Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia

Abstract

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 μg) and folic acid (400 μg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514

Effect of Combined Treatment With Folic Acid, Vitamin B 6 , and Vitamin B 12 on Plasma Biomarkers of Inflammation and Endothelial Dysfunction in Women

“…Our findings for CRP, IL-6, and fibrinogen appear consistent with the null findings for these biomarkers in other trials 12,17,19,26 Nine other trials examined plasma concentrations of IL-6 or fibrinogen, and most, 13,14,16,18,[21][22][23][24] but not all, 20 found no effect of B-vitamin supplementation on either biomarker. However, treatment duration in these trials was limited (6 months or less).…”

“…Several previous trials with treatment duration of up to 2 years also found no significant effect of Bvitamin supplementation on plasma concentration of this biomarker. 12,17,18,24,28,29 Our present findings extend these earlier null results for ICAM-1 to treatment durations of up to 7.3 years.…”

“…The WAFACS was a randomized, double-blind, placebocontrolled trial that evaluated whether a daily combination of folic acid (2.5 mg), vitamin B 6 (50 mg), and vitamin B 12 (1 mg) could reduce cardiovascular events among women with pre-existing CVD or 3 or more coronary risk factors. The WAFACS trial began in 1998 when the folic acid/B 6 /B 12 arm was added to the ongoing WACS (Women's Antioxidant Cardiovascular Study).…”

“…Others have speculated that the beneficial effects of homocysteine lowering may be countered by adverse effects of high-dose B vitamins such as an increase in inflammation or endothelial dysfunction. 11,12 With regard to this possibility, current evidence, including substudies of randomized trials, suggests that homocysteine lowering with B vitamins has little impact on plasma biomarkers of inflammation [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] and endothelial dysfunction. 12,17,18,24,28,29 However, most of these studies have been limited by small sample size (n<200) and short treatment duration (<2 years).…”

No Association between Elevated Total Homocysteine Levels and Functional Outcome in Elderly Patients with Acute Cerebral Infarction

“…The findings on the relationship between hyperhomocysteinemia and outcome after stroke have been inconsistent (Del Ser et al, 2001; Faeh et al, 2006). Moreover, trials investigating the effect of B vitamins, which reduce tHcy levels, on endothelial function and outcome of patients with cardiovascular disease have shown conflicting results (Chambers et al, 2000; Title et al, 2000; Woo et al, 2002; van Dijk et al, 2016). The heterogeneous methodologies included in these studies may partially explain discrepancies in the final results.…”