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Am J Physiol Heart Circ Physiol 294: H1971-H1977, 2008. First published March 28, 2008; doi:10.1152/ajpheart.91503.2007
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INVITED REVIEW

Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease

An L. Moens,1,2 Christiaan J. Vrints,2 Marc J. Claeys,2 Jean-Pierre Timmermans,2 Hunter C. Champion,1 and David A. Kass1

1Johns Hopkins Medical Institutions, Division of Cardiology, Baltimore, Maryland; and 2University of Antwerp, Division of Cardiology, Antwerp, Belgium


   ABSTRACT
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Folic acid (FA) is a member of the B-vitamin family with cardiovascular roles in homocysteine regulation and endothelial nitric oxide synthase (eNOS) activity. Its interaction with eNOS is thought to be due to the enhancement of tetrahydrobiopterin bioavailability, helping maintain eNOS in its coupled state to favor the generation of nitric oxide rather than oxygen free radicals. FA also plays a role in the prevention of several cardiac and noncardiac malformations, has potent direct antioxidant and antithrombotic effects, and can interfere with the production of the endothelial-derived hyperpolarizing factor. These multiple mechanisms of action have led to studies regarding the therapeutic potential of FA in cardiovascular disease. To date, studies have demonstrated that FA ameliorates endothelial dysfunction and nitrate tolerance and can improve pathological features of atherosclerosis. These effects appear to be homocysteine independent but rather related to their role in eNOS function. Given the growing evidence that nitric oxide synthase uncoupling plays a major role in many cardiovascular disorders, the potential of exogenous FA as an inexpensive and safe oral therapy is intriguing and is stimulating ongoing investigations.

endothelial nitric oxide synthase; uncoupling; superoxide; tetrahydrobiopterin; homocysteine

THE FIRST THERAPEUTIC USE of folic acid (FA) dates back to 1931, when Lucy Wills discovered that yeast extract was effective against tropical macrocytic anemia (97) and that the critical factor involved was FA. The main role of FA was found to be its involvement in the production and maintenance of new cells (39) because it has an essential role in the integrity and function of DNA. DNA synthesis and cell proliferation require the transfer of carbon groups, a task principally fulfilled by folates. As a consequence, FA deficiency leads to inadequate nucleic acid synthesis and impairs cell division. During pregnancy, this can lead to neural tube defects, such as spina bifida; orofacial cleft; and congenital heart defects (6, 20). The risk of these developmental abnormalities is significantly reduced by FA supplementation preceding conception and during pregnancy (77). FA deficiency is also associated with the development of neoplastic and preneoplastic conditions (17), neuropathy (56) and depression (1).

FA is a water-soluble B vitamin that derives its name from the Latin word for leaf (folium) because it was first isolated from spinach leaves. Humans are unable to synthesize folate de novo and thus rely on dietary intake to derive sufficient levels of the vitamin. Rich sources include citrus fruits and juices, dark green leafy vegetables such as spinach, wheat and other whole grains, and liver. The synthetic form of FA is usually designated as folate. 5-Methyltetrahydrofolate (5-MTHF), the active metabolite, has a structure very similar to that of tetrahydrobiopterin (BH4), an essential cofactor of endothelial nitric oxide (NO) synthase (eNOS), with the exception of an extended tail attached to 5-MTHF. It is also the primary form of folate entering the human circulation from the intestinal cells. The conversion of FA to 5-MTHF has limited capacity, however, and if enough FA is consumed orally, unaltered FA appears in the circulation (42), is taken up by cells, and is then reduced by dihydrofolate reductase to tetrahydrofolate. Over the past five years, the potential benefits of FA in the treatment of cardiovascular pathology have been revealed and have stimulated further clinical and experimental research. In this review, we discuss the potential mechanisms of action of FA and its role in the pathogenesis and treatment of different cardiovascular pathologies.

Mechanisms of Action of FA

FA is required for the remethylation of homocysteine to methionine, which in turn reduces the concentration of homocysteine available to support oxidative stress (52). FA decreases plasma homocysteine levels of both normo- and hyperhomocysteinemic subjects (61). However, FA also conveys protective effects in the absence of hyperhomocysteinemia by multiple mechanisms (Fig. 1). In the presence of sufficient cofactor BH4, the enzyme eNOS principally synthesizes NO. Oxidative stress can oxidize BH4 to its inactive form BH2. Diminished bioavailability of BH4 leads to eNOS uncoupling with subsequent decreased NO formation and increased generation of reactive oxygen species (19, 35, 45, 90). Folate can help to restore the bioavailability of BH4 by several mechanisms. MTHF can increase the effectiveness of BH4 on eNOS uncoupling. In theory, this can be explained by improved redox state or enhanced binding affinity of BH4 to eNOS (improved occupancy of eNOS by available BH4) or that MTHF facilitates the one-electron oxidation of BH4 to the BH4 radical (78). In addition, folate can enhance the regeneration of BH4 from the inactive form BH2 (41) and can chemically stabilize BH4 (Fig. 2). Hyndman et al. (38) also found that 5-MTHF is capable of binding the pterin site in eNOS and may directly interact with eNOS independent of BH4, although details of this interaction remain scant.


