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HeartFolate Lowers High Blood Pressure Risk for Women Folate, a vitamin already known for its power to prevent birth defects, also appears to reduce the risk of high blood pressure for women both young and old. New research shows that young women who consumed more than 800 micrograms of folate a day -- about the amount found in two multivitamins -- reduced their risk of developing high blood pressure by nearly a third compared to those who had less than 200 micrograms a day. Folate also reduced the risk of high blood pressure in older women, but to a lesser degree, the study found. The study was authored by Dr. John P. Forman, a research and clinical fellow at Brigham and Women's Hospital in Boston. It was presented Oct. 11 at the American Heart Association's annual high blood pressure research conference in Chicago. "Two small studies before ours found a positive association between folate intake and blood pressure reduction," Forman said, although the women in those studies already had high blood pressure. "As far as I know, this is the first study to look at a group of women who did not have a diagnosis of high blood pressure at baseline and look to see who got hypertension," he added. The study isn't proof-positive that high folate intake prevents high blood pressure, he emphasized, and more studies will be needed to confirm the finding. In this study, Forman's group evaluated 150,000 women, following them over eight years. One group included 62,260 women from the Nurses' Health Study I, aged 43 to 70. The other included 93,034 women from the Nurses' Health Study II, aged 26 to 46. The women answered questions about their food intake at the start and then every four years. They reported any physician-diagnosed high blood pressure every two years during the eight-year follow-up period. Among the younger women who took in more than 800 micrograms of folate a day, there was a 29 percent reduction in risk in high blood pressure, compared to those who consumed less than 200 micrograms a day. Older women who took in more than 800 micrograms daily had a 13 percent reduction in risk compared to those who took in less than 200 micrograms. There also was a somewhat decreased risk in those who took in 400 to 600 micrograms, compared to those who took in under 200, but the risk reduction wasn't statistically significant, Forman said. "Folate has been shown to reduce levels of homocysteine, a circulating compound in blood," Forman said. "Higher levels of homocysteine have been associated with cardiovascular disease." If the levels are too high, the production of nitric oxide, which relaxes blood vessels, drops, he explained. Folate is a B vitamin that is found naturally in leafy green vegetables such as spinach and turnip greens, fruits, dried beans and peas. To consume 800 micrograms a day, you would need to take a multivitamin plus eat three-quarters of a cup of breakfast cereal fortified with 400 micrograms of folate, or other foods. A half cup of spinach, for instance, has 100 micrograms, and three ounces of beef liver has 185 micrograms. Dr. Alice Lichtenstein, Gershoff Professor of Nutrition Science and Policy at Tufts University, called the report "interesting." But she cautioned that "the findings are associations only." And no one should suggest at this point that people start relying
on folate to decrease their blood pressure, she added. Doshi, McDowell, Moat, Lewis, Goodfellow Elevated plasma homocysteine is associated with increased cardiovascular risk but it remains unproven that the effect is directly causal. Folate and homocysteine metabolism are closely linked such that administration of folic acid in doses ranging from 0.2-10 mg/day lowers plasma total homocysteine (tHcy) by up to 25%. Folic acid has been widely advocated as a therapy which may reduce cardiovascular risk, but the clinical benefit remains as yet unproven and the choice of dose remains unclear. The effect of folic acid on endothelial function has been investigated in patients with proven coronary heart disease (CHD) by measuring flow-mediated dilatation (FMD) in the brachial artery. Oral folic acid (5 mg/day) markedly enhances endothelial function (FMD) and lowers homocysteine. Studies of the acute effects of folic acid have shown that this improvement occurs within the first 2-4 hours following the first dose, at which times there was no significant reduction in plasma tHcy. Administration of 5-methyltetrahydrofolate directly into the brachial artery markedly enhances FMD, an effect that is blocked by monomethyl arginine (LNMMA), suggesting that the effects of folate are mediated by nitric oxide. This Review summarises studies which show that pharmacological doses of folate markedly enhance endothelial function in patients with CHD. The discordance with changes in plasma homocysteine suggests that these effects may occur by mechanisms distinct from homocysteine lowering. Strandhagen, Landaas, Thelle OBJECTIVE: Elevated levels of plasma total homocysteine (tHcy)
are identified as independent risk factors for coronary heart disease
and for fetal neural tube defects. tHcy levels are negatively associated
with folic acid, pyridoxine and cobalamine, and positively associated
with coffee consumption and smoking. A total of 600 ml of filtered
coffee results in a tHcy increase that 200 mug of folic acid or
40 mg of pyridoxine supplementation might eliminate. Schofield, Wessel, Walker, Cleeton, Hill, Aranda BACKGROUND: Hyperhomocysteinemia is becoming recognized as a risk
factor for cardiovascular disease, yet there are limited data on
the prevalence of hyperhomocysteinemia in patients with heart failure.
