Folate and vitamin B-12 and risk of fatal cardiovascular disease: cohort study from Busselton, Western Australia
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7381.131 (Published 18 January 2003) Cite this as: BMJ 2003;326:131All rapid responses
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Hung and his colleagues conclude that the results of their cohort
study on serum folate and coronary heart disease,(1) provide evidence
against the view that folic acid prevents ischaemic heart disease. We
disagree and believe that they have misinterpreted the results in their
paper.
A meta-analysis of studies on serum homocysteine and cardiovascular
disease (2) (supported by other meta-analyses(3,4)), together with
randomised trial evidence on folic acid dose and serum homocysteine
reduction,(5) shows that the maximal effect of folic acid in lowering
serum homocysteine occurs at a dose of about 0.8mg/day, and that this
homocysteine reduction lowers the risk of ischaemic heart disease events
by about 16%. This effect while modest is worthwhile since folic acid is
inexpensive and safe. A folic acid dose of 0.8mg/day increases serum
folate by 20 mg/l,5 so in a cohort study one would expect a difference in
risk of about 16% for a serum folate difference of 20mg/l. The difference
in average serum folate between the highest and the lowest folate group in
the cohort study of Hung and colleagues was not stated in the paper. But
they state that the 93rd centile of serum folate in the cohort was 9mg/l
so the 85th centile (the median of the highest folate group) must have
been less than this, say 8mg/l. In the lowest folate group (Taking the serum folate difference between the highest and the lowest
group to be 7mg/l, one would expect a relative risk of ischaemic heart
disease death in the lowest compared to the highest serum folate group in
their study of about 1.05, consistent with the observed relative risks
(table 21) of 1.10 in men and 1.14 in women. These results weigh in
favour, not against, the view that folic acid reduces the risk of
cardiovascular disease.
Table 4 of their paper confirms this. Hung and colleagues present
data from six other cohort studies of serum or dietary folate and
ischaemic heart disease, which with their own study make a total of seven.
Each of these studies shows a higher risk of ischaemic heart disease in
the lowest folate group compared with the highest. This observation alone
is statistically highly significant. If there were no association half of
the studies in expectation would have relative risks above 1.0 and half
below; the probability that all 7 studies have estimates above 1.0 by
chance alone is ½ x ½ x ½ x ½ x ½ x ½ x ½ or 1 in 128, a p value of
0.008). The median of the seven relative risk estimates is 1.45. Their
negative conclusion is therefore inappropriate. The stronger than expected
association is probably explained partly by confounding (people with high
serum folate have diets that tend to be healthy independently of the
folate content), and partly by the modest cause and effect relationship
established by other sources of evidence.(2-4)
References
1 Hung J, Beilby JP, Knuiman MW, Divitini M. Folate and vitamin B-12 and
risk of fatal cardiovascular disease: cohort study from Busselton, Western
Australia. BMJ 2003;326:131-6
2 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease:
evidence on causality from a meta-analysis. BMJ 2002;325:1202-8
3 The Homocysteine Studies Collaboration. Homocysteine and risk of
ischaemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-22
4 Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, et al.
MTHFR 677®T polymorphism and risk of coronary heart disease: a meta-
analysis. JAMA 2002;288:2023-31
5 Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D, et al.
Randomised trial of folic acid supplementation and serum homocysteine
levels. Arch Intern Med 2001;161:695-700
Competing interests:
None declared
Competing interests: No competing interests
Hung and coworkers conclude that lower concentrations of B-vitamins
do not increase the risk for coronary heart disease or cardiovascular
disease.1 However, they found an inverse, albeit but not significant
correlation between serum folate concentrations and fatal cardiovascular
disease in women who had no cardiovascular disease at baseline. A possible
stronger association between serum folate concentrations and
cardiovascular risk may be masked by high interindividual variability of
folate concentrations, and replicate measurements of serum folate over
time have not been performed. The question arises why there is such a
great variability of folate concentrations between individuals.
