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Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial

van Dijk, Suzanne C.a; Enneman, Anke W.a; Swart, Karin M.A.b; van Wijngaarden, Janneke P.c; Ham, Annelies C.a; Brouwer-Brolsma, Elske M.c; van der Zwaluw, Nikita L.c; Blom, Henk J.d; Feskens, Edith J.c; Geleijnse, Johanna Mariannac; van Schoor, Natasja M.b; Dhonukshe-Rutten, Rosalie A.M.c; de Jongh, Renate T.e; Lips, Paulb , e; de Groot, Lisette C.P.G.M.c; Uitterlinden, Andre G.a , f; Smulders, Yvo M.e , g; van den Meiracker, Anton H.a; Mattace Raso, Francesco U.S.a; van der Velde, Nathaliea , h

doi: 10.1097/HJH.0000000000000647
ORIGINAL PAPERS: Blood vessels

Introduction: Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old, and is associated with elevated arterial stiffness in this age group. Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes, we aimed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients.

Methods: The B-PROOF study is a double-blind, randomized controlled trial, including 2919 elderly aged at least 65 years, with hyperhomocysteinemia (12–50 μmol/l), treated with B-vitamins (500 μg vitamin B12 and 400 μg folic acid) or placebo for 2 years. In a subgroup (n = 569), the effect of B-vitamins on pulse wave velocity (PWV) was investigated as a measurement of arterial stiffness. To measure atherosclerosis, carotid intima–media thickness (IMT) measures had been used. Incidents of cardiovascular and cerebrovascular events were determined via structured questionnaires, and blood pressure was also measured.

Results: Compared to placebo, B-vitamin supplementation lowered serum homocysteine by 3.6 μmol/l (P < 0.001). Analysis of covariance showed no effect of supplementation on PWV levels, and this was not different for patients without increased arterial stiffness at baseline. Furthermore, no effect on carotid IMT was observed.

Discussion: Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT. Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes.

aErasmus MC, Department of Internal Medicine, Rotterdam

bVU University Medical Center, EMGO Institute for Health and Care Research, Department of Epidemiology and Biostatistics, Amsterdam

cWageningen University, Division of Human Nutrition, Wageningen

dVU University Medical Center, Department of Clinical Chemistry

eVU University Medical Center, Department of Internal Medicine, Amsterdam

fNetherlands Consortium for Healthy Ageing, Rotterdam, Leiden

gVU University Medical Center, Institute for Cardiovascular Research ICaR-VU

hAcademic Medical Center, Department of Internal Medicine, Section of Geriatrics, Amsterdam, the Netherlands

Correspondence to Suzanne C. van Dijk, MD, PhD, Erasmus MC, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. Tel: +31 10 70 35979; fax: +31 10 70 34768; e-mail:

Abbreviations: AIx, augmentation index; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; Holo-TC, holotranscobalamin; IMT, intima–media thickness; MI, myocardial infarction; MMA, methylmalomic acid; PP, pulse pressure; PWV, pulse wave velocity

Received 21 September, 2014

Revised 6 May, 2015

Accepted 6 May, 2015

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