Figure 1
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  		Fig. 1. Different mechanisms of action and targets of folic acid in cardiovascular diseases. eNOS, endothelial nitric oxide (NO) synthase; EDHF, endothelium-derived hyperpolarizing factor; BH4, tetrahydrobiopterin.

 

Figure 2
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  		Fig. 2. Interaction of folic acid with eNOS. 5-Methyltetrahydrofolate (5-MTHF) is capable of directly interacting with eNOS (i). Folic acid also restores the bioavailability of BH4 by ameliorating the binding affinity of BH4 to eNOS (ii), by chemically stabilizing BH4 (iii), and by enhancing the regeneration of BH4 from the inactive form BH2 (iv). Oxidative stress-induced BH4 depletion leads to an imbalance between NO production and the generation of free radicals.

 
There is also evidence that FA exerts direct and indirect antioxidant effects, such as the improvement of the cellular antioxidant defense system (24, 36, 92). FA deficiency in rats increases lipid peroxidation and decreases cellular antioxidant defenses (24, 36). In healthy human volunteers, the beneficial effect of folates on postprandial endothelial dysfunction corresponded with decreased urinary excretion of malondialdehyde, a radical-damage end product (98). The administration of FA to smokers induced a significant reduction in plasma fibrinogen and D-dimer levels, markers of a prothrombotic state, and changes in plasma homocysteine did not correlate with these levels (54), suggesting an antithrombotic effect independent of homocysteine modulation. Other studies have shown antithrombotic effects of FA that are linked to a decline in homocysteine, which itself is prothrombotic (37, 47, 100) by its inhibition of a number of pathways, including thrombomodulin expression (50), antithrombin III-binding activity of heparan sulfate proteoglycan (34), and ecto-adenosine diphosphatase activity (34). Homocysteine also stimulates endothelial plasminogen activator inhibitor-1 expression (58) and monocyte tissue factor expression and potentiates platelet aggregation (23, 43).

There are several other mechanisms that may underlie the beneficial effect of FA, but these are presently less well defined. First, 5-MTHF has been reported to restore the defective production of an unidentified endothelium-derived hyperpolarizing factor in diabetic rats (21). Second, we recently demonstrated an improved myocardial high-energy phosphate metabolism from high-dose FA pretreatment in rats subjected to regional coronary occlusion (60). As a result, less superoxide was generated, eNOS was kept in his coupled state, myocardial function was preserved, and reperfusion injury was prevented.

FA and Congenital Heart Disease

Congenital heart defects occur in ~3–8 of every 1,000 births. In the United States alone, the number of deaths attributed to congenital heart defects is estimated to be ~6,000 annually (9). The etiology of nonsyndromic congenital heart defects is complex, involving genetic, epigenetic, and environmental risk factors. However, one of the most promising clues about the prevention of conotruncal defects (truncus arteriosus, transposition of great arteries, and tetralogy of Fallot) is that women who use FA-containing vitamins in early pregnancy have reduced risks of delivering offspring with conotruncal defects (10, 75). FA is well known for its beneficial effects on neural tube closure which depend on NO synthase (NOS) activity (64). Indeed, blocking NOS activity by inhibiting BH4 or calcium-calmodulin binding to NOS, results in ablated closure of the neural tube. Therefore, it is recommended that all women capable of becoming pregnant take 400 µg/day of FA in addition to a healthy diet (6). Women taking medications that interfere with folate metabolism (e.g., antiepileptic drugs such as carbamazepine and valproate) are advised to take higher doses of FA (1–5 mg/day) during preconception and throughout pregnancy. Furthermore, a recent study showed that the offspring of pregnant rats on a protein-restricted diet during pregnancy had higher systolic blood pressure, impaired acetylcholine-induced vasodilation, and reduced levels of eNOS mRNA in their thoracic aorta. Maternal folate supplementation during pregnancy in this model normalized blood pressure while having a modest effect on vascular function (84). These data provide a good example of how vitamin supplementation can ameliorate the adverse effects of micronutrient imbalance during pregnancy.

