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Treatment of coronary heart disease with folic acid: is there a future?

2004; American Physical Society; Volume: 287; Issue: 1 Linguagem: Inglês

10.1152/ajpheart.00952.2003

1522-1539

Stuart J. Moat, Sagar N. Doshi, Derek Lang, I.F.W. McDowell, Malcolm Lewis, Jonathan Goodfellow,

Cardiovascular Issues in Pregnancy

SPECIAL MEDICAL EDITORIALSTreatment of coronary heart disease with folic acid: is there a future?Stuart J. Moat, Sagar N. Doshi, Derek Lang, Ian F. W. McDowell, Malcolm J. Lewis, and Jonathan GoodfellowStuart J. Moat, Sagar N. Doshi, Derek Lang, Ian F. W. McDowell, Malcolm J. Lewis, and Jonathan GoodfellowPublished Online:01 Jul 2004https://doi.org/10.1152/ajpheart.00952.2003MoreFiguresReferencesRelatedInformationSectionsBiochemistry of Homocysteine and FolateHomocysteine Hypothesis of Cardiovascular DiseasePossible Mechanisms of Homocysteine-Mediated Cardiovascular DiseaseHomocysteine as a Marker of InflammationEndothelial Function as a Surrogate for Vascular DiseaseHomocysteine, Folate, and Endothelial FunctionPotential Mechanisms of Action of Folic AcidHomocysteine lowering. Reduction in superoxide production.Interaction with endothelial nitric oxide synthase.Is Folic Acid a Nutritional Supplement or a Pharmacological Agent?Implications for Folic Acid as Therapy for CHDSafety Implications With Widespread Use of Pharmacological Doses of Folic AcidConclusionsAUTHOR NOTESPDF (235 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat coronary heart disease (CHD) due to atheroma in the coronary arteries is a major cause of morbidity and mortality in the developed world. The recognition of atherosclerosis as an inflammatory condition and the identification of several of its modifiable risk factors have led to new treatments. Secondary prevention of CHD now includes lifestyle modification, smoking cessation, weight loss, regular exercise, and treatment with aspirin, β-blockers, statins, angiotensin-converting enzyme (ACE) inhibitors, and ω-3 fatty acids. These treatments have reduced the risk of further cardiovascular events, but there is still room for improvement. Thus the search for new modifiable risk factors continues and one relatively new potential candidate is plasma total homocysteine (tHcy).Biochemistry of Homocysteine and FolateThe metabolism of homocysteine and folate are closely linked (Fig. 1). Homocysteine is a naturally occurring sulfur-containing amino acid derived from the dietary amino acid methionine. Methionine is converted to S-adenosylmethionine via the enzyme methionine adenosyltransferase. S-adenosylmethionine is then demethylated to S-adenosylhomocysteine, which is the only methyl-donating pathway in humans. This pathway is essential in providing methyl groups to produce many biomolecules such as DNA, creatine, proteins, phospholipids, and neurotransmitters. S-adenosylhomocysteine is then hydrolyzed to homocysteine in a reversible reaction, in which S-adenosylhomocysteine formation is favored. Once formed, homocysteine can be remethylated to methionine by two different pathways: 1) via the enzyme methionine synthase, which utilizes vitamin B12 as a cofactor and 5-methyltetrahydrofolate as the methyl donor, and 2) via the enzyme betaine-homocysteine methyltransferase. Alternatively, homocysteine can be metabolized via the vitamin B6-dependent enzyme cystathionine β-synthase (CβS) to cystathionine, which is then hydrolyzed to cysteine by cystathionase, which also requires vitamin B6 as a cofactor. Cysteine is then either converted to glutathione, taurine, or sulfate, which is excreted in the urine. During periods of excess methionine intake or if the requirements for methyl groups are low, homocysteine will enter the transsulfuration pathway. During periods of low methionine intake and/or increased requirements for methyl groups, homocysteine is remethylated to methionine.Fig. 1.Metabolism of folate and homocysteine. SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; CβS, cystathionine β-synthase; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; BHMT, betaine-homocysteine methyl transferase; DHF, dihydrofolate; THF, tetrahydrofolate; 5,10-MTHF, 5,10-methylenetetrahydrofolate; 5-MeTHF, 5-methyltetrahydrofolate; B2, vitamin B2; B6, vitamin B6; B12, vitamin B12.Download figureDownload PowerPointHomocysteine Hypothesis of Cardiovascular DiseaseIn 1969, a report linking marked elevations of homocysteine (homocystinuria) to arteriosclerosis and thromboembolism in children with different inherited abnormalities of homocysteine metabolism led to the concept of homocysteine as a mediator of vascular disease (44). In homocystinuria, it is clear that the grossly elevated tHcy concentrations (>100 μmol/l) may play a direct role in the development of vascular and thrombotic disease. In the general population, however, tHcy concentrations are much lower ( 13 μmol/l) by ∼50% has been observed in the Framingham offspring population study (33). Disappointingly, despite this significant reduction in plasma tHcy concentrations, no reduction in the incidence of cardiovascular mortality has yet been reported in the United States. However, a longer follow-up period may be needed to fully substantiate any effect of homocysteine lowering on cardiovascular mortality in the general population.Many studies have confirmed the homocysteine-lowering effects of folic acid supplementation, but there are relatively few data on the effect of folate supplementation on CHD outcome. The observations that high-dose folic acid will improve endothelial function, reduce carotid artery plaque size, and reduce coronary artery restenosis rates after angioplasty are of significant potential importance, given that folic acid is a safe, cheap, and well-tolerated treatment.In homocystinuria, due to a deficiency in the enzyme CβS, folic acid and vitamin B6 lower the grossly elevated tHcy concentrations (>100 μmol/l) observed in these patients and significantly reduce cardiovascular events. This benefit is observed despite residual tHcy concentrations being several times the upper limit of “normal” (∼15 μmol/l), further suggesting beneficial actions of B vitamins independent