From the School of Public Health and Community Medicine (G.S.O.),
Departments of Epidemiology (S.A.A.B.) and of Medicine and Genetics (A.G.M.),
University of Washington, Seattle, Wash.
The list of
preventable and reversible risk factors for atherosclerotic
cardiovascular disease continues to grow. Cigarette
smoking, high blood pressure, physical inactivity, elevated
cholesterol, underlying lipoprotein abnormalities,
lipoprotein(a), diabetes, overweight, male gender, and age are
well-established risk factors. During the 1990s, there have been many
reports associating elevated plasma homocysteine levels with
arteriosclerotic cardiovascular
disease and consistent evidence that dietary and supplemental
folic acid can reduce homocysteine
levels.1 2
The article by Robinson and colleagues3 in
this issue of Circulation presents further evidence of
the importance of homocysteine and suggestive evidence that plasma
folate and plasma pyrixodal-L-phosphate (vitamin B6) are
protective factors. Their study is part of the European Concerted
Action Project,4 which examined 750 patients
younger than age 60 with diagnoses within the previous 12 months of
coronary, cerebrovascular, or peripheral vascular
disease and 800 healthy control subjects. The patient groups were young
(47 years for cases and 44 years for control subjects) and
heterogeneous, with nonfatal clinical events or symptoms of
arteriosclerotic cardiovascular
disease supported by ECG, angiographic, or Doppler evidence; the
study involved 19 centers in nine European countries. Men in the
highest quintile for fasting total homocysteine (tHcy), compared with
the remainder of the population, had an estimated relative risk of 2.2
(95% confidence interval [CI], 1.6 to 2.9), with a striking
dose-response relationship and a more-than-multiplicative interaction
with cigarette smoking and high blood pressure on vascular disease
risk4 ; the corresponding estimated relative risk
for coronary heart disease was similar (2.0; 95% CI 1.6 to
2.8). (tHcy is the sum of homocysteine and homocysteinyl moieties
of oxidized disulfides, homocystine, and
cysteine- homocysteine.)
Robinson and colleagues3 examined three B
vitamins in detail to determine their effects on fasting and
post–methionine-loading tHcy levels and any independent effects on
cardiovascular disease risk. The results should be
considered preliminary. Low folate and low vitamin B6 levels were
statistically significantly more frequent among patients than among
control subjects; a similar tendency for plasma B12 was not
statistically significant. The inverse association with disease for
folate was in part accounted for by increased tHcy levels, but the
association for vitamin B6 was not. Relative risks for the top quintile
of fasting tHcy and for high postload tHcy were 1.69 (CI, 1.26 to 2.26)
and 1.62 (CI, 1.22 to 2.16), respectively, compared with all other
quintiles, after adjustment for the vitamin effects. These relative
risks are similar to the weighted means of other studies; it should be
noted that one must scrutinize reported results for the choice of
comparison groups and the units of change in homocysteine when
comparing estimated relative risks between
studies.2
The findings regarding folate and B6 by Robinson et
al3 would be stronger if they better matched the
metabolic roles of the vitamins in homocysteine
metabolism. Homocysteine is formed from the
sulfur-containing essential amino acid methionine. Homocysteine can be
transsulfurated to cysteine via two B6-dependent reactions or
remethylated to methionine via B12- and folate-dependent reactions.
Because fasting levels are more influenced by remethylation and
post–methionine-load levels are more influenced by transsulfuration,
one would expect folate (and B12) to be acting primarily on fasting
levels and B6 to be primarily acting on postload levels. Both measures
of tHcy were investigated in the 1550 study participants, but no such
differential effects of folate and B6 were found.
In one of several reports since the meta-analyses by our
group,2 5 Verhoef et al6
found relative risks of 1.3 (CI, 1.0 to 1.6) for each 1 SD increase
(5 µmol/L) in fasting tHcy in a comparison of 131 patients with
88 less severely affected patients with coronary artery disease
and 101 population control subjects. Within patients and within control
subjects, there was the expected inverse relationship between each of
the three B vitamins and tHcy levels; but, contrary to expectations,
pyridoxal-5-phosphate and folate levels were not lower in patients
compared with the combined control groups. Among men who had received
routine examinations in London, tHcy was strongly associated with death
from ischemic heart disease (estimated relative risk, 2.9; CI,
2.0 to 4.1, after adjustment for apolipoprotein B and blood
pressure).7 Nygard et al8
reported mortality results for 587 patients with angiographically
confirmed coronary artery disease. After a median follow-up of
4.6 years, 64 had died (50 from cardiovascular causes).
There was a striking graded relationship between plasma tHcy and
overall mortality (eg, 25% of those with tHcy levels of
Not all new studies are consistent regarding the risk of tHcy.
