Atherosclerosis folates

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Compared with healthy controls, 51 patients with epilepsy taking a variety of antiepileptic drugs (mostly carbamaze-pine) had higher mean plasma concentrations of homocysteine (130). This effect, which could be related to reductions in the concentrations of folate and vitamin B6, was likely to be drug-induced, but a causative role of the underlying disease could not be excluded. Although homocysteine is an experimental convulsant and a risk factor for atherosclerosis, the clinical relevance of these findings is uncertain. 

The identification of hyperhomocysteinemia as an independent risk factor in atherosclerosis and coronary heart disease (Section 10.3.4.2) has led to suggestions that intakes of vitamin Be higher than are currently considered adequate to meet requirements may be desirable. Homocysteine is an intermediate in methionine metabolism and may undergo one of two metabolic fates, as shown in Figure 9.5 remethylation to methionine (a reaction that is dependent on vitamin B12 and folic acid) or onward metabolism leading to the synthesis of cysteine (trans-sulfuration). Therefore, intakes of folate, vitamin B12, and/or vitamin Be may affect homocysteine metabolism. 

A consequence of these studies is that the Food and Drug Administration (fTDA) has recomtnended that commercially available flour and cereal products be fortified w ith folic acid 1-4 tug folic acid/kg flour) for preventing NTDs (Tucker cf ai, 1996). The consumer interested in the folate level in any particular food can view the label on the package. Folic acid supplements have the effect of reducing the level of homocysteine in the blood. This homocysteine effect appears directly relevant to the prevention of atherosclerosis, but may also be relevant to neural tube defects. The reader interested in continuing developments regarding neural tube defects and folate should take note of the relationship between folate and homocysteine, presented in the Vitamin 8 section. 

A study of 1401 subjects involved measuring plasma homocysteine and measuring the lesions in the carotid artery, one of the arteries in the body that tends to acquire atherosclerotic lesions. The thickness of the lesions were measured by ultrasonography. Plasma folate, vitamin Bg, and vitamin B12 were also measured. A correlation was found between narrowing of the artery and homocysteine levels at above 15 xM homocysteine. A correlation with narrowing of the artery was also found with folate levels below 2.5 ng/ml, and with vitamin Bg levels below 30 nM (Selhub et al, 1995). A study of 231 normal subjects and 304 patients with atherosclerosis (coronary artery under 30% normal diameter) revealed a striking correlation between plasma homocysteine of 12 pM, or greater, and atherosclerosis (Robinson et al, 1995). These studies help define an upper limit of acceptable plasma homocysteine levels. 

Antoniades, C., Antonopoulos, A.S., Tousoulis, D., Marinou, K., and Stefa-nadis, C., 2009a. Homocysteine and coronary atherosclerosis from folate fortification to the recent clinical trials. European Heart Journal. 30 6-15. 

Siri, P.W., Verhoef, P., and Kok, F.J., 1998. Vitamins Bg, B12 and folate association with plasma total homocysteine and risk of coronary atherosclerosis. Journal of the American College of Nutrition. 17 435-441. 

High Hey is associated with an elevated risk of vascular disease independent of all traditional risk factors. Low folate and Be confer an increased risk of atherosclerosis. 

According to Kuller and Evans (1998), Hey and B vitamins levels may contribute to the development of vascular disease through mechanisms independent of the atherosclerosis process. In fact, whereas high Hey levels are directly related to development of atherosclerosis, a decrease in folate or vitamins B12 and Bg increases the risk of vascular disease independently of atherosclerosis. High Hey levels could be associated with an enhancement of inflammatory process and increased risk of thrombosis. 

However, in a prospective study, atherosclerosis risk in communities (ARIC), there was doubt about a relation between CHD and Hey and no association between CHD and C677T mutation of methylenetetrahydro-folate reductase gene or three mutations of cystathionine P-synthase gene. However, it was possible that vitamin Bg offered an independent protection (143), and recently a review concluded that there is insufficient evidence to regard Hey levels as a causative factor in atherosclerosis (144). 

The potential of folate in preventive medicine against neural tube defects, cardiovascular disease, and various cancers (colon) (reviewed in Ref. 2) has greatly attracted attention to this vitamin in recent years. It is now estabUshed that folic acid can prevent neural tube defects such as spina bifida. More recently, it has been shown that folic acid, along with vitamin and B12, can reduce plasma homocysteine concentration, an amino acid that has been linked to possible increased risk of atherosclerosis (3-5). 

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