478) and 10.1% among women (11/109), with a strong, graded dose-response
relationship to homocysteine levels. Kaplan-Meier estimate of 4-year mortality
was 3.8% for patients with homocysteine levels under 9 umol /l, 8.6% for
those with levels between 9 and 14.9, and 24.7% for those with levels of
15 or greater. These results were not adjusted for age, sex or other potential
In a multivariate model, after adjustment for age, sex, homocysteine
level, LV ejection fraction, serum creatinine, total cholesterol, extent
of CAD, treatment for hypertension, diabetes, smoking status, platelet
count and aspirin use, the three most significant predictors of mortality
were LV ejection fraction, serum creatinine and serum homocysteine. The
adjusted mortality ratio for these three predictors were (adapted from
Table 1 in the article):
||Number of patients
||Adjusted mortality ratio
Left Ventricular ejection fraction
Serum Creatinine (mg/dl)
Plama homocysteine (umol/l)
This relationship between homocysteine and mortality held up in multiple
The dose-response relationship between homocysteine level and mortality
was nearly linear, with a steeper slope at higher levels, however. At a
level of 15 umol/l, the mortality ratio for an increase in homocysteine
of 5 umol/l was roughly 2.
Lipid factors were only weakly or not at all related to mortality, in
this study. Serum folate was weakly related to mortality, but this association
disappeared after adjustment for homocysteine level. B12 level was not
associated. The relationship between homocysteine and mortality was not
affected by adjustment for either serum folate or B12 levels.
When only cardiovascular causes of mortality were considered (50 out
of the 78 deaths), the relationship was strengthened slightly.
Predictors of coronary disease and previous MI
The extent of coronary disease at the time of angiography was only weakly
related to the homocysteine level, but strongly related to serum lipids.
In contrast, a history of previous MI was strongly related to homocysteine
level, but not to lipid levels. Serum folate and B12 levels were related
to neither of these.
The authors make a number of points in their discussion, including the
The relationship between homocysteine levels and mortality was apparent
early (within a few months) and the dose-response effect was seen across
a broad range of homocysteine levels.
Although the results of this study suggest that homocysteine is associated
with the risk of thrombotic events, while lipid levels are associated with
the development of atherosclerosis, these processes are not mutually exclusive
and other studies have found an association between homocysteine and extent
of vascular disease.
Although there is always the potential for confounding in studies such
as these (homocysteine being just a marker for another, causal factor),
the multiple adjustments that were made here, and the consistency across
various subgroups makes this less likely.
The authors conclude that their results should provide an additional
incentive to performing intervention trials with homocysteine-lowering
This study looked at all-cause mortality in a group of patients with angiographically-documented
coronary artery disease. Patients with higher plasma homocysteine levels
at baseline had a higher mortality. Homocysteine did not correlate with
the degree of coronary disease, however. Furthermore, serum lipids, which
did correlate with the extent of coronary disease, did not correlate well
with mortality. The authors conclude that homocysteine has a role in the
development of thrombotic events, whereas the role of lipids is more in
the development of atherosclerosis, per se.
This study is thus interesting for two reasons: it provides another
piece of evidence that moderately elevated homocysteine levels contribute
to vascular morbidity and mortality, and it also hypothesizes a mechanism
for the respective roles of homocysteine and lipids in the pathogenesis
of these conditions.
Evidence that homocysteine is involved in vascular pathology has been
accumulating for many years; interest in its role has increased greatly
over the past few years. There have been numerous studies published, most
of which confirm an association. Many of these studies were case-control.
The study presented here is a cohort follow-up study, which is somewhat
less prone to selection bias.
Obviously, an association neither guarantees causality nor ensures that
lowering elevated homocysteine levels will decrease morbidity, but it is
an important first step. Controlled intervention trials are urgently needed
and will hopefully be undertaken soon.
The hypothesis that homocysteine contributes to the thrombotic side
of the story, whereas lipids contribute to the atherosclerotic side is
fascinating. Not all previous studies confirm this but, as the authors
point out, the pathogenesis of atherosclerosis is a complex process. Thrombotic
events can lead to a progression of atherosclerosis and might explain some
studies that have found a correlation between the extent of vascular disease
and homocysteine levels. Certainly, if the mechanism hypethesized here
turns out to be correct, one could envision a dual-pronged approach to
the problem of vascular disease: combatting the atherosclerotic process
with lipid-lowering therapy while decreasing the incidence of acute events
by lowering homocysteine levels. The statin-manufacturers are probably
breathing a little sigh of relief, here.
I suspect that we will be seeing and hearing much more about this topic
in the near future -- the Sunday New York Times Magazine had an article
on it a few weeks ago.
September 2, 1997
related to this article from the NLM's PubMed
Date: Wed, 03 Sep 1997
From: Colin Rose <firstname.lastname@example.org>
Actually, the randomized trials have already been done but it wasn't
realized at the time that the intervention was in part hypohomocysteinemic.
I refer of course to all those diet trials showing reduction of coronary
events and regression of atherosclerosis (Ornish, Renaud, STARS, etc.)
in which meat was reduced and fruits and vegetables increased. This is
exactly the type of diet which would reduce blood homocysteine.
Homocysteine is a metabolite of methionine, an essential amino acid
which can only enter to body via food. The food which contains the most
methionine is animal protein. Folate, which is required for the metabolism
of homocysteine, comes from vegetables. Ergo, less meat and more vegetables
is the answer. If you also make the diet low fat you also reduce cholesterol.
On this type of diet almost nobody should get CAD and those who have it
should almost eliminate events and regress their disease.
Dr. Colin Rose
This is an excellent point. Of course, the only way to tell how
much event reduction is due to homocysteine reduction and how much to cholesterol
reduction would be to measure both and do regression analysis or adjustment.
I wonder if any of these trials have samples left over in which homocysteine
could be measured... -- mj
Date: Tue, 11 Nov 1997
From: "Aloyzio Achutti" <email@example.com>
Another confounding factor to be discussed on the meat & homocysteine
x cholesterol issue, is the role of iron for people with enhanced intestinal
absorption of this element. Heterozygotic hemochromatosis is said to be
one of the most frequent chromosomal anomalies in the general population.
Meat (particularly red meat) is also one of the sources of iron. Exaggerated
iron deposits are implicated in the free radicals mechanism and in atherosclerosis.
Home page: http://www.plug-in.com.br/~achutti
January 5, 1998
to the editor about this article, from the November 27, 1997 New England
Journal of Medicine.
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