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Abstract
Introduction: Observational studies have suggested a causal relationship between hyperhomocysteinemia and cardiovascular complications
such as stroke and ischemic heart disease. The Homocysteine Lowering Trialists' Collaboration has shown that daily administration of folic
acid can significantly decrease homocysteine levels up to 25%.
Aim of this study was to investigate the effect of daily supplementation of folic acid (5 mg) on IMT after 18 months of treatment in
patients with at least one cardiovascular risk factor.
Methods: We enrolled 103 patients with at least one cardiovascular risk factor who were randomized to receive either a daily dose of 5 mg
folic acid (group I, n = 53) or placebo (group II, n = 50) for 18 months.
Results: After 18 months of folic acid supplementation, homocysteine levels were significantly reduced in the active treatment group
compared to a non-significant increase in the placebo group. Folic acid levels were markedly increased in the former group and nonsignificantly reduced in the latter. Significant regression of carotid IMT was observed (0.961 0.092 to 0.933 0.077 mm, p b 0.001)
compared to significant IMT progression in the placebo group (0.964 0.099 to 0.984 0.094 mm).
Conclusion: Folic acid supplementation results in significant IMT reduction after 18 months in patients with at least one cardiovascular risk.
2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Atherosclerosis; Folic acid; Homocysteine; Intima-media thickness
1. Introduction
Observational studies have suggested a causal relationship
between hyperhomocysteinemia and cardiovascular complications such as stroke and ischemic heart disease [1]. The
Homocysteine Lowering Trialists' Collaboration has shown
that daily administration of folic acid can significantly
decrease homocysteine levels up to 25% [2]. The effect of B12
supplementation is much weaker resulting in a further
reduction of up to 5%, whereas B6 had no significant
Corresponding author. S. Kiriakidi 1, AHEPA Hospital, Thessaloniki,
54636, Greece. Tel.: +30 6972770288; fax: +30 2310993480.
E-mail address: ntaiosgeorge@yahoo.gr (G. Ntaios).
0167-5273/$ - see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2009.01.023
influence [2]. Currently, several large, prospective, randomized, placebo-controlled, clinical trials are underway to
investigate the effect of homocysteine-lowering therapy on
cardiovascular risk [3]. The results of the trials that have
already been published are controversial, raising the hypothesis that perhaps, homocysteine is just an epiphenomenon of
atherosclerosis and not a causative risk factor.
Carotid intima-media thickness (IMT) is a reliable marker
of early atherosclerosis and has been associated with
increased incidence of cardiovascular events [4]. Intimamedia thickness has been used extensively as a primary end
point in interventional trials which sought to investigate the
effect of antihypertensives [5] and hypolipidemic [6] drugs
on atherosclerosis.
17
Fig. 1. Adjustment of the normal distribution (red curve) on the histogram of baseline IMT values. The application of chi-square test (X2) in this case shows that
the probability density of these values can be reliably (p b 0.05) approximated by the normal distribution curve.
2. Methods
Table 1
Clinical characteristics and biochemical parameters of the patients on
randomization.
Group I (n = 53) Group II (n = 50) p
Female gender (n %)
Age (years SD)
Body mass index (kg/m2 SD)
Coronary artery disease (n %)
Prior stroke (n %)
Arterial hypertension (n %)
Diabetes mellitus (n %)
Smoking (n %)
Statins
Antiplatelets
Beta blockers
Calcium channel blockers
ACE inhibitors/ARB
Homocysteine (mol/l SD)
Folic acid (nmol/l SD)
B12 (pmol/l SD)
Triglycerides (mg/dl SD)
Total cholesterol (mg/dl SD)
LDL- cholesterol (mg/dl SD)
HDL-cholesterol (mg/dl SD)
Creatinine (mg/dl SD)
30 (56.6%)
73.2 4.6
26.26 3.42
17 (32%)
39 (73.6%)
36 (67.9%)
19 (35.8%)
20 (37.7%)
34 (64.1%)
48 (90.5%)
31 (58.5%)
17 (32.1%)
31 (58.5%)
13.9 4.9
19.9 8.7
321 319
160.2 91.7
202.6 39.6
179.2 47.7
51.4 14.9
0.94 0.26
27 (54%)
73.9 4.3
27.57 3.03
16 (32%)
33 (66%)
33 (66%)
19 (38%)
20 (40%)
36 (72%)
42 (84%)
34 (68%)
12 (24%)
24 (48%)
14.1 4.9
18.2 6.1
352 329
172.4 57.1
213.1 46.8
194.1 47.9
49.8 9.2
0.95 0.28
0.94a
0.99b
0.37 b
0.99 a
0.53 a
0.99 a
0.98 a
0.97 a
0.51 a
0.62 a
0.47 a
0.56 a
0.45 a
0.84 b
0.26 b
0.63 b
0.43 b
0.20 b
0.12 b
0.52 b
0.85 b
18
4. Discussion
Our study confirmed the beneficial effect of folic acid
supplementation on homocysteine levels and demonstrated a
significant regression of IMT after 18 months of treatment in
patients with at least one cardiovascular risk factor. We chose
to supplement patients only with folic acid (and not with B12
and B6 as well) because it has been shown that the main
reduction of homocysteine is due to folic acid, whereas B12
provides only little further decrease [2]. The limitations in
our study were the modest sample size and the medium
duration of follow-up.
The impact of B-vitamins on IMT has been previously
investigated in certain patient groups with conflicting,
Table 2
IMT, folic acid and homocysteine plasma concentrations on randomization
and after treatment.
Group I (n = 53)
Group II (n = 50)
Folic acid
Baseline (nmol/l SD)
Follow up (nmol/l SD)
p (baseline vs. follow up)
19.9 8.7
44.6 1.6
s
18.2 6.1
17.1 5.4
ns
ns
s
Homocysteine
Baseline (mol/l SD)
Follow up (mol/l SD)
p (baseline vs. follow up)
13.9 4.9
11.2 3.6
s
14.1 4.9
14.5 4.9
ns
ns
s
Mean IMT
Baseline (mm SD)
Follow up (mm SD)
p (baseline vs. follow up)
Overall difference (mm SEM)
0.961 0.092
0.933 0.077
s
-0.028 0.004
0.964 0.099
0.984 0.094
s
0.0198 0.0024
ns
s
s
SD: standard deviation, SEM: Standard Error of the Mean, s: p b 0.001, ns:
p N 0.05.
19
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