FA and Homocysteine

The best-known beneficial action of FA is its homocysteine-lowering effect. Homocysteine is a sulfur-containing amino acid generated during the catabolism of methionine. Homocysteine is metabolized by two pathways, either remethylation in the case of insufficient methionine or transsulfuration in the case of excess methionine. In the remethylation pathway, homocysteine is reconverted to methionine by methionine synthase, requiring vitamin B12 as a cofactor and FA as a methyl donor (26). With the use of the transsulfuration pathway, homocysteine is catabolized by cystathionine β-synthase, with vitamin B6 as a cofactor, to cystathionine and subsequently to cysteine, which is excreted in the urine or incorporated into glutathionine. Hyperhomocysteinemia is therefore associated with low concentrations of methionine, FA, or vitamin B12.

As a consequence of the involvement of FA in the homocysteine pathway, the oral administration (0.5–5 mg/day) results in a 25–30% reduction in the fasting homocysteine concentration (25, 33, 37a, 68, 87). No difference in the homocysteine-lowering effects of supplementary FA has been found with daily intake ranging 0.4–5 mg (37a, 87), except in patients with chronic renal failure who require a higher dose. Supplementation with vitamin B12 (0.02–1 mg daily) produces an additional 7% reduction in homocysteine levels and simultaneously eliminates the theoretical risk of precipitating subacute combined degeneration of the spinal cord. Vitamin B6 supplementation has no additional effect on fasting homocysteine levels but does significantly lower postmethionine load homocysteine and cystathionine concentrations (68). Hyperhomocysteinemia, found in up to 40% of individuals with cerebrovascular, coronary, or peripheral vascular diseases (18), can be considered an independent cardiovascular risk factor (11, 76). However, the strength of association of homocysteine with the risk of cardiovascular disease may be weaker than previously believed. An updated meta-analysis of several large-scaled observational studies found that a decline in blood homocysteine of 25% (~3 µmol/l) was associated with ~11% lower risk of coronary heart disease and 19% lower risk of stroke (37b). However, most large prospective studies were underpowered for this level of risk reduction, and even larger studies are needed to prove or disprove risk modulation (3, 53).

FA and Endothelial Dysfunction

Endothelial dysfunction is a major marker of cardiovascular risk (69, 79, 94) and is characterized by reduced production/availability of NO and/or an imbalance between endothelium-derived relaxation (prostacyclin and endothelium-derived hyperpolarizing factor) and contracting (endothelin and angiotensin) factors and oxidants. A number of studies have assigned a pivotal role to oxygen-derived free radicals in accelerating NO degradation. These oxygen-derived free radicals, in particular superoxide anion, easily react with NO, decreasing its half-life.

The prevention or amelioration of coronary vascular endothelial dysfunction is an attractive goal for therapeutic interventions aimed at reducing symptoms or clinical events. In the past few years, studies have reported improved endothelial function after FA supplementation in patients with hyperhomocysteinemia (8, 14, 15, 83, 88, 99), and normohomocysteinemic patients with familial hypercholesterolemia (92, 93), diabetes (89), stable coronary artery disease (22, 59), and in smokers (55, 66). Chronic FA treatment for 6 wk in subjects with an acute myocardial infarction resulted in improved endothelial function (61). Nitroglycerin and other nitrates are the mainstay therapies for coronary artery disease but can be associated with oxygen-free radical-induced nitrate tolerance and subsequent endothelial dysfunction (81). The development of tolerance during continuous therapy is a major factor limiting the efficacy of these drugs. Supplemental FA may be instrumented in preventing such tolerance and endothelial dysfunction (32).

FA and Atherosclerosis

FA may have beneficial effects on atherosclerosis. Carnicer et al. (13). demonstrated in apolipoprotein E-deficient mice that FA led to a decline in atherosclerotic lesions associated with increased apolipoprotein AI, AIV, and B levels and decreased oxidative stress. This was independent of plasma homocysteine and cholesterol levels. Clinical studies have employed more mixed cocktails of B vitamins. For example, a 1-yr daily B-vitamin supplementation (2.5 mg FA, 25 mg vitamin B6, and 0.5 mg vitamin B12) reduced carotid intima-media thickness compared with placebo administration (82). In one study, a long-term FA treatment (~10 yr) at a much higher dose than currently used (40–80 mg/day) was found to lower the incidence of myocardial infarction, angina pectoris, and the requirement for nitroglycerin in patients with coronary artery disease (67). This study was not placebo controlled, however, and remains an isolated observation.