of homocysteine lowering (81).There are currently several large-scale randomized controlled clinical trials underway to assess the beneficial effects of folic acid and other B vitamins on cardiovascular outcome (19). These studies are designed to test the “homocysteine hypothesis” of vascular disease, and this is reflected in the dose of folic acid used. Most of the trials underway at the moment are using moderate doses of folic acid in the range of 0.2–2.5 mg/day. Hence, if folic acid has other direct pharmacological actions other than homocysteine lowering, these effects may be lost because the dose of folic acid is too low. The recently proposed Cardiac “Poly Pill” being advocated as a panacea for the treatment of CVD includes folic acid at a dose of 800 μg as one of the ingredients (76). This dose was selected as the minimum needed to ensure maximum plasma tHcy lowering (74) and the premise that reducing homocysteine will prevent CVD (75). This view should be taken with caution, because there are dangers in concluding causality from a meta-analysis of observational data. Results from the United Kingdom's Cambridge Heart Antioxidant Study (5), a seconday intervention trial of high-dose folic acid (5 mg/day) on cardiovascular events in patients with ischemic heart disease, have recently been reported. This study comprised 942 patients on folic acid and 940 patients on placebo, with a median follow-up of 1.7 yr. Treatment significantly reduced plasma tHcy (from 11.2 ± 6.9 to 9.7 ± 5.3 μmol/l), and a twofold reduction in nonfatal myocardial infarction was observed. However, no reduction in total deaths was seen, possibly reflecting the small cohort of patients used and the short study duration. In contrast, the Goes study (40), a secondary intervention trial comprising 593 patients with CHD (300 received folic acid and 293 controls) recently reported no clinical benefit after a 2-yr intervention with low-dose folic acid (0.5 mg/day), even though plasma tHcy concentrations were significantly lowered from 12.0 ± 4.83 to 9.4 ± 3.5 μmol/l. This study was underpowered and the dose of folic acid used may be too low to demonstrate any beneficial effect other than plasma tHcy lowering. It is also important to mention that three large randomized controlled studies assessing the effect folic acid on outcomes will also be underpowered. Recruitment for the Vitamin Intervention for Stroke Prevention trial, the Women's Antioxidant Cardiovascular Disease Study, and the HEART Outcomes Prevention Evaluation were initiated before the introduction of the fortification of cereals and grains with folic acid by the United States and Canadian governments. As a result, these trials will be substantially underpowered to test the hypothesis for which they were designed (8). For these reasons, it is important to urge caution when interpreting results from these studies (19). Further studies of longer duration and inclusion of larger sample sizes with the appropriate dose of folic acid and with all vascular events being recorded will be needed to clarify these results.Safety Implications With Widespread Use of Pharmacological Doses of Folic AcidIt should be noted that the pharmacological doses of folic acid used in the majority of clinical studies far exceed the nutritional requirement for its normal physiological function. One issue of the potential adverse effects of fortification with or the administration of large doses of folic acid is that of masking the hematological effects of vitamin B12 deficiency, thereby allowing the progression of neurological damage. The neuropathy, if untreated, may not be reversible by subsequent treatment with vitamin B12. Therefore, testing for B12 deficiency, or supplementation with vitamin B12, may be advisable to avoid such complications. Another issue of possible concern is the appearance of high circulating concentrations of unmetabolized folic acid after the ingestion of large doses (36). The long-term effects of exposure to high doses of the synthetic form of folic acid are unknown, although as yet there is no evidence of toxicity.ConclusionsThe view that a raised plasma tHcy level is causal in the development of vascular disease is an attractive hypothesis if only because folic acid offers an easy, inexpensive, and generally safe means of lowering it. This review challenges the hypothesis that tHcy is causal and raises the possibility that an increased tHcy is an epiphenomenon. Moreover, there is evidence that the beneficial vascular effects with folic acid are only achieved in pharmacological doses. Low-dose folic acid will reduce plasma tHcy, but a high dose may be required to produce the beneficial effects on vascular function, which occur before, and apparently independently of, homocysteine lowering. The current clinical trials are on the whole designed to test the homocysteine hypothesis of vascular disease using relatively low doses of folic acid. While these trials will undoubtedly show that folic acid lowers tHcy effectively, it is unlikely that the expected reduction in cardiovascular events will be seen. However, it is important therefore not to discount treatment with folic acid if these trials are negative, because it is possible that high-dose folic acid may have a beneficial effect on outcome via mechanisms independent of homocysteine lowering. Elucidation of these mechanisms is important in the drive to develop effective treatments for prevention of CHD.S. J. Moat is a Research Fellow funded by the Bristish Heart Foundation. We thank Dr. Hilary Powers for critically reviewing this manuscript. The contribution of S. J. Merrett to the figures is greatly appreciated.AUTHOR NOTESAddress for reprint requests and other correspondence: S. J. Moat, Wales Heart Research Institute, Univ. of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK (E-mail: moatsj@cardiff.ac.uk). Download PDF Back to Top Next FiguresReferencesRelatedInformationREFERENCES4 Bailey LB and Gregory JF III. Folate metabolism and requirements. J Nutr 129: 779–782, 1999.Crossref | PubMed | ISI | Google Scholar5 Baker F, Picton D, Blackwood S, Hunt J, Erskine M, Dyas M, Ashby M, Siva A, and Brown MJ. Blinded comparison of folic acid and