HYPOTHESIS: The purpose of this study was to examine the prevalence
of hyperhomocysteinemia in patients with severe heart failure and
to correlate serum homocysteine levels with factors that may affect
homocysteine metabolism. Merchant, Hu, Spiegelman, Willett, Rimm, Ascherio Peripheral arterial disease (PAD) causes morbidity and is associated with mortality. B vitamin intake has been inversely associated with coronary heart disease, but their effects on PAD are not known. We examined prospectively the relationships between dietary folate, vitamin B-6 and B-12 and PAD risk in 51529 male U.S. health professionals, aged 40 to 75 y, who answered a detailed 131-item questionnaire to assess diet and vitamin supplement use. The study population consisted of 46036 men free of PAD, cardiovascular disease and diabetes at baseline followed for 12 y during which we documented 308 incident PAD cases. For every 400 microg/d increment of folate intake, the multivariate adjusted PAD risk decreased by 21% [relative risk (RR) = 0.79, 95% CI 0.64-0.96]. Men in the top category of folate intake (median = 840 micro g) were at 33% lower risk of PAD than men in the bottom category (median = 244 microg) (RR = 0.67, 95% CI 0.45-0.96, P-value, test for trend = 0.03) after multivariate adjustment. There were weak inverse associations between intake of vitamin B-6 and PAD risk (RR = 0.70, 95% CI 0.48-1.02, P-value, test for trend = 0.06) and B-12 (RR = 0.77, 95% CI 0.54-1.11, P-value, test for trend = 0.12). These results suggest that higher consumption of folate may contribute to the prevention of PAD. Das OBJECTIVES: The possible link between folic acid or folate and tetrahydrobiopterin (H(4)B), vitamin C, polyunsaturated fatty acids (PUFAs), and nitric oxide (NO), which may explain the beneficial actions of these nutrients in various vascular conditions, was investigated. METHODS: The literature pertaining to the actions of folic acid/folate, H(4)B, vitamin C, PUFAs, and NO was reviewed. RESULTS: Impaired endothelial NO (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions. It stimulates endogenous H(4)B regeneration, a cofactor necessary for eNO synthesis, inhibits intracellular superoxide generation, and thus enhances the half-life of NO. H(4)B in turn enhances NO generation and augments arginine transport into the cells. Folic acid increases the concentration of omega-3 PUFAs, which also enhance eNO synthesis. Vitamin C augments eNO synthesis by increasing intracellular H(4)B and stabilization of H(4)B. Insulin stimulates H(4)B synthesis and PUFA metabolism, suppresses the production of proinflammatory cytokine tumor necrosis factor-alpha and superoxide anion, and enhances NO generation. The ability of folate to augment eNO generation is independent of its capacity to lower plasma homocysteine levels. CONCLUSIONS: The common mechanism by which folic acid, H(4)B, vitamin C, omega-3 fatty acids, and L-arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production. Hence, it remains to be determined whether a judicious combination of folic acid, vitamins B12, B6, and C, H(4)B, L-arginine, and omega-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, peripheral vascular disease, and some neurodegenerative conditions.