An updated analysis of Physicians' Health Study data yielded a
relative risk for elevated tHcy of only 1.3 (CI, 0.5 to
3.1).9 An analysis of the MRFIT cohort
showed no effect of tHcy after adjustments for other variables
(relative risk, 0.94; CI, 0.56 to 1.56).10 The
ARIC study showed no association between the incidence of
coronary heart disease and tHcy (A Folsom, unpublished data,
1997).
Thus, many questions remain regarding the relationship of folate,
vitamin B12, and vitamin B6 to levels of tHcy; the relationship of
homocysteine to cardiovascular risk; and the best ways
to demonstrate and recommend risk reduction for individual patients and
for populations.
What Is the Best Estimate for the Increased Risk of
Coronary Heart Disease Mortality Associated With Elevated
tHcy Levels?
On balance, based on the references above and the
meta-analysis,5 we believe the best
estimate is a relative risk of 1.4 for the difference between tHcy
levels of >15 µmol/L compared with levels of <10 µmol/L
after adjustment for other cardiovascular risk factors.
This effect is similar to the impact expected from a reduction in total
serum cholesterol from 7.1 to 4.9 µmol/L (275 versus
189 mg/dL).4
How Much Supplementation With Folate (or Other B Vitamins) Is
Desirable and Safe?
We believe it is desirable to bring tHcy levels down to the range
of 9 to 10 µmol/L. Diet alone is unlikely to be sufficient to
increase circulating folate levels and decrease tHcy
levels.2 Also, the bioavailability of folic acid
from typical conjugated folates in the diet is one half that from
supplements. Feeding studies are needed; they must incorporate
information on
methylenetetrahydrofolate reductase
(MTHFR) genotypes (see below) to account for marked variation
in response.
Fourteen intervention studies5 showed substantial
decreases in average tHcy levels after the administration of 650 to
10 000 µg of supplemental folic acid. tHcy concentrations do not
appear to reach a plateau until folate intakes approach 400 µg/d and
serum folate reaches
Clinical trials with folic acid in at least four countries have shown
that the incidence of children born with neural tube closure defects
(spina bifida, meningomyelocoele, anencephaly) to mothers with a prior
neural tube defect–affected pregnancy can be reduced by 50% to 75%,
leading to an official Centers for Disease Control and Prevention
recommendation that all women of childbearing age consume
Fortification, of course, leads to exposure for the total population,
which stimulated urgent consideration of potential health risks,
especially for older adults and any persons with a B12 deficiency. One
of us recalls that Dr William B. Castle informed the first-year Harvard
Medical School class that one should "never give folic acid without
giving B12 first" to avoid potential exacerbation of possibly
irreversible neurological impairments. It is hard to find documentation
for serious neurological complications in previously undiagnosed
persons.13 Nevertheless, to prevent such adverse
outcomes even in individuals with lack of intrinsic factor for B12
absorption, 200 to 1000 µg of cobalamin (B12) could be included in
supplements that contain 400 µg of folic
acid.2 13
Is There Evidence of Genetic Variation in Folate and
Homocysteine Levels?
The original proposal that hyperhomocysteinemia might be important
in atherosclerosis came from work by
McCully14 on the vascular pathology of the inborn
error of metabolism, homocystinuria. However, carriers for
homocystinuria (1 in 400 population), who have half-deficiency of
cystathionine ß-synthase, rarely account for the homocysteine
elevations observed in vascular disease.15 A
common thermolabile variant of the enzyme MTHFR is homozygous in 10%
to 13% of the Caucasian population (TT genotype).
Such individuals, particularly in the presence of suboptimal folate
nutrition, tend to have slightly elevated homocysteine
levels.16 In two different European studies, 35%
of working men in the top decile of tHcy levels had the TT
genotype,17 as did almost everyone with
tHcy levels of >20 µmol/L.18 Despite
several reports that the TT genotype is increased
among patients with premature vascular disease,16
no such association could be demonstrated in 2029 patients with
coronary heart disease when compared with 1639 control subjects
across seven different independent studies (A.G. Motulsky, unpublished
data, 1997). It is noteworthy that homozygotes for the TT
variant had a 21% reduction in tHcy levels after supplementation with
1000 µg of folic acid compared with lesser reductions among
heterozygotes (13%) and the more common homozygotes for the
CC variant (7%).16 It is likely,
therefore, that genetic variants in MTHFR and other enzymes related to
folic acid metabolism (eg, methionine synthase) will
require individuals to have different nutritional and supplement
needs.19 Nutritional needs and intervention
dosages must be tailored to the underlying pathophysiology, a general
challenge we still face in national guidelines for screening and
treatment of elevated serum cholesterol values.
What Kinds of Prevention Trials Are Needed and May Be
Feasible?
Cardiovascular researchers have led the way with
large-scale randomized trials of interventions for patients with
specific clinical conditions (secondary prevention) and for healthy
populations with risk factors for developing
cardiovascular end points (primary prevention trials).