Another manifestation of vascular disease where FA may be helpful is restenosis following balloon angioplasty. Schnyder et al. (72) examined 205 patients with stable coronary artery disease treated with a combination of FA (1 mg), vitamin B12 (400 µg), and pyridoxine (10 mg) and found reduced restenosis rates (19.6% vs. 37.6%). The extent of restenosis was also less severe. This group also observed that patients with plasma homocysteine levels below 9 µmol/l have a 49% lower rate of coronary restenosis than those with higher levels (71). However, other studies did not confirm these results (49), potentially in part because of the greater use of vascular stents in this latter study. In the Swiss Heart Study, a reduction in restenosis with FA was most observed in vessels treated with angioplasty only (10.3% vs. 41.9%, P < 0.001), whereas the benefit in stented lesions did not reach statistical significance (20.6% vs. 29.9%, P = 0.32). Differences in the pathophysiology entailed with stent placement could underlie the difference. Since thrombotic complications from sirolimus- and paclitaxel-eluting coronary stents have recently come into focus (77), the potential use of FA may again be revisited.

FA and Hemodynamic Parameters

FA has been examined for potential effects on arterial blood pressure. Tawakol et al. (80) found that high doses of FA (30 mg) acutely reduced systolic, diastolic, and mean arterial pressure. In regions of normal coronary flow, FA did not alter myocardial blood flow or adenosine reserve, whereas in abnormal zones, FA significantly improved flow reserve (49% increase with adenosine), despite the decline in pressure. Additionally, FA increased vasodilator reserve by 83% in abnormal segments but had no effect in normal segments. In another study, low-dose FA (5 mg/day), administered for 3 wk, lowered brachial pulse pressure, without altering mean arterial pressure (96), coupled to improvement in regional artery compliance.

FA and Cardiovascular Mortality

Low-serum folate levels are associated with a high risk of fatal coronary artery disease, especially when folate levels fall below 6.8 nmol/l (=3 ng/ml) (63). This inverse relationship between folate status and atherosclerotic vascular diseases has also been demonstrated in the Nutrition Examination Survey (28, 31, 51), the Kuopio Ischemic Heart Disease Risk Factor Study (95), and the Framingham Heart Study (74), although it has not been confirmed by others: the Physicians' Health Study (16) and Atherosclerosis Risk in Communities Study (27). Antifolate therapy with methotrexate has been suggested to promote atherosclerosis (48). Beyond dietary reductions, a common mutation of 5,10-MTHF reductase caused increased thermolability and reduced activity of the enzyme catalyzing reduction of 5,10-methylenetetrahydrofolate to 5-MTHF. This mutation has been reported as a risk factor for cardiovascular disease (29, 30, 40, 46, 62).

Pharmacological Considerations of FA

In general, FA supplementation is considered safe (12), and there is no evidence that high natural folate intake poses a toxicity risk (65). No adverse effects have been reported when high doses of FA (40–80 mg/day) are administered for as long as 10 years (67). Only one study reported on the use of FA (300 mg/kg, once a week for 4 wk) in rats as a model for interstitial nephritis (86). However, converting this dose from a rat to a human of 75 kg results in a dose of 22.5 g. The main safety concern lies in the fact that folate can mask the diagnosis of pernicious anemia, because high FA levels correct the anemia but allow the neuropathy to progress undiagnosed to an irreversible degeneration of the spinal cord (73). Therefore, vitamin B12 levels should always be measured before the start of supplementation with FA. Another concern that needs special attention is the role of FA in carcinogenesis. In established neoplasms, the inhibitory and promoting effect of folate deficiency and supplementation, respectively, has been well described and has been the basis for cancer chemotherapy with several antifolate agents (e.g., methotrexate) and 5-fluorouracil. In neoplastic cells, in which DNA replication and cell division occur at an accelerated rate, the interruption of folate metabolism causes ineffective DNA synthesis, resulting in the inhibition of tumor growth (32, 33). In contrast, the role of FA, and in particular of folate fortification, on de novo carcinogenesis in normal tissue has been the subject of many contradictory reports over the past decade (44). Very recently, Bayston et al. (7) reported that there is no ground of concern to avoid the fortification with FA and that FA supplementation will not enhance the risk on colorectal carcinomas.

The synthetic form of FA (folate) is used in supplements and is added to food because of its high stability and bioavailability. The metabolic active form of FA, 5-MTHF, is also readily available. Unlike FA, 5-MTHF has to be converted to tetrahydrofolate via the vitamin B12-dependent enzyme methionine synthase. In case of vitamin B12 deficiency, 5-MTHF is not converted to tetrahydrofolate and thus is not able to improve megaloblastic anemia, even when given at high doses. Furthermore, 5-MTHF does not require a reduction by dihydrofolate reductase to be incorporated into the active cellular folate pool (101). However, low-dose 5-MTHF is equally effective since FA in reducing homocysteine concentrations in healthy persons (91) and restoration of endothelial function can also be performed by an infusion of 5-MTHF (92).

