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THE HOMOCYSTEINE INDCATION FOR HEART DISEASE: THE SCIENTIFIC BASIS OF THE VITAMIN B6, B9 (folate), AND B12 DOSAGE OF NUTRITION INVESTIGATOR

Since 1995, the primary medical and scientific literature has had a steady stream of well-designed, carefully controlled studies demonstrating a new risk factor for heart disease. Just as high cholesterol levels, smoking, lack of exercise, and family history are significant factors in predicting whether an individual will develop heart disease, the level of homocysteine in the blood is a risk factor. " [E]levated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis"(20). Homocysteine is an amino acid, produced from the required amino acid methionine. Homocysteine is not used in making proteins, and is normally metabolized back to methionine or degraded, relying on three vitamins, B6 (pyridoxal), B9 (folic acid), and B12 (cobalamin) for the metabolism. One theory is that the modern American diet is so rich in protein that the methionine content overwhelms our ability to metabolize it, and those with low intakes of those three vitamins are unable to regulate the homocysteine level adequately. "Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation" (1). As an example of the importance of vitamins, in one major study of 14,916 men (2), those with the lowest 20% of folate levels had a relative risk of 1.4 for heart attack or death. Those with the lowest 20% of vitamin B6 levels had a relative risk of 1.5. Supplementation of the diet with those vitamins leads to a corresponding decrease in risk. Thus, many authors have proposed supplementing foods or giving vitamin supplements to people to reduce the level of homocysteine in the blood, and thus the risk of heart disease.

Thus far, studies have looked at levels of B-vitamins in the diet, rather than conducting long term clinical trials for elevated dosages. The existing evidence strongly supports the value and safety of RDA levels of supplementation of vitamins B6, B9, and B12. All three are GRAS (Generally Recognized As Safe) substances, but presently there is no evidence that dosages above the RDA provide any benefit to the average individual.

QUOTATIONS FROM SOME PUBLISHED HOMOCYSTEINE STUDIES 1. "Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease," Duell PB; Malinow MR, Curr Opin Lipidol, 1997 Feb, 8:1, 28-34

"Homocysteine is an intermediate compound formed during metabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12..."

2. "A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians," Chasan-Taber L; Selhub J; Rosenberg IH; Malinow MR; Terry P; Tishler PV; Willett W; Hennekens CH; Stampfer MJ , J Am Coll Nutr, 1996 Apr, 15:2, 136-43

"To assess prospectively the risk of myocardial infarction (MI) associated with decreased plasma levels of folate and pyridoxal phosphate (PLP, a form of vitamin B6) in relation to elevated levels of total homocysteine (tHcy)... SETTING: Participants in the Physicians' Health Study. SUBJECTS: 14,916 male physicians, aged 40-84 years, with no prior MI or stroke provided plasma samples at baseline and were followed for 7.5 years. ... RESULTS:...men with the lowest 20% of folate levels ... had a relative risk of 1.4...compared with those in the top 80%. For the lowest 20% of vitamin B6 values, the relative risk was 1.5 ... these prospective data are compatible with the hypothesis that low dietary intake of folate and/or vitamin B6 contribute to risk of MI. "

3. "Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study", Giles WH; Kittner SJ; Anda RF; Croft JB; Casper ML , Stroke, 1995 Jul, 26:7, 1166-70

"A serum folate concentration < or = 9.2 nmol/L has been associated with elevated levels of plasma homocyst(e)ine. Elevated homocyst(e)ine levels have been associated with ischemic stroke in case-control studies..These findings suggest that a folate concentration < or = 9.2 nmol/L may be a risk factor for ischemic stroke"

4. "Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation," Gallagher PM; Meleady R; Shields DC; Tan KS; McMaster D; Rozen R; Evans A; Graham IM; Whitehead AS, Circulation, 1996 Nov 1, 94:9, 2154-8

"Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the enzyme methylenetetrahydrofolate reductase (MTHFR)... MTHFR, which modulates basal plasma homocysteine concentration, is folate dependent, and dietary supplementation or fortification with folic acid may reduce plasma homocysteine levels and consequent coronary risk in a significant proportion of the general population. "

5. "Serum total homocysteine and coronary heart disease," Arnesen E; Refsum H; B naa KH; Ueland PM; F rde OH; Nordrehaug JE , Int J Epidemiol, 1995 Aug, 24:4, 704-9

"The only prospective study was based on US physicians, and concluded that homocysteine was associated with subsequent myocardial infarction (MI)... We conducted a nested case-control study among the 21,826 subjects, aged 12-61 years.. In the general population serum total homocysteine is an independent risk factor for CHD... "

6. "New directions in dietary studies of coronary heart disease," Ascherio A; Willett WC , J Nutr, 1995 Mar, 125:3 Suppl, 647S-655S

"Antioxidants, and in particular vitamin E, are emerging as potentially useful protective factors, and there is increasing evidence that hyperhomocysteinemia is a risk factor that may be modified by dietary changes"

7. "Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study," NygÜrd O; Vollset SE; Refsum H; Stensvold I; Tverdal A; Nordrehaug JE; Ueland M; KvÜle G , JAMA, 1995 Nov 15, 274:19, 1526-33

"A total of 7591 men and 8585 women, 40 to 67 years of age, with no history of hypertension, diabetes, coronary heart disease, or cerebrovascular disease were included... --Elevated plasma tHcy level was associated with major components of the cardiovascular risk profile, ie, male sex, old age, smoking, high blood pressure, elevated cholesterol level, and lack of exercise. "

8. "Prevention of myocardial infarction by vitamin B6," Ellis JM; McCully, Res Commun Mol Pathol Pharmacol, 1995 Aug, 89:2, 208-20

"Hyperhomocysteinemia, a risk factor for atherosclerosis, is associated with deficiencies of vitamin B6, folate, and cobalamin. Patients who were given vitamin B6 for carpal tunnel syndrome and other degenerative diseases were found to have 27% of the risk of developing acute cardiac chest pain or myocardial infarction, compared with patients who had not taken vitamin B6. Among elderly patients of the author (JE) expiring at home, the average age at death from myocardial infarction was 8 years later in those who had taken vitamin B6..."

9."Plasma homocysteine levels and mortality in patients with coronary artery disease," Nyg rd O; Nordrehaug JE; Refsum H; Ueland PM; Farstad M; Vollset SE , N Engl J Med, 1997 Jul 24, 337:4, 230-6

" the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined...We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients...: Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease."

10. "The role of folic acid in deficiency states and prevention of disease," Swain RA; St Clair L , J Fam Pract, 1997 Feb, 44:2, 138-44

"Folic acid... may reduce the incidence of neural tube defects by 45% in women who receive 400 micrograms per day. It is recommended that all women of childbearing age take 400 micrograms of folate per day."

11. "Folic acid fortification of the food supply. Potential benefits and risks for the elderly population," Tucker KL; Mahnken B; Wilson PW; Jacques P; Selhub J , JAMA, 1996 Dec 18, 276:23, 1879-85

"To estimate the potential benefits and risks of food folic acid fortification for an elderly population. Benefits are expected through the improvement of folate and homocysteine status, but there is also a risk of masking or precipitating clinical manifestations related to vitamin B12 deficiency with increasing exposure to folic acid"

12. "Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population," Selhub J; Jacques PF; Bostom AG; D'Agostino RB; Wilson PW; Belanger AJ; O'Leary DH; Wolf PA; Rush D; Schaefer EJ; Rosenberg, J Nutr, 1996 Apr, 126:4 Suppl, 1258S-65S

"we analyzed plasma samples from the 20th biannual examination of the Framingham Heart Study cohort to determine distribution of plasma homocysteine concentrations with emphasis on relationships to B vitamins and prevalence of carotid artery stenosis. Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B-12 and pyridoxal-5'-phosphate (PLP). Homocysteine was also inversely associated with intakes of folate and vitamin B-6, but not vitamin B-12. Prevalence of high homocysteine (>14 micromol/l) was 29.3% in this cohort, and inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine."