OBJECTIVES: To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels. DESIGN: We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin. OUTCOME MEASURES: Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects. RESULTS: The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a beta blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation). CONCLUSION: The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention. Chang, Chu, Shen, Wu, Liang, Shieh BACKGROUND: Plasma total homocysteine (tHcy) level is an independent risk factor for cardiovascular disease (CVD) even among children. The purpose of this study is to evaluate the determinants and distributions of plasma tHcy levels and the relationship between plasma tHcy, folate and vitamin B12 levels among school children in Taipei. METHODS: After multi-stage sampling, we randomly selected 1234 school children (609 boys and 625 girls) with the mean age of 13 years (from 12 to 15 years) in this study. Fasting plasma tHcy levels were measured using an ABBOTT IMx analyzer (Axis Biochemicals ASA, Oslo, Norway). Plasma folate and vitamin B12 levels were measured by ACS:180 automated chemiluminescence analyzer (Bayer, Tarrytown, NY, USA). RESULTS: The distribution of plasma tHcy levels were skewed to the right with the mean values of 10.50 and 8.95 micromol/l and medians of 9.67 and 8.474 micromol/l for boys and girls, respectively. Plasma tHcy concentrations were lower in younger children and progressively increased with increasing age. Boys had significantly higher plasma tHcy levels than girls (10.50 +/- 4.134 vs. 8.95 +/- 2.61 micromol/l, p < 0.01) and lower plasma folate levels (6.05 +/- 2.85 vs. 6.39 +/- 2.58 nmol/l, p < 0.01), and vitamin B12 levels (444.8 +/- 158.4 vs. 495.0 +/- 181.5 pmol/l, p < 0.001). Plasma tHcy levels were significantly positively associated with anthropometric measures in boys; but these characteristics attenuated and became insignificant after adjusting for other potential confounders in girls. Plasma tHcy levels were negatively associated with plasma folate and vitamin B12 levels even after adjusting for BMI and other potential confounders in both genders. CONCLUSIONS: From this study, the distributions of tHcy levels were skewed to the right and the boys had higher plasma tHcy levels than girls. Plasma tHcy levels were significantly positively associated with BMI among boys. Further studies are needed to evaluate the relationship between tHcy and CVD risk factors among children for the better prevention of heart disease in early life. Woo, Qiao, Chook, Poon, Chan, Lau, Fung, Woo Atherosclerosis is an important medical problem of the 21st century, but traditional risk factors could only account for 50% of the problem. Hyperhomocysteinemia is emerging as an independent atherosclerosis risk factor, associated with folate deficiency, renal failure, and relative deficiency of MTHFR (C677T polymorphism) or other enzymes depending on gender, age, and smoking status. Hyperhomocysteinemia has been reported to occur in 11-22% of western people, in 3-5% of normal asymptomatic Chinese subjects aged 18-70 years in Hong Kong, Macau, Sydney, and San Francisco, 23-36% of Chinese in Hong Kong with premature coronary artery disease, and 29% of a nonselective series of coronary subjects in Hong Kong. Evidence is accumulating that documents its associations with atherosclerosis disease in both case-control observations and prospective cohort studies, in vitro experiments, and in vivo experimental models in both animals and human subjects, as well as the successful improvement by homocysteine-lowering of endothelial function as surrogate atherosclerosis endpoints in asymptomatic human and coronary patients (secondary prevention). A number of large scale homocysteine-lowering trials are currently underway for stroke and heart attacks prevention. Collectively these trials will include more than 65,000 patients at high-risk for cardiovascular and stroke events, and should provide a reliable evidence-base for prevention. Hung, Beilby, Knuiman, Divitini OBJECTIVE: To test the hypothesis that the incidence of fatal coronary heart disease and cardiovascular disease in a general population is related to serum and red cell folate and vitamin B-12 concentrations. DESIGN: Cohort study with follow up of 29 years. SETTING: Busselton, Western Australia. PARTICIPANTS: 1419 men and 1531 women aged 20 to 90 years, who were alive more than three years after their participation in the 1969 Busselton health survey. 