Uremic patients usually have elevated levels of homocysteine and are relatively resistant to FA therapy. The reason for this phenomenon is unknown but may be due to impaired intestinal absorption and/or impaired metabolic transformation of FA to an active form (57). Folinic acid (5-formyltetrahydrofolate) supplementation to this population may be more efficient in reducing the high homocysteine level in uremia (2, 57, 85). Folinic acid can be given intravenously, where it normally is readily converted (via 5,10-methenyltetrahydrofolate and 5,10-methylenetetrahydrofolate) to 5-MTHF (70). This form of FA is best known for counteracting the therapeutic and toxic effects of FA antagonists, such as methothrexate, in the treatment of tumors, rheumatoid arthritis, and psoriasis.

Conclusion

Coronary artery disease has become the leading cause of death in Western countries. Various studies have demonstrated an association between low-serum folate levels and the risk of fatal coronary artery disease. In light of this observation, FA not only appears important for risk stratification but also opens new therapeutic possibilities in the treatment of cardiovascular diseases. Apart from various promising results on eNOS-dependent superoxide generation in animal studies and its well-known homocysteine-lowering effect, FA can benefit on endothelial dysfunction, and recent work suggests a potential to preserve myocardial function and prevent tissue damage.

Some of these effects may require high doses of FA, much higher than those tested to date, and clearly much higher than those obtainable through the diet. Precisely when and why higher doses might be required for some therapeutic targets remain unclear and somewhat controversial. Clearly, additional studies are needed to further clarify the potential role of FA, not only for risk stratification but also for cardiovascular disease treatment and/or prevention.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. L. Moens, Univ. Hospital of Antwerp, Div. of Cardiology, Wilrijkstraat 10, 2650 Antwerp-Edegem, Belgium (e-mail: an.moens{at}uza.be)


