There is some interesting work on 5-methyltetrahydrofolate as a potent quencher of peroxynitrite, which plays a major role in the ischemia/reperfusion injury of strokes & heart attacks. The most remarkable thing about the Moens et al study below was that if rats were injected with high dose folic acid 10 minutes after the onset of experimental ischemia, their hearts were largely protected. While humans don't convert folic acid to THF efficiently, I'd love to see a trial in which emergency medical personnel were issued autoinjectors with follinic acid, to see if disability & mortality from strokes & heart attacks could be reduced.
Rezk, B. M., Haenen, G. R., van der Vijgh, W. J., & Bast, A. (2003). Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore. FEBS letters, 555(3), 601-605.
Szabó, C., Ischiropoulos, H., & Radi, R. (2007). Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nature Reviews Drug Discovery, 6(8), 662-680.
Moens, A. L., Champion, H. C., Claeys, M. J., Tavazzi, B., Kaminski, P. M., Wolin, M. S., ... & Kass, D. A. (2008). High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury. Circulation, 117(14), 1810-
Tian, R., & Ingwall, J. S. (2008). How does folic acid cure heart attacks?.Circulation, 117(14), 1772-1774.
Bailey, S. W., & Ayling, J. E. (2009). The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proceedings of the National Academy of Sciences, 106(36), 15424-15429.
Meanwhile, homocysteine modulation appears mostly futile. Much of the association of elevated homocysteine with cardiovascular disease may be a coincident marker of too much high-methionine protein (in many animal products) and not enough folate containing plant foods in the diet. Genetic predispositions to lifelong moderately higher homocysteine have little or no effect on cardiovascular risk, indicating that moderately increased homocysteine doesn't play a large causal role. Moreover, trials of homocysteine lowering interventions (combinations of B12, B6, folic acid, betaine and/or choline supplements) have failed to reduce risk. In animal studies, high methionine intake increases homocysteine, but is also sufficient to increase atherosclerosis even in the absence of elevated homocysteine. And in a study of the MTHFR C677T polymorphism, which lowers levels of methyl-THF and elevates homocysteine, the authors suggest that elevated homocysteine may just be a marker of low methyl-THF status, which has the more direct role in atherosclerosis.
Clarke, R., Bennett, D. A., Parish, S., Verhoef, P., Dötsch-Klerk, M., Lathrop, M., ... & MTHFR Studies Collaborative Group. (2012). Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS medicine, 9(2), e1001177.
Wierzbicki, A. S. (2007). Homocysteine and cardiovascular disease: a review of the evidence. Diabetes and Vascular Disease Research, 4(2), 143-149.
Troen, A. M., Lutgens, E., Smith, D. E., Rosenberg, I. H., & Selhub, J. (2003). The atherogenic effect of excess methionine intake. Proceedings of the National Academy of Sciences, 100(25), 15089-15094.
Antoniades, C., Shirodaria, C., Leeson, P., Baarholm, O. A., Van-Assche, T., Cunnington, C., ... & Channon, K. M. (2009). MTHFR 677 C> T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis. Circulation, 119(18), 2507-2515.
Albedo, check your personal messages.