Insufficient dietary intake usually is considered as the cause for
deficiency of B-vitamins folate and vitamin B-12, but still there is also
evidence that other factors may influence folate concentrations, e.g
immune activation.2
Atherosclerosis and coronary heart disease are associated with chronic
immune activation, reflected by increased markers of immune activation,
e.g. neopterin or C-reactive protein.3 In states of immune activation,
especially activated macrophages produce a record of reactive oxygen
intermediates, which oxidize antioxidants, LDL-lipoproteins and other
oxidation-sensitive compounds. Methyl-tetrahydrofolate, the active form of
folate and a necessary cofactor in many methylation-reactions, is readily
oxidized, and so is vitamin B-12. On-going oxidative stress in scope with
chronic immune activation could therefore lead to the depletion of these
compounds, depending on the severity and the course of disease the redox-
balance in patients could be influenced strongly and increase the demand
for B-vitamins. Then vitamin deficiency is no longer a primary event in
atherogenesis. However, depletion of antioxidants or vitamins could be
reduced or even prevented by vitamin- and antioxidant-rich diets required
to compensate for their enhanced consumption. In several studies it was
demonstrated that supplementation of folate was able to lower homocysteine
levels and also improve endothelial function, the latter effect was even
shown to be independent of homocysteine lowering. 4 Therefore
supplementation of folate and other vitamins by diets containing huge
amounts of fruit and vegetables may on the one hand provide an adequate
explanation for a high interindividual variability of measured vitamin
concentrations and may on the other hand also appear promising to prevent
the development of cardiovascular disease.5
Katharina Schroecksnadel
Barbara Frick
Dietmar Fuchs
Institute of Medical Chemistry and Biochemistry,
University of Innsbruck, Innsbruck, Austria
E-mail: dietmar.fuchs@uibk.ac.at
References
1.Hung J, Beilby JP, Knuiman MW, Divitini M. Folate and vitamin B-12 and
risk of fatal cardiovascular disease: cohort study from Busselton, Western
Australia. BMJ 2003;326:131.
2.Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner-Dworzak E, Leblhuber
F. Is hyperhomocysteinemia due to oxidative depletion of folate rather
than insufficient dietary intake. Clin Chem Lab Med 2001;39:691-4.
3.Erren M, Reinecke H, Junker R, Fobker M, Schulte H, Schurek JO et al.
Systemic inflammatory parameters in patients with atherosclerosis of the
coronary and peripheral arteries. Arterioscler Thromb Vasc Biol
1999;19:2355-63.
4.Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ et al.
Folic acid improves endothelial function in coronary artery disease via
mechanisms largely independent of homocysteine lowering. Circulation
2002;105:22-6.
5.Eichholzer M, Luthy J, Gutzwiller F, Stahelin HB. The role of folate,
antioxidant vitamins and other constituents in fruit and vegetables in the
prevention of cardiovascular disease: the epidemiological evidence. Int J
Vitam Nutr Res 2001;71:5-17.
Competing interests:
None declared
Competing interests: No competing interests
about 50% on infarct patients do not have overt hyperlipidemia. thus
one is on the lookout for a novel marker of atherogenesis. homocystein is
one such novel
marker. however multiple studies have shown that homocystein is not in
fact a risk factor for coronary artery disease. using prospective studies,
ascertaining
homocystein levels before the start of study found no relationship
between homocystein levels and vascular risk. it is perhaps the reason why
this study did not
reveal any difference in mortality based on B12 AND FOLATES levels.
an interesting observation is whereas Europeans tend to be
deficient in folate, Indians are cobalamine deficient as shown by one
study. it is not known if this study can be extrapolated to whole of
india. earlier it was beleived that risk to coronary artery disease is
limited to those with modest to high elevations of homocystein
levels.however, the lack of compelling evidence, make it uneconomical to
screen these patients for homocystein. also there does not appear to be a
case for dietary supplements en masse. mutation in the methylene
tetrahydrofolate reductase gene (mthfr) which leads to severe elevations
of homocystein have failed to show any association of ischaemic heart
disease in these group.from a genetic perspective, it is not useful to
screen these patients for homocystein. other conditions which lead to
elevation of homocystein are renal failure, hypothyroidism,and
carbamazepine and methotrexate use. in none of these conditions have there
been any association to coronary artery disease.in usa, food is fortified
with folates to reduce incidence of neural tube defects. this has lead to
a fall of homocystein levels in the population by a mean of 10%. also the
there has been a drop by 50% in those patients having a modest elevation
of homocystein of 150umol/l.(i.e high risk patients).thus screening for
homocystein in these patients is not warranted.
this brings to question the very high incidence of coronary artery disease
among young male indians.earlier it was postulated that high levels of
homcystein levels
may be a cause. high values of lipoprotein"a" was another. indian practice
of chewing tobacco (called gutka) may be contributing.
Competing interests:
None declared
Competing interests: No competing interests
I have two points of contention with this study, as with all the studies that showed that HRT reduced cardiac risk enormously in post-menopausal women, and vitamin antioxidants similarly in the general population (both men and women). (By the way, both claims have now been refuted by large randomized trials, and almost no one in their right mind would prescribe Vitamin E, C, or estrogen or progesterone before the prescription of proven aspirin, statins, ace inhibitors, and beta blockers, if at all).
