Studies on homocysteine-lowering B-vitamin therapy in patients with coronary artery diseas : sub-studies from the Western Norway B-vitamin intervention trial (WENBIT)

Abstract

Background: A high plasma level of total homocysteine (tHcy) is a risk factor for cardiovascular disease, and is related to important components of atherosclerosis such as inflammation and endothelial dysfunction. Objectives: To test the effect of homocysteine-lowering B-vitamin therapy on 1) tHcy, and metabolites and determinants of tHcy, 2) inflammatory markers associated with atherosclerosis and 3) coronary endothelial and vascular function. Design: Single centre, double-blind clinical interventional study, randomised in a 2x2 factorial design into daily oral treatment with A) folic acid (0.8 mg)/vitamin B12 (0.4 mg)/vitamin B6 (40 mg), B) folic acid/vitamin B12, C) vitamin B6 alone or D) placebo. For the first two weeks, groups A and B received additional folic acid 5 mg/day. Subjects and methods. Two sub-groups of patients participating in the Western Norway Bvitamin Intervention Trial (WENBIT); Patient group 1: Ninety patients (21 female, aged 38- 80 years) with suspected coronary artery disease (CAD). Blood samples were collected at baseline, after 3 days, 2 weeks, 1, 3, 6 months and one year of B-vitamin intervention. An oral methionine loading test (0.1 g/kg body weight) was done at baseline and after 3 months. Patient group 2: Forty patients (8 female, aged 39-74 years) with CAD. They were examined at baseline, and after 9 and 24 months, coronary blood flow (CBF) was assessed by coronary angiography and Doppler flow-wire measurements during intra-coronary infusion of saline (basal), incremental (0.72 μg/min, 7.2 μg/min and 36.0 μg/min) doses of acetylcholine, 2.4 mg/min adenosine and nitroglycerin. Results: In patient group 1, we documented a reduction of 31% on plasma tHcy and a pronounced reduction of post methionine load (PML) tHcy by folic acid/vitamin B12. Vitamin B6 reduced cystathionine and particularly PML cystathionine. There was a strong inverse relation between PML betaine and PML increase in tHcy, a relation that was abolished by folic acid/vitamin B12 treatment for 3 months. Treatment with folic acid/vitamin B12 or vitamin B6 for 6 months had no effects on levels of neopterin, sCD40L, IL 6 or CRP. During the two years of follow-up of patient group 2, basal CBF and adenosine-stimulated CBF increased among patients treated with folic acid /B12 as opposed to those not receiving folic acid /B12. Conclusions: The doses of folic acid/B12 applied in WENBIT give adequate tHcy lowering effect. Cystathionine may be a useful marker for assessment of the vitamin B6 effect. Plasma betaine is a strong determinant of the PML increase in tHcy in patients not supplemented with B-vitamins which emphasizes the complementary relationship between betaine and folate metabolism. Although we observed improved coronary vascular function after treatment with folic acid/vitamin B12, failure to reverse inflammatory processes associated with atherosclerosis may partly explain the negative results of previous B-vitamin intervention trials among patients with established CVD.