2314 (78.4%) had no cardiovascular disease at the initial survey. MAIN OUTCOME MEASURES: Hazard ratios for fatal coronary heart disease and cardiovascular disease in men and women according to baseline concentrations of serum and red cell folate and serum vitamin B-12. RESULTS: 213 men and 159 women died from coronary heart disease, and 342 men and 302 women died from cardiovascular disease. Serum and red cell folate concentrations showed a moderate positive correlation (r=0.26, P<0.001) but otherwise serum and red cell folate and serum B-12 concentrations were not strongly correlated with each other or with other standard risk factors. After age and standard risk factors were adjusted for, there was no independent association between folate and B-12 concentrations and death from coronary heart disease or cardiovascular disease in the full cohort or the subcohort with no cardiovascular disease at baseline. The multivariate adjusted hazard ratio for death from cardiovascular disease in the lowest versus the highest category of red cell folate concentration was 1.05 (95% confidence interval 0.77 to 1.43) in men and 1.10 (0.81 to 1.51) in women. CONCLUSIONS: These findings do not support the hypothesis that lower folate and B-12 concentrations increase the risk of fatal cardiovascular disease in a general population. The routine use of these vitamins for preventing cardiovascular disease should await evidence from clinical trials. Wald, Law, Morris OBJECTIVE: To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them. DESIGN: Meta-analyses of the above three diseases using (a) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and (b) 20 prospective studies (3820 participants) of serum homocysteine and disease risk. MAIN OUTCOME MEASURES: Odds ratios of the three diseases for a 5 micromol/l increase in serum homocysteine concentration. RESULTS: There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 micromol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies. CONCLUSIONS: The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant results-strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 micromol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%). Klerk, Verhoef, Clarke, Blom, Kok, Schouten CONTEXT: In observational studies, individuals with elevated levels of plasma homocysteine tend to have moderately increased risk of coronary heart disease (CHD). The MTHFR 677C-->T polymorphism is a genetic alteration in an enzyme involved in folate metabolism that causes elevated homocysteine concentrations, but its relevance to risk of CHD is uncertain. OBJECTIVE: To assess the relation of MTHFR 677C-->T polymorphism and risk of CHD by conducting a meta-analysis of individual participant data from all case-control observational studies with data on this polymorphism and risk of CHD. DATA SOURCES: Studies were identified by searches of the electronic literature (MEDLINE and Current Contents) for relevant reports published before June 2001 (using the search terms MTHFR and coronary heart disease), hand searches of reference lists of original studies and review articles (including meta-analyses) on this topic, and contact with investigators in the field. STUDY SELECTION: Studies were included if they had data on the MTHFR 677C-->T genotype and a case-control design (retrospective or nested case-control) and involved CHD as an end point. Data were obtained from 40 (34 published and 6 unpublished) observational studies involving a total of 11 162 cases and 12 758 controls. DATA EXTRACTION: Data were collected on MTHFR 677C-->T genotype, case-control status, and plasma levels of homocysteine, folate, and other cardiovascular risk factors. Data were checked for consistency with the published article or with information provided by the investigators and converted into a standard format for incorporation into a central database. Combined odds ratios (ORs) for the association between the MTHFR 677C-->T polymorphism and CHD were assessed by logistic regression. DATA SYNTHESIS: Individuals with the MTHFR 677 TT genotype had a 16% (OR, 1.16; 95% confidence interval [CI], 1.05-1.28) higher odds of CHD compared with individuals with the CC genotype. There was significant heterogeneity between the results obtained in European populations (OR, 1.14; 95% CI, 1.01-1.28) compared with North American populations (OR, 0.87; 95% CI, 0.73-1.05), which might largely be explained by interaction between the MTHFR 677C-->T polymorphism and folate status. CONCLUSIONS: Individuals with the MTHFR 677 TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status. These results support the hypothesis that impaired folate metabolism, resulting in high homocysteine levels, is causally related to increased risk of CHD. Schnyder, Roffi, Flammer, Pin, Hess CONTEXT: Plasma homocysteine level has been recognized as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis and influences restenosis rate after percutaneous coronary intervention. OBJECTIVE: To evaluate the effect of homocysteine-lowering therapy on clinical outcome after percutaneous coronary intervention. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind placebo-controlled trial involving 553 patients referred to the University Hospital in Bern, Switzerland, from May 1998 to April 1999 and enrolled after successful angioplasty of at least 1 significant coronary stenosis (> or = 50%). INTERVENTION: Participants were randomly assigned to receive a combination of folic acid (1 mg/d), vitamin B12 (cyanocobalamin, 400 micro g/d), and vitamin B6 (pyridoxine hydrochloride, 10 mg/d) (n = 272) or placebo (n = 281) for 6 months. MAIN OUTCOME MEASURE: Composite end point of major adverse events defined as death, nonfatal myocardial infarction, and need for repeat revascularization, evaluated at 6 months and 1 year. RESULTS: After a mean (SD) follow-up of 11 (3) months, the composite end point was significantly lower at 1 year in patients treated with homocysteine-lowering therapy (15.4% vs 22.8%; relative risk [RR], 0.68; 95% confidence interval [CI], 0.48-0.96; P =.03), primarily due to a reduced rate of target lesion revascularization (9.9% vs 16.0%; RR, 0.62; 95% CI, 0.40-0.97; P =.03). A nonsignificant trend was seen toward fewer deaths (1.5% vs 2.8%; RR, 0.54; 95% CI, 0.16-1.70; P =.27) and nonfatal myocardial infarctions (2.6% vs 4.3%; RR, 0.60; 95% CI, 0.24-1.51; P =.27) with homocysteine-lowering therapy. These findings remained unchanged after adjustment for potential confounders. CONCLUSION: Homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 significantly decreases the incidence of major adverse events after percutaneous coronary intervention. García Closas, Serra Majem, Sabater Sales, Olmos
Castellvell, Ribas Barba, Salleras Sanmartí BACKGROUND: The subclinical deficiency of certain micronutrients (vitamin C, folic acid, vitamin B12) has been associated with disorders as cardiovascular diseases, cancer, cataracts, immunodepression and fetal neural tube defects. The purpose of this study was to determine the serum concentration of vitamin C, folic acid and vitamin B12 in the Catalan population and to examine the prevalence of deficits of these micronutrients. SUBJECTS AND METHOD: We studied a subsample of individuals (n = 378) from a representative sample of people aged 18 to 75 years who had participated in the study of the Nutritional Status of the Catalan Population (1992-93). Serum concentrations of vitamin C, folic acid and vitamin B12 were determined. RESULTS: The serum concentration of vitamin C was lower in men than in women. 4.6 and 0.5% subjects were found to have marginal and severe deficits of vitamin C, respectively. 4 and 1.6% subjects had marginal and severe deficits of folic acid, respectively. Folic acid deficit involved up to 12.9% women aged 18-34 years and up to 9.1% men within the same age group. Subjects who had a severe deficit of folic acid consumed more than 20 g/day of alcohol. The serum concentration of vitamin B12 was greater in women than in men. 1.9% individuals had a marginal deficit of this vitamin. CONCLUSION: The sample of individuals studied were found to have a correct nutritional status with regard to vitamin C, folic acid and vitamin B12. This may explain the lower incidence of cancer and ischemic heart disease associated with the Mediterranean diet. Voutilainen, Rissanen, Virtanen, Lakka, Salonen BACKGROUND: Although several prospective studies have shown that low folate intake and low circulating folate are associated with increased risk of coronary heart disease (CHD), the findings are inconsistent. METHODS AND RESULTS: We studied the associations of dietary intake of folate, vitamin B(6), and vitamin B(12) with the risk of acute coronary events in a prospective cohort study of 1980 Finnish men 42 to 60 years old examined in 1984 to 1989 in the Kuopio Ischemic Heart Disease Risk Factor Study. Nutrient intakes were assessed by 4-day food record. During an average follow-up time of 10 years, 199 acute coronary events occurred. In a Cox proportional hazards model adjusted for 21 conventional and nutritional CHD risk factors, men in the highest fifth of folate intake had a relative risk of acute coronary events of 0.45 (95% CI 0.25 to 0.81, P=0.008) compared with men in the lowest fifth. This association was stronger in nonsmokers and light alcohol users than in smokers and alcohol users. A high dietary intake of vitamin B(6) had no significant association and that of vitamin B(12) a weak association with a reduced risk of acute coronary events. CONCLUSIONS: The present work in CHD-free middle-aged men is the first prospective cohort study to observe a significant inverse association between quantitatively assessed moderate-to-high folate intakes and incidence of acute coronary events in men. Our findings provide further support in favor of a role of folate in the promotion of good cardiovascular health. Eichholzer, Lüthy, Gutzwiller, Stähelin An intake of about 400 micrograms folate equivalents/day seems to be required to achieve stable low homocysteine blood levels. Five of eight epidemiologic studies show significant inverse associations between folate and cardiovascular