   REFERENCES
TOP
 ABSTRACT
 REFERENCES
 

  1. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev 55: 145–149, 1997.[Web of Science][Medline]
  2. Apeland T, Mansoor MA, Pentieva K, McNulty H, Seljeflot I, Strandjord RE. The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs. Epilepsy Res 51: 237–247, 2002.[CrossRef][Web of Science][Medline]
  3. B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 151: 282–287, 2006.[CrossRef][Web of Science][Medline]
  4. Bailey LB, Berry RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr 81: 1213S–1217S, 2005.[Abstract/Free Full Text]
  5. Bayston R, Russell A, Wald NJ, Hoffbrand AV. Folic acid fortification and cancer risk. Lancet 370: 2004, 2007.[Web of Science][Medline]
  6. Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Newcombe RG, Lewis MJ. Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Invest 29: 659–662, 1999.[CrossRef][Web of Science][Medline]
  7. Boneva RS, Botto LD, Moore CA, Yang Q, Correa A, Erickson JD. Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979–1997. Circulation 103: 2376–2381, 2001.[Abstract/Free Full Text]
  8. Botto LD, Mulinare J, Erickson JD. Occurrence of congenital heart defects in relation to maternal multivitamin use. Am J Epidemiol 151: 878–884, 2000.[Abstract/Free Full Text]
  9. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274: 1049–1057, 1995.[Abstract/Free Full Text]
  10. Campbell NR. How safe are folic acid supplements? Arch Intern Med 156: 1638–1644, 1996.[Abstract/Free Full Text]
  11. Carnicer R, Navarro MA, Arbones-Mainar JM, Acin S, Guzman MA, Surra JC, Arnal C, de Las Heras M, Blanco-Vaca F, Osada J. Folic acid supplementation delays atherosclerotic lesion development in apoE-deficient mice. Life Sci 80: 638–643, 2007.[CrossRef][Web of Science][Medline]
  12. 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 102: 2479–2483, 2000.[Abstract/Free Full Text]
  13. Chao CL, Chien KL, Lee YT. Effect of short-term vitamin (folic acid, vitamins B6 and B12) administration on endothelial dysfunction induced by post-methionine load hyperhomocysteinemia. Am J Cardiol 84: 1359–1361, 1999.[CrossRef][Web of Science][Medline]
  14. Chasan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, Willett W, Hennekens CH, Stampfer MJ. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 15: 136–143, 1996.[Abstract]
  15. Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr 130: 129–132, 2000.[Abstract/Free Full Text]
  16. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324: 1149–1155, 1991.[Abstract]
  17. Cosentino F, Katusic ZS. Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 91: 139–144, 1995.[Abstract/Free Full Text]
  18. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA 274: 1698–1702, 1995.[Abstract/Free Full Text]
  19. De Vriese AS, Van d V, Blom HJ, Vanhoutte PM, Verbeke M, Lameire NH. The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin-induced diabetic rats is restored by 5-methyltetrahydrofolate. Diabetologia 43: 1116–1125, 2000.[CrossRef][Web of Science][Medline]
  20. Doshi SN, McDowell IF, Moat SJ, Lang D, Newcombe RG, Kredan MB, Lewis MJ, Goodfellow J. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 21: 1196–1202, 2001.[Abstract/Free Full Text]
  21. Durand P, Lussier-Cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 11: 1157–1168, 1997.[Abstract]
  22. Durand P, Prost M, Blache D. Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis 121: 231–243, 1996.[CrossRef][Web of Science][Medline]
  23. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 131: 363–375, 1999.[Abstract/Free Full Text]
  24. Finkelstein JD, Kyle W, Harris BJ. Methionine metabolism in mammals. Regulation of homocysteine methyltransferases in rat tissue. Arch Biochem Biophys 146: 84–92, 1971.[CrossRef][Web of Science][Medline]
  25. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 98: 204–210, 1998.[Abstract/Free Full Text]
  26. Ford ES, Byers TE, Giles WH. Serum folate and chronic disease risk: findings from a cohort of United States adults. Int J Epidemiol 27: 592–598, 1998.[Abstract/Free Full Text]
  27. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111–113, 1995.[CrossRef][Web of Science][Medline]
  28. Gallagher PM, Meleady R, Shields DC, Tan KS, McMaster D, Rozen R, Evans A, Graham IM, Whitehead AS. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation 94: 2154–2158, 1996.[Abstract/Free Full Text]
  29. Giles WH, Kittner SJ, Anda RF, Croft JB, Casper ML. Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study. Stroke 26: 1166–1170, 1995.[Abstract/Free Full Text]
  30. Gori T, Burstein JM, Ahmed S, Miner SE, Al Hesayen A, Kelly S, Parker JD. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation 104: 1119–1123, 2001.[Abstract/Free Full Text]
  31. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 354: 407–413, 1999.[CrossRef][Web of Science][Medline]
  32. Harpel PC, Zhang X, Borth W. Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr 126: 1285S–1289S, 1996.[Abstract/Free Full Text]
  33. Heinzel B, John M, Klatt P, Bohme E, Mayer B. Ca2+/calmodulin-dependent formation of hydrogen peroxide by brain nitric oxide synthase. Biochem J 281: 627–630, 1992.[Web of Science][Medline]
  34. Henning SM, Swendseid ME, Ivandic BT, Liao F. Vitamins C, E and A and heme oxygenase in rats fed methyl/folate-deficient diets. Free Radic Biol Med 23: 936–942, 1997.[CrossRef][Web of Science][Medline]
  35. Hjemdahl P. Smoking, nicotine and thrombotic risk—a role for platelet dependent thrombin generation? Eur Heart J 22: 16–18, 2001.[Free Full Text]
