Homocysteine‐lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease

Abstract

. Objectives. A high level of total homocysteine (tHcy) is a risk marker for cardiovascular disease (CVD), and is related to inflammation. We wanted to test the effect of homocysteine‐lowering B‐vitamin therapy, as used in the Western Norway B‐vitamin Intervention Trial (WENBIT), on inflammatory markers associated with atherosclerosis. Design. Single centre, prospective double‐blind clinical interventional study, randomised in a 2 × 2 factorial design. Subjects and methods. Ninety patients (21 female) with suspected coronary artery disease (CAD), aged 38–80 years, were blindly randomised into one of four groups of 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. Blood samples were collected before and after 6 months of treatment. Results. Before intervention, median levels of the analytes were: tHcy 11.0 μmol L−1, neopterin 8.1 nmol L−1, soluble CD40 ligand (sCD40L) 3.9 ng mL−1, interleukin (IL)‐6 1.9 pg mL−1, C‐reactive protein (CRP) 1.9 mg L−1 and low‐density lipoprotein (LDL) cholesterol 3.3 mmol L−1. tHcy was significantly associated with neopterin (r = 0.49, P < 0.001) and with IL‐6 (r = 0.29, P = 0.01), but not with CRP or sCD40L. Neither treatment with folic acid/B12 nor with B6 induced significant changes in any of these inflammatory biomarkers (P ≥ 0.14). In patients receiving folic acid/B12 (groups A and B), tHcy was reduced with 33% (P < 0.001). Conclusions. In patients with stable CAD, homocysteine‐lowering therapy with B‐vitamins does not affect levels of inflammatory markers associated with atherogenesis. Failure to reverse inflammatory processes, may partly explain the negative results in clinical secondary B‐vitamin intervention trials.

Effect of supplementation with B vitamins and antioxidants on levels of asymmetric dimethylarginine (ADMA) and C-reactive protein (CRP): a double-blind, randomised, factorial design, placebo-controlled trial

“…Intervention studies carried out evaluating the effect of B vitamins on CRP concentrations have been conducted in subjects who were undergoing haemodialysis [53], or stable coronary artery disease patients [54], or those with hyperhomocysteinemia [55]. Two out of three reported no significant treatment effect on CRP levels [54,55].…”

“…Intervention studies carried out evaluating the effect of B vitamins on CRP concentrations have been conducted in subjects who were undergoing haemodialysis [53], or stable coronary artery disease patients [54], or those with hyperhomocysteinemia [55]. Two out of three reported no significant treatment effect on CRP levels [54,55]. However, Chang et al demonstrated that a 3-month intervention with a combined B vitamin supplement effectively lowered tHcy and CRP concentrations in haemodialysis subjects, although this study was a randomised, open-labelled study which used doses higher than those in this current study (folic acid (5 mg/d) and vitamin B complex) [53].…”

Early Increase of Plasma Homocysteine in Sepsis Patients with Poor Outcome

“…Likewise, in patients with cardiovascular, neurodegenerative and autoimmune disorders, rather close associations have been described between the concentrations of total homocysteine and immune activation and inflammation markers: for example, neopterin (7,8) and C-reactive protein (9), which themselves are significant predictors of cardiovascular risk (10)(11)(12). Neopterin concentrations serve as a reliable immune response marker because a great amount of neopterin is released by monocyte-derived macrophages and dendritic cells upon stimulation with Th1-type cytokine interferon-γ (13)(14)(15).…”

Homocysteine metabolism and its relation to health and disease

“…However, these results have largely been refuted by the predominantly negative results of subsequent trials, including the NORVIT, WENBIT, HOPE-2, VISP, VITATOPS, and VITRO studies (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). These studies generally had a mean follow-up time of several years and assessed a wide variety of vascular indicators and endpoints including carotid intima-media thickness and flow-mediated dilation (52), markers of arterial inflammation (49)(50)(51)(52)(53)(54)(55)(56)(57)(58), need for revascularization procedures (54), occurrence of thromboembolism (53,55), occurrence of stroke and myocardial infarction (48,50,54,56,57,59), as well as overall or coronary/vascular-related mortality (48,50,51,54,56,59). Unfortunately, there appears to be no effect of homocysteine-lowering Bvitamin therapy on Alzheimer's disease and cognitive decline (66)(67)(68) or type 2 diabetes (69), and the results are conflicting regarding potential effects on bone mineral density and turnover, and fracture occurrence <...>…”