The homocysteine hypothesis should be well suited to a direct test with
folic acid as the intervention. However, as with all trials, the choice
of the study population, choice of the agent or combination of agents,
determination of an adequate and safe dose, and parameters
of the design (incidence rates for the end points, size of effect
expected, duration of intervention and follow-up, and allowance for
nonadherence and for competing causes of death) must all be taken into
account. Potential study populations include cardiac patients and
healthy populations, and genotyped and high tHcy subgroups of
each. Many investigators around the world are considering such trials;
pilot trials will be needed. The lesson learned from the randomized
trials in Finland and the United States that tested the seemingly
compelling hypothesis that ß-carotene would reduce lung cancer and
coronary heart disease incidence and found that this
vitamin/chemical instead increased lung cancer incidence and
cardiovascular mortality20 is
that statistical associations do not prove cause-and-effect
relationships and do not rule out adverse effects. Associations should
not be described as "effects."
Potential trials are complicated by the introduction of folate
fortification of grains and by increasing recommendations for the use
of folic acid supplements in the general population and in cardiac
patients. The Beta-Carotene and Retinol Efficacy Trial (CARET) faced a
similar dilemma when ß-carotene was being added to cereals and
multivitamins and was highly promoted before the trial results were
obtained. It may prove impossible to mount a sufficiently powerful
trial. In that case, the stronger the biochemical,
pathophysiological, nutritional, and genetic
information about the cascade from dietary intake and genetic variation
to circulating levels of folate and tHcy, the more persuasive will be
the current inference of benefit. In CARET, we are analyzing the full
cascade, from food frequency questionnaire estimates of folate intake
and polymerase chain reaction analyses of genetic variation in
the MTHFR enzyme to serum folate and B12 levels, tHcy concentrations,
and observed fatal cardiovascular end points (G.S.
Omenn, M.R. Malinow et al, unpublished data).
The Vitamins in Stroke Prevention (VISP) trial is recruiting 3600
patients with nondisabling strokes to receive a multivitamin
combination containing 2.5 mg of folic acid, 25 mg of B6, and 0.4 mg of
B12 versus a multivitamin with 20 mg of folic acid, 0.2 mg of B6, and 6
mg of B12, with a primary end point of recurrent stroke and secondary
end points of death from cardiovascular disease or
myocardial infarction. The trial is based on a pilot study of
homocysteine lowering in patients with acute
stroke.21 In addition, a protocol has been
announced for a nested case-control study among 30 000 patients
receiving drugs for heart disease or high blood pressure in general
practices in Norway.22
What Should Clinicians Do With Present Knowledge?
Because we interpret the totality of the current evidence linking
folic acid, homocysteine, and cardiovascular disease
risk as remaining strong with respect to the potential benefits of
increasing folic acid intake on a population-wide basis, we recommend
that everyone consume
Footnotes
Reprint requests to Gilbert S. Omenn, MD, PhD, Executive Vice President for Medical Affairs, The University of Michigan, Ann Arbor, MI 48109-0624.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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© 1998 American Heart Association, Inc.
Editorials
Preventing Coronary Heart Disease
B Vitamins and Homocysteine
Key Words: Editorials • heart disease • vitamins • homocysteine
15
µmol/L had died compared with 4% of those with levels of <9
µmol/L). tHcy levels were strongly related to history of myocardial
infarction, left ventricular ejection fraction, and serum
creatinine level but much less related to extent of
coronary artery disease on angiography. 15 µmol/L.11 Other
studies have shown significantly lower tHcy levels in persons taking
supplements containing folic acid than in those relying on diet. Thus,
a supplement containing 400 µg of folic acid is expected to produce
an average reduction of 5 µmol/L tHcy in nonusers of
supplements.2 5 A higher dose of folic acid might
be necessary in some persons (see below). 400 µg/d
folate.12 This public health intervention may be
one of the most important steps to prevent serious birth defects.
Because surveys showed that only 7% to 12% of women were taking folic
acid supplements at the time they became pregnant, in March 1996 the
Food and Drug Administration responded to advice and petitions by
requiring that cereal grain products be fortified at the level of
140 µg of folic acid/100 g of product, beginning in January
1998. 400 µg of folic acid/d. Potentially pregnant
women should take more to maximize the protective effect against neural
tube closure defects. Screening for tHcy levels would be useful for
individual risk profiles and for targeting efforts at adherence or
recommendations for higher doses. Common multivitamins contain 2 to 3
mg of B6 and 6 to 9 µg of B12. We have no recommendation on B6
because definitive evidence of an inverse association with tHcy levels
and of an optimal dose does not exist. As noted above, we
recommended2 and urged the Food and Drug
Administration to mandate inclusion of sufficient B12 in folic acid
capsules (200 to 1000 µg) to ensure adequate absorption by passive
mechanisms even in the absence of intrinsic factor. Inclusion of B12 in
the fortified grains deserves consideration, as well; if it is not
included, B12 should be prescribed, especially to protect older
individuals with various degrees of B12
deficiency.13
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