Context Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B 12 can lower plasma total homocysteine levels.Objective To assess the effect of treatment with folic acid and vitamin B 12 and the effect of treatment with vitamin B 6 as secondary prevention in patients with coronary artery disease or aortic valve stenosis.Design, Setting, and Participants Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double-or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes.Interventions Using a 2ϫ2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B 12 , 0.4 mg, plus vitamin B 6 , 40 mg (n=772); folic acid plus vitamin B 12 (n=772); vitamin B 6 alone (n=772); or placebo (n=780). Main Outcome MeasuresThe primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. ResultsMean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B 12 . The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B 12 vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P=.36) and 200 participants (13.0%) receiving vitamin B 6 vs 222 (14.3%) not receiving vitamin B 6 (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P=.28).Conclusions This trial did not find an effect of treatment with folic acid/vitamin B 12 or vitamin B 6 on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease.

In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents. (Funded by the Norwegian Research Council and others; NORSTENT ClinicalTrials.gov number, NCT00811772 .).

for the Integrated Biomarker and Imaging Study-2 InvestigatorsBackground-Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. Methods and Results-This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA 2 inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. Background therapy was comparable between groups, with no difference in low-density lipoprotein cholesterol at 12 months (placebo, 88Ϯ34 mg/dL; darapladib, 84Ϯ31 mg/dL; Pϭ0.37). In contrast, Lp-PLA 2 activity was inhibited by 59% with darapladib (PϽ0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (Pϭ0.22) or plasma highsensitivity C-reactive protein (Pϭ0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5Ϯ17.9 mm 3 ; Pϭ0.009), whereas darapladib halted this increase (Ϫ0.5Ϯ13.9 mm 3 ; Pϭ0.71), resulting in a significant treatment difference of Ϫ5.2 mm 3 (Pϭ0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (Pϭ0.95). Conclusions-Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA 2 inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA 2 inhibition may represent a novel therapeutic approach.

Choline is involved in the synthesis of phospholipids, including blood lipids, and is the immediate precursor of betaine, which serves as a methyl group donor in a reaction converting homocysteine to methionine. Several cardiovascular risk factors are associated with plasma homocysteine, whereas little is known about their relationship to choline and betaine.We examined the relation of plasma choline and betaine to smoking, physical activity, BMI, percent body fat, waist circumference, blood pressure, serum lipids, and glucose in a population-based study of 7074 men and women aged 47-49 and 71-74 y. Overall plasma concentrations (means 6 SD) were 9.9 6 2.3 mmol/L for choline and 39.5 6 12.5 mmol/L for betaine. Choline and betaine were lower in women than in men and in younger subjects compared with older (P , 0.0001).Multivariate analyses showed that choline was positively associated with serum triglycerides, glucose, BMI, percent body fat, waist circumference (P , 0.0001 for all), and physical activity (P , 0.05) and inversely related to HDL cholesterol (P , 0.05) and smoking (P , 0.0001). Betaine was inversely associated with serum non-HDL cholesterol, triglycerides, BMI, percent body fat, waist circumference, systolic and diastolic blood pressure (P , 0.0001 for all), and smoking (P , 0.05) and positively associated with HDL cholesterol (P , 0.01) and physical activity (P , 0.0001). Thus, an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations. Choline and betaine were associated in opposite directions with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline dehydrogenase pathway. J. Nutr. 138: 914-920, 2008.