Homocysteine, B-vitamins and CVD

Abstract

There is considerable interest in plasma homocysteine (tHcy) as a CVD risk factor. Although the secondary prevention trials published to date have been inconclusive in confirming a benefit of tHcy-lowering treatment with B-vitamins on CVD events generally, such studies are widely recognised to have been insufficiently powered to detect a significant effect for the predicted magnitude of association between tHcy and heart disease risk, and therefore cannot be interpreted as evidence that no relationship exists. In fact, a recent meta-analysis of clinical trials has confirmed that folic acid supplementation reduces the risk of stroke, particularly in individuals without a history of stroke. Evidence supporting a causal relationship between elevated tHcy and heart disease also comes from genetic studies. The most important genetic determinant of tHcy in the general population is the common C677T variant in methylenetetrahydrofolate reductase (MTHFR) that results in higher tHcy. Individuals with the homozygous mutant (TT) genotype have a significantly higher (14-21 %) risk of heart disease. Plasma tHcy is very responsive to intervention with the B-vitamins required for its metabolism, in particular folic acid, and to a lesser extent vitamins B 12 and B 6 . Thus, although primarily aimed at reducing neural-tube defects, folic acid fortification may have an important role in the primary prevention of CVD via tHcy lowering. Besides folate, riboflavin is required as a cofactor for MTHFR and enhanced riboflavin status results in a marked lowering in tHcy specifically in individuals with the TT genotype, presumably by neutralising the variant form of the enzyme. About 10 % of the UK and Irish populations have the TT genotype. In the present paper the potential role of folate and related B-vitamins in the primary prevention of CVD and the implications for nutrition policy are explored. B-vitamins: Folate: Homocysteine: CVD Elevated homocysteine as a risk factor for CVDEvidence from numerous prospective and retrospective case-control studies has emerged in recent years to link elevated plasma homocysteine (tHcy) levels with an increased risk of CVD. Meta-analyses of prospective studies have predicted that lowering tHcy by 3 mmol/l (or a reduction of 25% based on an average tHcy of 12 mmol/l) would reduce the risk of heart disease by 11-16 % and stroke by 19-24 % (1,2) . Although none of the secondary prevention trials published in more recent years have been able to confirm the benefit of tHcy-lowering therapy on CVD events generally (3)(4)(5) , it should not be assumed that no relationship exists. It is now generally recognised that these trials lacked sufficient statistical power to detect an effect for the predicted magnitude of association between tHcy and heart disease (6) . In support of this viewpoint, a clear benefit in reducing stroke was shown in one of the previously mentioned 'negative' trials, although this result was not explicit in the conclusions (4) . Moreover, evidence just published from a meta-analysis o...

Health effects of vegan diets

“…Elevated homocysteine has been considered a risk factor for CVD (73) and osteoporotic bone fractures (74). Vitamin B-12 deficiency can produce abnormal neurologic and psychiatric symptoms that include ataxia, psychoses, paresthesia, disorientation, dementia, mood and motor disturbances, and difficulty with concentration (75).…”

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

“…Moreover, exercise reduced plasma homocysteine concentrations 42 36% within the group fed only the control diet. The prevention of hyperhomocysteinemia by 43 exercise appears, at least in part, to be the result of increased folate-independent homocysteine 44 remethylation owing to a 2-fold increase in renal betaine homocysteine S-methyltransferase. To 45 our knowledge, this is the first report demonstrating the prevention of hyperhomocysteinemia by 46 exercise in a dietary folate-restriction model.…”

“…However, clinical trials targeting homocysteine management by the utilization of B-vitamin 237 supplementation as a means to lower circulating homocysteine concentrations have not been as 238 effective as anticipated [38][39][40][41]. Numerous reviews have debated the various explanations for 239 these findings and the associative vs. causal role of homocysteine in vascular disease [42][43][44]. 240…”

Supra-physiological folic acid concentrations induce aberrant DNA methylation in normal human cells in vitro

“…4,5 Epidemiologic studies suggest that the micronutrients folate and selenium may modulate the risk of several human diseases. [6][7][8][9][10] The main biochemical role for folate is in the supply of one-carbon moieties for DNA synthesis and the synthesis of S-adenosylmethionine (SAM), the universal methyl donor in biological methylation reactions including the methylation of DNA. 11,12 Selenium also plays a role in the metabolism of SAM.…”