  36. Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316: 894–898, 1998.[Abstract/Free Full Text]
  37. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288: 2015–2022, 2002.[Abstract/Free Full Text]
  38. Hyndman ME, Verma S, Rosenfeld RJ, Anderson TJ, Parsons HG. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 282: H2167–H2172, 2002.[Abstract/Free Full Text]
  39. Kamen B. Folate and antifolate pharmacology. Semin Oncol 24: S18–30–S18–39, 1997.
  40. Kang SS, Passen EL, Ruggie N, Wong PW, Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 88: 1463–1469, 1993.[Abstract/Free Full Text]
  41. Kaufman S. Some metabolic relationships between biopterin and folate: implications for the "methyl trap hypothesis". Neurochem Res 16: 1031–1036, 1991.[CrossRef][Web of Science][Medline]
  42. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 65: 1790–1795, 1997.[Abstract/Free Full Text]
  43. Khajuria A, Houston DS. Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis. Blood 96: 966–972, 2000.[Abstract/Free Full Text]
  44. Kim YI. Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr 80: 1123–1128, 2004.[Abstract/Free Full Text]
  45. Kinoshita H, Tsutsui M, Milstien S, Katusic ZS. Tetrahydrobiopterin, nitric oxide and regulation of cerebral arterial tone. Prog Neurobiol 52: 295–302, 1997.[CrossRef][Web of Science][Medline]
  46. Kluijtmans LA, Kastelein JJ, Lindemans J, Boers GH, Heil SG, Bruschke AV, Jukema JW, van den Heuvel LP, Trijbels FJ, Boerma GJ, Verheugt FW, Willems F, Blom HJ. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 96: 2573–2577, 1997.[Abstract/Free Full Text]
  47. Kuch B, Bobak M, Fobker M, Junker R, von Eckardstein A, Marmot M, Hense HW. Associations between homocysteine and coagulation factors—a cross-sectional study in two populations of central Europe. Thromb Res 103: 265–273, 2001.[CrossRef][Web of Science][Medline]
  48. Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity. Lancet 355: 1616–1617, 2000.[CrossRef][Web of Science][Medline]
  49. Lange H, Suryapranata H, De LG, Borner C, Dille J, Kallmayer K, Pasalary MN, Scherer E, Dambrink JH. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 350: 2673–2681, 2004.[Abstract/Free Full Text]
  50. Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 88: 1906–1914, 1991.[Web of Science][Medline]
  51. Loria CM, Ingram DD, Feldman JJ, Wright JD, Madans JH. Serum folate and cardiovascular disease mortality among US men and women. Arch Intern Med 160: 3258–3262, 2000.[Abstract/Free Full Text]
  52. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 98: 5–7, 1996.[Web of Science][Medline]
  53. Loscalzo J. Homocysteine trials—clear outcomes for complex reasons. N Engl J Med 354: 1629–1632, 2006.[Free Full Text]
  54. Mangoni AA, Arya R, Ford E, Asonganyi B, Sherwood RA, Ouldred E, Swift CG, Jackson SH. Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial. Thromb Res 110: 13–17, 2003.[CrossRef][Web of Science][Medline]
  55. Mangoni AA, Sherwood RA, Swift CG, Jackson SH. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med 252: 497–503, 2002.[CrossRef][Web of Science][Medline]
  56. Manzoor M, Runcie J. Folate-responsive neuropathy: report of 10 cases. Br Med J 1: 1176–1178, 1976.[Abstract/Free Full Text]
  57. Massy ZA. Reversal of hyperhomocyst(e)inaemia in chronic renal failure-is folic or folinic acid the answer? Nephrol Dial Transplant 14: 2810–2812, 1999.[Free Full Text]
  58. Midorikawa S, Sanada H, Hashimoto S, Watanabe T. Enhancement by homocysteine of plasminogen activator inhibitor-1 gene expression and secretion from vascular endothelial and smooth muscle cells. Biochem Biophys Res Commun 272: 182–185, 2000.[CrossRef][Web of Science][Medline]
  59. Moat SJ, Madhavan A, Taylor SY, Payne N, Allen RH, Stabler SP, Goodfellow J, McDowell IF, Lewis MJ, Lang D. High- but not low-dose folic acid improves endothelial function in coronary artery disease. Eur J Clin Invest 36: 850–859, 2006.[CrossRef][Web of Science][Medline]
  60. Moens AL, Champion HC, Claeys MJ, Tavazzi B, Kaminski PM, Wolin MS, Borgonjon DJ, Van Nassauw L, Haile A, Zviman M, Bedja D, Wuyts FL, Elsaesser RS, Cos P, Gabrielson KL, Lazzarino G, Paolocci N, Timmermans JP, Vrints CJ, Kass DA. High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury. Circulation. In press.
  61. Moens AL, Claeys MJ, Wuyts FL, Goovaerts I, Van Hertbruggen E, Wendelen LC, Van Hoof VO, Vrints CJ. Effect of folic acid on endothelial function following acute myocardial infarction. Am J Cardiol 99: 476–481, 2007.[CrossRef][Web of Science][Medline]
  62. Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 95: 2032–2036, 1997.[Abstract/Free Full Text]
  63. Morrison HI, Schaubel D, Desmeules M, Wigle DT. Serum folate and risk of fatal coronary heart disease. JAMA 275: 1893–1896, 1996.[Abstract/Free Full Text]
  64. Nachmany A, Gold V, Tsur A, Arad D, Weil M. Neural tube closure depends on nitric oxide synthase activity. J Neurochem 96: 247–253, 2006.[CrossRef][Web of Science][Medline]
  65. National Academy of Sciences. Dietary Reference Intakes: Folate, Other B-vitamins and Choline. Washington, DC: National Academy Press, 2000.
  66. O'Grady HL, Leahy A, McCormick PH, Fitzgerald P, Kelly CK, Bouchier-Hayes DJ. Oral folic acid improves endothelial dysfunction in cigarette smokers. J Surg Res 106: 342–345, 2002.[CrossRef][Web of Science][Medline]
  67. Oster K. Atherosclerosis treated with folic acid (Abstract). Federation Proceedings 40: 865, 1981.
  68. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 49: 31–62, 1998.[CrossRef][Web of Science][Medline]