13. "Cigarette smoking, intracellular vitamin deficiency, and occurrence of micronuclei in epithelial cells of the buccal mucosa," Piyathilake CJ; Macaluso M; Hine RJ; Vinter DW; Richards EW; Krumdieck CL, Cancer Epidemiol Biomarkers Prev, 1995 Oct-Nov, 4:7, 751-8

"The study focuses on the assessment of chromosomal damage associated with folate and vitamin B12 deficiency.... The presence of vitamin B12 in the immediate environment (saliva) and vitamin C and E in the plasma, however, appear to be marginally protective against chromosomal damage in buccal mucosal cells."

14. "Impaired antibody responses to pneumococcal polysaccharide in elderly patients with low serum vitamin B12 levels," Fata FT; Herzlich BC; Schiffman G; Ast AL, Ann Intern Med, 1996 Feb 1, 124:3, 299-304

"To determine whether immunocompetent elderly patients with low serum vitamin B12 levels have impaired serum antibody responses to the 23-polyvalent pneumococcal polysaccharide vaccine. ..: Patients with low vitamin B12 levels had impaired antibody responses to pneumococcal vaccine."

15. "Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis," Selhub J; Jacques PF; Bostom AG; D'Agostino RB; Wilson PW; Belanger AJ; O'Leary DH; Wolf PA; Schaefer EJ; Rosenberg IH , N Engl J Med, 1995 Feb 2, 332:5, 286-91

"BACKGROUND. Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis... a cross-sectional study of 1041 elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study... CONCLUSIONS. High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly."

16. "Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate," Verhoef P; Stampfer MJ; Buring JE; Gaziano JM; Allen RH; Stabler SP; Reynolds RD; Kok FJ; Hennekens CH; Willett WC , Am J Epidemiol, 1996 May 1, 143:9, 845-59

"Elevated plasma homocyst(e)ine levels are an independent risk factor for vascular disease. .. Dietary and plasma levels of vitamin B6 and folate were lower in cases than in controls, and these vitamins were inversely associated with the risk of myocardial infarction, independently of other potential risk factors... the authors found that impairment of remethylation of homocyst(e)ine (dependent of folate and vitamin B12 rather than on vitamin B6-dependent transsulfuration) was the predominant cause of high homocyst(e)ine levels in cases. Accordingly, plasma folate and, to a lesser extent, plasma vitamin B12, but not vitamin B6, correlated inversely with plasma homocyst(e)ine, even for concentrations at the high end of normal values. These data provide further evidence that plasma homocyst(e)ine is an independent risk factor for myocardial infarction. In this population, folate was the most important determinant of plasma homocyst(e)ine, even in subjects with apparently adequate nutritional status of this vitamin."

17. "Free radicals, oxidative stress, oxidized low density lipoprotein (LDL), and the heart: antioxidants and other strategies to limit cardiovascular damage," Sinatra ST; DeMarco J , Conn Med, 1995 Oct, 59:10, 579-88

"The heart is the most susceptible of all the organs to premature aging and free radical oxidative stress. Clinical research has clearly documented the role of free radical damage and the progression of numerous degenerative diseases, particularly cardiovascular disease. ..The effects of antioxidant nutrients have been extensively evaluated in epidemiological, population, and clinical studies... The B complex, particularly folic acid, B12, and B6 are also essential in the prevention of hyperhomocysteinemia "

18. "Homocysteine and coronary atherosclerosis," Mayer EL; Jacobsen DW; Robinson K , J Am Coll Cardiol, 1996 Mar 1, 27:3, 517-27

"Homocysteine is increasingly recognized as a risk factor for coronary artery disease...This review presents the clinical and basic scientific evidence supporting the risk and mechanisms of vascular disease associated with elevated homocysteine concentrations as well as the results of preliminary therapeutic trials. "