1) The above shows the whopping disparity between randomized trials and observational data. The observational data on folate/B12 clearly conflict. Therefore I am not sure if this large observational study adds anything to the literature. By definition, an observational study can't equalize all confounding, unknown, and unmeasured covariates, which thus introduces enormous bias into the study.
2) There is no comment on measuring homocysteine, at least in the abstract.
3) Homocysteine is the end sum of multiple gene-environment interactions, including, amongst other agents: drugs, thyroid dysfunction, renal dysfunction, HRT, MTHFR gene, cobalamin synthase gene, AND last but not least B6, B12, and folic acid in diet.
Competing interests:
None declared
Competing interests: No competing interests
It has been argued that hyperhomocysteinemia might be the result of
an inadequacy of mitochondrial oxidative phosphorylation, or “lactic
acidosis” (1). It has been further proposed that cardiovascular diseases
and their other associated risk factors might be the result of an
inadequacy of oxidative phosphorylation in endothelial cells and adjacent
cells. In which case the beneficial effects of vitamin B supplements that
have been observed in some studies (2) might have been due to the ability
of commercially available folate supplements to produce a time-dependent
inhibition of xanthine oxidase rather than to their ability to reduce the
levels of homocysteine (3).
Inhibiting xanthine oxidase not only prevents the generation of free
radicals but appears also to limit the loss of adenine nucleotide as uric
acid in the urine and thus preserving the ability to replenish ATP stores
by oxidative phosphorylation. Xanthine oxidase inhibitors can, however,
only be effective if xanthine dehydrogenase has been converted to xanthine
oxidase by activation of the calcium-dependent protease by hyoxia or
cytokine release. The implication is that patients in whom beneficial
effects of folate supplements were observed might have had an inadequacy
of mitochondrial oxidative phosphorylation.
The discrepancy between the effects of folate and B12 supplements
reported in the present study (4) and that reported in others might,
therefore, be due to differences in the content of pterin aldehyde (2-NH2
-4-OH-pteridine-6-aldehyde), a photolytic breakdown product of folic acid
(3). The inhibitory effects which commerical preparations of folate have
upon xanthine oxidase appear to be due to this contaminant rather than the
folate per se.
1. "Lactic acidosis": the common denominator? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003
2. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, et al.
Decreased rate of coronary restenosis after lowering of plasma
homocysteine levels. N Engl J Med 2001; 345: 1593-1600
3. Spector T, Ferone R. Folic acid does not inactivate xanthine oxidase. J
Biol Chem. 1984 Sep 10;259(17):10784-6.
4. Folate and vitamin B-12 and risk of fatal cardiovascular disease:
cohort study from Busselton, Western Australia Joseph Hung, John P Beilby,
Matthew W Knuiman, and Mark Divitini BMJ 2003; 326: 131.
Competing interests:
None declared
Competing interests: No competing interests
If the conclusions of this study had been applied to the multi-
billion dollar cholesterol lowering industry in its infancy, no such
industry would exist today.
Heart disease is not the only reason for increasing folic acid intake
-- what about cancer of the colon? NTD? etc, etc...
Competing interests:
None declared
Competing interests: No competing interests
Let it be Phase 4 clinical trial - Distribute vitamin B6, B12 and Folic acid to all and then see the trends of various medical conditions in population
B-complex vitamins are water soluble vitamins and hypervitaminosis is
not seen generally because excess gets removed in urine. Vitamin B6
(Pyridoxal Phosphate), B9 (Folic acid) and B12 (cynocobalamin) are
implicated in Methionine- homocysteine metabolism and their administration
causes reduction of homocysteine. Subjects with raised tHcy levels have
increased risk of cardiovascular and noncardiovascular mortality, and are
more likely to suffer from depression and from cognitive deficit
(elderly). Among women, raised tHcy levels are associated with decreased
bone mineral density and increased risk of osteoporosis. Women with raised
tHcy levels also have an increased risk of having suffered from pregnancy
complications and an adverse pregnancy outcome1.
Though these vitamins lower the total homocysteine levels but present
research is inconclusive of their benefit in lowering the morbidity and
mortality due to various medical conditions. Instead of doing small
studies, why not distribute these vitamins to all??!! And then see the
impact on health of the population subgroups, as such these vitamins are
harmless.
References:
1. Refsum H, Nurk E, Smith AD, Ueland PM, Gjesdal CG, Bjelland I,
Tverdal A, Tell GS, Nygård O, Vollset SE.The Hordaland Homocysteine Study:
a community-based study of homocysteine, its determinants, and
associations with disease. J Nutr. 2006 Jun;136(6 Suppl):1731S-1740S.
Review
Competing interests:
None declared
Competing interests: No competing interests