Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Double-standards
- Ron Law (17 January 2003)
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On the beneficial effects of contaminants in folate supplements
- Richard G Fiddian-Green (17 January 2003)
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Observational studies are fatally flawed by unmeasured confounders.
- D.G. Hackam (18 January 2003)
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homocystein not a coronary risk factor
- dr.manan vasenwala md,mrcp (19 January 2003)
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B-vitamins and cardiovascular risk
- Dietmar Fuchs, Katharina Schroecksnadel, Barbara Frick (23 January 2003)
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Misinterpretation of Study Results
- David S Wald, Malcolm Law, Joan Morris, Nicholas Wald (4 February 2003)
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Ron Law, Principal Beyond Alternative Solutions
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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 |
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Richard G Fiddian-Green, None None
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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 |
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D.G. Hackam, Dept of Medicine McMaster Univ, Hamilton, Canada
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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 |
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dr.manan vasenwala md,mrcp, consultant-cardiologist (non-invasive) k.k.heart center, aligarh.202002,INDIA
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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 |
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Dietmar Fuchs, Unievrsity of Innsbruck A-6020 innsbruck, Austria, Katharina Schroecksnadel, Barbara Frick
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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
Institute of Medical Chemistry and Biochemistry,
University of Innsbruck, Innsbruck, Austria
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 |
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David S Wald, Specialist Registrar in Cardiology Southampton General Hospital, UK SO17 1PJ, Malcolm Law, Joan Morris, Nicholas Wald
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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 (<3mg/l) the median serum folate is likely to have been at least 1mg/l, so the difference was about 7mg/l. This is a narrow range of values, indicating that few of the study participants took folic acid tablets and that the variation in fruit and vegetable consumption between them was relatively small. This limits the ability of the study to demonstrate an effect. 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 ˝ x ˝ x ˝ x ˝ x ˝ x ˝ x ˝ 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 |
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