disease. Graham, O'Callaghan Coronary heart disease is the leading cause of death in the developed world. Current surgical and pharmacological interventions are essentially palliative and interest in preventive strategies, particularly through nutrition and avoidance of tobacco has increased in recent years. Basic scientific, clinical and epidemiological evidence indicates a positive association between the plasma level of the amino acid homocysteine and vascular disease. Homocysteine levels are inversely related to both intake and plasma levels of folate. Less strong evidence indicates an inverse relationship between folate intake and coronary heart disease risk. It is likely that current estimates of dietary folate requirements are lower than optimal. Folic acid supplementation reliably reduces homocysteine levels, and may also modify endothelial function independent of this effect on homocysteine. Such treatment is cheap and appears to be essentially free of risk. However, until present randomised control trials are complete, it will not be known definitively whether or not increasing folate intake reduces cardiovascular risk. Wald, Bishop, Wald BACKGROUND: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear. METHODS: We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. RESULTS: Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical. CONCLUSIONS: A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction. Vermeulen, Stehouwer BACKGROUND: A high plasma homocysteine concentration is associated with increased risk of atherothrombotic disease. We investigated the effects of homocysteine-lowering treatment (folic acid plus vitamin B6) on markers of subclinical atherosclerosis among healthy siblings of patients with premature atherothrombotic disease. METHODS: We did a randomised, placebo-controlled trial among 158 healthy siblings of 167 patients with premature atherothrombotic disease. 80 were assigned placebo and 78 were assigned 5 mg folic acid and 250 mg vitamin B6 daily for 2 years. The primary endpoint was the development or progression of subclinical atherosclerosis as estimated from exercise electrocardiography, the ankle-brachial pressure index, and carotid and femoral ultrasonography. FINDINGS: Ten participants in the treatment group, and 14 in the placebo group dropped out. Vitamin treatment, compared with placebo, was associated with a decrease in fasting homocysteine concentration (from 14.7 to 7.4 micromol/L vs from 14.7 to 12.0 micromol/L), and in postmethionine homocysteine concentration (from 64.9 to 34.9 micromol/L vs from 64.8 to 50.3 micromol/L). It was also associated with a decreased rate of abnormal exercise electrocardiography tests (odds ratio 0.40 [0.17-0.93]; p=0.035). There was no apparent effect of vitamin treatment on ankle-brachial pressure indices (0.87 [0.56-1.33]), or on carotid and peripheral-arterial outcome variables (1.02 [0.26-4.05] and 0.86 [0.47-1.59], respectively). INTERPRETATION: Homocysteine-lowering treatment with folic acid plus vitamin B6 in healthy siblings of patients with premature atherothrombotic disease is associated with a decreased occurrence of abnormal exercise electrocardiography tests, which is consistent with a decreased risk of atherosclerotic coronary events. Nygard, Nordrehaug, BACKGROUND: Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined. METHODS: We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically. RESULTS: After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. We found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died, as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher. Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infarction, the left ventricular ejection fraction, and the serum creatinine level. The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter, 2.8 for those with levels of 15.0 to 19.9 micromol per liter, and 4.5 for those with levels of 20.0 micromol per liter or higher (P for trend=0.02). When death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between homocysteine levels and mortality was slightly strengthened. CONCLUSIONS: Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease.
CONTEXT: Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear. OBJECTIVE: To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors. DESIGN: Case-control study. SETTING: Nineteen centers in 9 European countries. PATIENTS: A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years. MEASUREMENTS: Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, serum cholesterol, smoking, and blood pressure were also measured. RESULTS: The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of at-risk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensive subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels. CONCLUSIONS: An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.
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