  69. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101: 1899–1906, 2000.[Abstract/Free Full Text]
  70. Schalhorn A, Kuhl M. Clinical pharmacokinetics of fluorouracil and folinic acid. Semin Oncol 19: 82–92, 1992.[Web of Science][Medline]
  71. Schnyder G, Pin R, Roffi M, Flammer Y, Hess OM. Association of plasma homocysteine with the number of major coronary arteries severely narrowed. Am J Cardiol 88: 1027–1030, 2001.[CrossRef][Web of Science][Medline]
  72. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B, Turi ZG, Hess OM. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 345: 1593–1600, 2001.[Abstract/Free Full Text]
  73. Scott J, Weir D. Folate/vitamin B12 inter-relationships. Essays Biochem 28: 63–72, 1994.[Medline]
  74. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 332: 286–291, 1995.[Abstract/Free Full Text]
  75. Shaw GM, O'Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 59: 536–545, 1995.[CrossRef][Web of Science][Medline]
  76. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 268: 877–881, 1992.[Abstract/Free Full Text]
  77. Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 356: 998–1008, 2007.[Abstract/Free Full Text]
  78. Stroes ES, van Faassen EE, Yo M, Martasek P, Boer P, Govers R, Rabelink TJ. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 86: 1129–1134, 2000.[Abstract/Free Full Text]
  79. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101: 948–954, 2000.[Abstract/Free Full Text]
  80. Tawakol A, Migrino RQ, Aziz KS, Waitkowska J, Holmvang G, Alpert NM, Muller JE, Fischman AJ, Gewirtz H. High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol 45: 1580–1584, 2005.[Abstract/Free Full Text]
  81. Thomas GR, DiFabio JM, Gori T, Parker JD. Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: evidence of a free-radical-mediated mechanism. J Am Coll Cardiol 49: 1289–1295, 2007.[Abstract/Free Full Text]
  82. Till U, Rohl P, Jentsch A, Till H, Muller A, Bellstedt K, Plonne D, Fink HS, Vollandt R, Sliwka U, Herrmann FH, Petermann H, Riezler R. Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamins B6 and B12. Atherosclerosis 181: 131–135, 2005.[CrossRef][Web of Science][Medline]
  83. Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 36: 758–765, 2000.[Abstract/Free Full Text]
  84. Torrens C, Brawley L, Anthony FW, Dance CS, Dunn R, Jackson AA, Poston L, Hanson MA. Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47: 982–987, 2006.[Abstract/Free Full Text]
  85. Touam M, Zingraff J, Jungers P, Chadefaux-Vekemans B, Drueke T, Massy ZA. Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. Kidney Int 56: 2292–2296, 1999.[CrossRef][Web of Science][Medline]
  86. Tsutsumi T, Ichihara T, Kawabe M, Yoshino H, Asamoto M, Suzuki S, Shirai T. Renal toxicity induced by folic acid is associated with the enhancement of male reproductive toxicity of di(n-butyl)phthalate in rats. Reprod Toxicol 18: 35–42, 2004.[CrossRef][Web of Science][Medline]
  87. Ubbink JB, Becker PJ, Vermaak WJ, Delport R. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem 41: 1033–1037, 1995.[Abstract/Free Full Text]
  88. Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst(e)inaemia: restoration by folic acid. Clin Sci (Lond) 96: 235–239, 1999.[Medline]
  89. Van Etten RW, de Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ. Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 45: 1004–1010, 2002.[CrossRef][Web of Science][Medline]
  90. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95: 9220–9225, 1998.[Abstract/Free Full Text]
  91. Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 77: 658–662, 2003.[Abstract/Free Full Text]
  92. Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans HA, Rabelink TJ. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 97: 237–241, 1998.[Abstract/Free Full Text]
  93. Verhaar MC, Wever RM, Kastelein JJ, van Loon D, Milstien S, Koomans HA, Rabelink TJ. Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation 100: 335–338, 1999.[Abstract/Free Full Text]
  94. Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 81: 491–497, 1990.[Abstract/Free Full Text]
  95. Voutilainen S, Lakka TA, Porkkala-Sarataho E, Rissanen T, Kaplan GA, Salonen JT. Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Eur J Clin Nutr 54: 424–428, 2000.[CrossRef][Web of Science][Medline]
  96. Williams C, Kingwell BA, Burke K, McPherson J, Dart AM. Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype. Am J Clin Nutr 82: 26–31, 2005.[Abstract/Free Full Text]
  97. Wills L. Treatment of pernicious anaemia of pregnancy and tropical anaemia with special reference to yeast extracts as curative agent. Br Med J 1: 1059–1064, 1931.[Free Full Text]
  98. Wilmink HW, Stroes ES, Erkelens WD, Gerritsen WB, Wever R, Banga JD, Rabelink TJ. Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol 20: 185–188, 2000.[Abstract/Free Full Text]
  99. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol 34: 2002–2006, 1999.[Abstract/Free Full Text]
  100. Yarnell JW, Sweetnam PM, Rumley A, Lowe GD. Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study. Arterioscler Thromb Vasc Biol 20: 271–279, 2000.[Abstract/Free Full Text]
  101. Zakrzewski SF, Nichol CA. Evidence for a single enzyme reducing folate and dihydrofolate. J Biol Chem 235: 2984–2988, 1960.[Free Full Text]



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C. Antoniades, A. S. Antonopoulos, D. Tousoulis, K. Marinou, and C. Stefanadis
Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials
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