Folic acid cardiovascular disease

Elevated homocysteine concentrations have been associated with an increased risk for cardiovascular disease in both epidemiologic and clinical studies.43 Several studies have evaluated the benefit of lowering homocysteine levels with folic acid supplementation. One study reported a reduction in major cardiac events with the combination of folic acid, vitamin B12, and vitamin B6 following PCI.44 However, a more recent study found an increased risk of instent restenosis and the need for target-vessel revascularization with folate supplementation following coronary stent placement.45 The role of folate in the management of IHD is currently unclear. 

Because the potential benefits outweigh the possibilities of harm, many experts recommend a daily multivitamin that does not exceed the RDA of it component vitamins. Multivitamins ensure an adequate intake for those vitamins—folic acid, vitamin B6, vitamin B12, and vitamin D—that are most likely to be deficient. However, the the evidence is insufficient to recommend for or against the use of supplements of vitamins A, C, or E multivitamins with folic acid or antioxidant combinations for the pre vention of cancer or cardiovascular disease. Most experts recommend against the use of p-carotene supplements, either alone or in combina Don, for the prevention of cancer or cardiovascular disease. 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

There exists an inverse association between folate and cardiovascular disease. Folic acid deficiency may result from ... 

In the Heart Outcomes Prevention Evaluation 2 (HOPE-2) study, 5522 patients aged 55 or older with vascular disease or diabetes were randomized to treatment with either placebo or a combination 2, 5 mg of folic acid, 50 mg vitamin B6, and I mg vitamin B 2, for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. Mean plasma homocysteine levels decreased by 2.4 jimol/L in the treatment group and increased by 0.8 jimol/L in the placebo group. The primary outcome occurred in 18.8% of patients assigned to active therapy and in 19.8% of those assigned to placebo (relative risk = 0.95 95% Cl = 0.84-1.07 P = 0.41) (68). 

Morgan SL, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm,low dose methotrexate therapy for rheumatoid arthritis implications for cardiovascular disease prevention. J Rheumatol 1998 25(3) 44l-446. 

Homocysteine and cardiovascular disease evidence on causality from a meta-analysis. British Medical Journal 325 1202-1206 Wald DS, Law M, Morris JK (2004). The dose-response relationship between serum homocysteine and cardiovascular disease implications for treatment and screening. European Journal of Cardiovascular Prevention and Rehabilitation 11 250-253 Wang X, Qin X, Demirtas H et al. (2007). Efficacy of folic acid supplementation in stroke prevention a meta-analysis. Lancet 369 1876-1882... 

Although folate is widely distributed in foods, dietary deficiency is not uncommon, and a number of commonly used drugs can cause folate depletion. Marginal folate status is a factor in the development of neural tube defects and supplements of 400 fj,g per day periconceptually reduce the incidence of neural tube defects significantly. High intakes of folate lower the plasma concentration of homocysteine in people genetically at risk of hyperhomo-cysteinemia and may reduce the risk of cardiovascular disease, although as yet there is no evidence from intervention studies. There is also evidence that low folate status is associated with increased risk of colorectal and other cancers and that folate may be protective. Mandatory enrichment of cereal products with folic acid has been introduced in the United States and other countries, and considered in others. 

Deficiency of either folic acid or vitamin B12 results in a clinically similar megaloblastic anemia because of the neurological damage that accompanies the megaloblastic anemia of vitamin B12 deficiency, the condition is generally known as pernicious anemia. Suhoptimal folate status is also associated with increased incidence of neural tube defects (Section 10.9.4), hyperhomocys-teinemia leading to increased risk of cardiovascular disease (Section 10.3.4.2), and undermethylation of DNAleadingto increased cancerrisk (Section 10.9.5). 

Supplements of400 /xg per day of folic acid, begun before conception, halve the risk of neural tube defect (Section 10.9.4), and similar supplements reduce the plasma concentration of homocysteine in people homozygous for the ther-molabile variant of methylene-tetrahydrofolate reductase (Section 10.3.4.2), although it is not known whether or not this will reduce their risk of cardiovascular disease. A number of manufacturers voluntarily enrich foods with folic acid. In the United States and other countries, there is mandatory enrichment of cereal products with folic acid. 

It remains to be seen whether mandatory enrichment of cereal products with folic acid will reduce death from cardiovascular disease. But this, and the widespread voluntary enrichment of foods in other countries, means that intervention studies with folic acid supplements for cancer prevention are unlikely to yield useful results, because the control group will also be receiving a high intake of folic acid. 

Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J, et al. D. A. CH.-Liga Homocystein (German, Austrian, and Swiss Homocysteine Society) consensus paper on the rational clinical use of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases guidelines and recommendations. J Kardiol 2003 10 190-9. 

There is reason to conclude that vitamin deficiency might contribute to arteriosclerosis. There is a correlation between elevated homocysteine levels and incidence of cardiovascular disease (59). There is debate as to whether homocysteine contributesto the dam e of cells on the interior of blood vessel or whether homocysteine is a marker of intensive cell repair and formation of replacement cells. Nevertheless, administration of pyridoxine, folic acid, and (yanocobalamin are being recommended along with the two antioxidant vitamins, a-tocopherol and ascorbic acid for arteriosclerosis. Vitamin Bg is required for two of the steps in the catabolism of homocysteine to succinyl CoA (Fig. 8.52). Note in Fig. 8.52 (bottom) that biotin and a coenzyme form of cobalamin also are required for... 

Folic acid/cobalamin/pyridoxine hydrochloride are nutritional combinations. Folic acid and cobalamin reduce homocysteine by metabolizing it to methionine. Pyridox-ine facilitates breakdown of homocysteine to cysteine and other by-products. They are indicated for nutritional requirement of patients with end-stage renal failure, dialysis, hyperhomocysteinemia, homocystinuria, nutrient malabsorption or inadequate dietary intake, particularly for patients with or at risk for cardiovascular disease, cerebrovascular disease, peripheral vascular disease, arteriosclerotic... 

Ward M, McNulty H, McPartlin J, Strain JJ, Weir DG, Scott JM. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. Qjm—Monthly J Assoc Physicians. 1997 90(8) 519—524. 

B vitamin intake or vitamin blood concentrations have also been related to various cancers. The cancer types that have been best investigated with respeet to folic acid are colon cancer and colorectal cancer. Convincing evidence from observational studies led to the initiation of randomized controlled trials with folic acid in colorectal adenomas. However, similar to cardiovascular disease, there seems to be a discrepancy between the observational epidemiological studies that reported in the majority an inverse association of folate and cancer risk, and the effect of folic acid supplementation in the randomized controlled trials, which reported no effect of folic add on recurrence of colorectal adenoma risk. 

Bostom, A.G., Carpenter, M.A., Kusek, J.W., Levey, A.S., Hunsicker, L., Pfeffer, M.A., Selhub, J., Jacques, P.F., Cole, E., Gravens-Mueller, L., House, A.A., Kew, C., McKenney, J.L., Pacheco-Silva, A., Pesavento, T., Pirsch, J., Smith, S., Solomon, S., and Weir, M., 2011. Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial. Circulation. 123 1763-1770. 

Table 3.1 Folic acid, Bg, B12 and cardiovascular outcomes. This table summarizes all the important double-blind randomized clinical trials with the use of folie acid, Bg and B12 vitamins for cardiovascular disease prevention. 5-MTHF 5-methyl tetrahydrofolate CKD chronic kidney disease CVD cardiovascular disease DVT deep vein thrombosis ESRD end stage renal disease FA folic acid f/u follow-up MI myocardial infarction RR relative risk UA unstable angina.

Albert, C.M., Cook, N.R., Gaziano, J.M., Zaharris, E., MacFadyen, J., Danielson, E., Buring, J.E., and Manson, J.E., 2008. Elfect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease a randomized trial. JAMA, the Journal of the American Medical Association. 299 2027-2036. 

Supplements combining folic acid (2.5 mg) and vitamins Bs (50 mg) and B (1 mg) did not reduce the risk of major cardiovascular events in patients with vascular disease. 

B vitamins. Among the 13 vitamins, B vitamins are eight water-soluble vitamins (vitamin Bp thiamine vitamin B2 riboflavin vitamin B3 niacin vitamin B5 pantothenic acid vitamin Bg pyridoxine, pyridoxal or pyridoxamine vitamin B7 biotin vitamin B9 folic acid or folate and vitamin B cyanoco-balamin). Folate and vitamins Bg and B12 have joint effects on homocysteine. Cardiovascular disease. Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels and includes coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease (malformations of heart structure existing at birth) and deep vein thrombosis and pulmonary embolism. 

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