HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wilcken, D. E. Articles by Brattström, L. Search for Related Content PubMed Articles by Wilcken, D. E. Articles by Brattström, L. Agricola Articles by Wilcken, D. E. Articles by Brattström, L.

Reply to R Cerone et al

Department of Cardiovascular Medicine, University of New South Wales, The Prince Henry and Prince of Wales Hospitals, Sydney, Australia
Department of Medicine, County Hospital, SE-391 85 Kalmar, Sweden, E-mail: lars.brattstrom{at}ltkalmar.se

Dear Sir:

We thank Cerone et al for their comments about our article. In relation to the 2 questions they posed, the first relates to the question of whether to treat patients with mild hyperhomocysteinemia but no 677CT mutation (C-to-T substitution at nucleotide 677) of the MTHFR gene or patients homozygous for the mutation but with normal total homocysteine concentrations. We attempted to answer this question in a meta-analysis of 23 case-control studies involving 5869 patients with established atherosclerotic vascular disease and in 6644 control subjects. We found no significant difference in the prevalence of the mutant gene in the vascular disease patients regardless of whether it was associated with a mild elevation in homocysteine (1). Thus, the presence of the gene variant does not itself provide an indication for folate treatment. Furthermore, in our recent article that included a meta-analysis of 2683 patients with venous thromboembolism and 3306 control subjects, the prevalence of homozygotes for the mutant TT genotype was the same in patients with venous thrombosis and control subjects (2). Thus, all of these results are consistent with our view that the presence of the MTHFR gene mutation is benign and does not itself enhance cardiovascular risk.

With regard to the second question about homocysteine measurement, it should be remembered that an abnormal increase in homocysteine after a methionine load reflects impaired transsulfuration, which is pyridoxine-dependent, and not the remethylation of homocysteine to methionine, which is predominantly folate-dependent but also requires vitamin B-12. Thus, a practical approach is simply to measure total homocysteine concentrations after an overnight fast because elevated concentrations reflect abnormalities in either of these 2 pathways. Total free homocysteine concentrations may be a more accurate indicator of homocysteine-related endothelial dysfunction (3).

The most important and as yet unresolved question is whether therapy that lowers modestly elevated circulating homocysteine concentrations also reduces cardiovascular risk. This will be determined within the next few years when the results of ongoing trials designed specifically to answer this question are available (4). In the meantime, it is reasonable to consider treatment in patients with established vascular disease and a paucity or absence of conventional risk factors other than a modest elevation in homocysteine.

REFERENCES

1. Brattström L, Wilcken DEL, Öhrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease. Circulation 1998;98:2520–6.
2. Brattström L, Wilcken DEL. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000;72:315–23.
3. Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation 2000;102:2479–83.
4. Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B₆ reduce cardiovascular risk? Design of clinical trials to test the homocysteine hypothesis of vascular disease. J Cardiovasc Risk 1998;5:249–55.

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wilcken, D. E. Articles by Brattström, L. Search for Related Content PubMed Articles by Wilcken, D. E. Articles by Brattström, L. Agricola Articles by Wilcken, D. E. Articles by Brattström, L.