Effect of homocysteine-lowering treatment with folic acid plus vitamin B on cerebrovascular atherosclerosis and white matter abnormalities as determined by MRA and MRI: a placebo-controlled, randomized trial.
BACKGROUND
A high plasma homocysteine concentration is an independent risk factor for large and possibly small vessel disease. We investigated the effects of homocysteine-lowering treatment with folic acid plus vitamin B(6) on markers of cerebrovascular atherosclerosis and cerebral microangiopathy.


METHODS
Using 158 healthy siblings (mean age 46.0 +/- 7.6 years) of patients with premature atherosclerotic disease, we performed a randomized, placebo-controlled trial using 5 mg of folic acid plus 250 mg of vitamin B(6) daily (n = 78) or placebo medication (n = 80). Participants were followed for 2 years with magnetic resonance angiography (MRA) (carotid stenosis; carotid and/or vertebral elongation) and magnetic resonance imaging (MRI) (white matter abnormalities; cerebral atrophy).


RESULTS
Seventeen (10.8%) subjects refused MRA/MRI owing to claustrophobia and were excluded. From the remaining 141 participants, 68 received vitamin and 73 received placebo medication [42 (61.8%) and 48 (65.8%) had postmethionine hyperhomocysteinaemia, respectively]. Twenty-four participants (15.2%; 10 in the treatment and 14 in the placebo group) did not complete both years of the trial. Vitamin treatment was associated with an increase in plasma folate (13-fold vs. placebo; P < 0.001) and vitamin B(6) (8.8-fold; P < 0.001). Fasting and postmethionine total homocysteine concentrations decreased 38.7% (95% CI, 27.4-50.0) and 29.1% (95% CI, 19.2-39.0) vs. placebo (all P < 0.001). During follow up six individuals in the vitamin-treated and 11 in the placebo-treated group deteriorated in their outcome measurements. Vitamin treatment, as compared with placebo, was associated with nonsignificantly improved outcomes on both MRA and MRI outcome measurements (odds ratio 0.48; 95% CI 0.17-1.41; P = 0.18 and 0.48; CI 0.14-1.60; P = 0.23, respectively).


CONCLUSIONS
These results could indicate a possible favourable effect of homocysteine-lowering treatment on cerebrovascular atherosclerosis and cerebral microangiopathy among healthy siblings of patients with premature atherosclerotic disease, but larger trials are required to establish this with certainty.
Vermeulen
E G J
EG
'Vrije Universiteit' Medical Center (VUMC), Institute for Cardiovascular Research (IcaR-VU), Amserdam, the Netherlands. EJG.Vermeulen@gelre.nl
Stehouwer
C D A
CD
Valk
J
J
van der Knaap
M
M
van den Berg
M
M
Twisk
J W R
JW
Prevoo
W
W
Rauwerda
J A
JA
D000328:Adult; D001161:Arteriosclerosis / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D002560:Cerebrovascular Circulation / Q000502:physiology; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D006397:Hematinics / Q000097:blood / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D018810:Magnetic Resonance Angiography / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D016896:Treatment Outcome; D025101:Vitamin B 6 / Q000097:blood / Q000627:therapeutic use*
D015415:Biomarkers; D006397:Hematinics; D006710:Homocysteine; D025101:Vitamin B 6; D005492:Folic Acid