(Circulation. 2000;102:2479.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
From the National Heart and Lung Institute (J.C.C., J.S.K.), Imperial College School of Medicine, Hammersmith Hospital, London, UK; the Department of Pharmacology (P.M.U., H.R.), University of Bergen, Armauer Hansen Hus, Bergen, Norway; Department of Human Nutrition (O.A.O.), St Bartholomews and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London, UK; and the Department of Cardiology (J.W.), Ealing Hospital, Middlesex, UK.
Correspondence to Dr J.S. Kooner, MD, FRCP, Senior Lecturer and Consultant Cardiologist, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail j.kooner{at}ic.ac.uk
| Abstract |
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Methods and ResultsWe investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flowmediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B12 (1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B12 were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5±3.2% to 4.0±3.7%, P=0.002) but not placebo (2.3±2.6% to 1.9±2.6%, P=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0±3.4 to 9.3±1.9 µmol/L, P<0.001), protein-bound homocysteine (from 8.7±2.8 to 6.2±1.4 µmol/L, P<0.001), and free homocysteine (from 4.3±1.2 to 3.0±0.6 µmol/L, P<0.001) and raised concentrations of serum folate (from 10.3±4.3 to 31.2±10.8 ng/mL, P<0.001) and vitamin B12 (from 314±102 to 661±297 pg/mL, P<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (r=-0.26, P=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B12. Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo.
ConclusionsFolic acid and vitamin B12 supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.
Key Words: endothelium nutrition arteriosclerosis
| Introduction |
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Increasing evidence suggests that the adverse vascular effects of elevated homocysteine are mediated through endothelial dysfunction,7 10 11 12 13 14 15 16 17 18 19 20 an early manifestation of atherosclerosis. Studies investigating the effects of lowering homocysteine concentrations on vascular endothelial function have yielded conflicting results.21 22 23 24 25 26 27 In primates, folate supplementation is reported to reduce plasma homocysteine concentrations but not to affect vascular function.21 In healthy human subjects, folate supplementation is associated with reduced homocysteine concentrations and improved vascular endothelial function,22 23 26 although in these studies, there was no relationship between homocysteine concentrations and endothelial function, implying that the effects of B vitamins on endothelial function may not be mediated through homocysteine lowering.26 27 However, a major limitation of previous studies is that they have used total plasma homocysteine concentrations as the sole index of homocysteine status.
We have studied the effects of dietary folate and vitamin B12 supplementation on vascular endothelial function in patients with CHD and examined the relationship between vascular endothelial function and concentrations of total, protein-bound, and free plasma homocysteine.
| Methods |
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1 major epicardial vessel). Patients were not
studied within 3 months of myocardial infarction or coronary
intervention. All subjects were receiving regular medication for CHD;
this remained unchanged during the course of the study, and
cardiovascular drugs were omitted on the day of
investigation. The present study was approved by the local ethics
committee, and all subjects gave written informed consent to
participate.
Procedures
Brachial artery flowmediated dilatation
(endothelium dependent) and
nitroglycerin (NTG)-induced dilatation
(endothelium independent) were measured before and 8
weeks after either (1) folic acid (5 mg) and vitamin
B12 (1 mg) daily (n=59) or (2) matched placebo
(n=30). Treatment allocation was randomized and double blind.
Brachial Artery Diameter
Brachial artery flowmediated dilatation was measured by using
a 7.0-MHz linear array transducer, an Acuson 128XP/10 system, and a
high-resolution ultrasonic vessel wall tracking system (Vadirec,
Ingenious Systems) as previously described.17 18 In brief,
the brachial artery was scanned longitudinally, and brachial artery
diameter was measured at end diastole. After the baseline
resting scan, a pneumatic cuff placed at the level of the mid forearm
was inflated to 300 mm Hg for 4.5 minutes. The second scan was
performed 55 to 65 seconds after cuff deflation. Fifteen minutes was
allowed for vessel recovery, after which the second baseline scan was
performed. NTG (400 µg) was then administered, and the fourth scan of
the brachial artery was undertaken. The vessel diameter was measured by
2 independent observers unaware of the clinical details of the subjects
and the type and stage of the study. The technique for measurement of
brachial artery flowmediated dilatation is reproducible in our
laboratory. The intraindividual between-day coefficient of variation
for flow-mediated dilatation is 3%, which compares favorably with that
in other centers.28 Flow-mediated dilatation of conduit
arteries is endothelium dependent and largely mediated
by NO.29
Biochemical Measurements
For each subject, concentrations of total plasma homocysteine,
free (unbound) plasma homocysteine, serum folate, vitamin
B12, glucose, total cholesterol, HDL
cholesterol, and triglycerides were measured at
baseline and at 8 weeks. All samples were collected in the fasting
state (overnight). For measurement of homocysteine species, blood was
drawn into lithium heparin tubes and immediately centrifuged at
10 000g for 1 minute. The plasma was then divided into 2
aliquots. The first aliquot was deproteinized with sulfosalicylic acid,
and the supernatant was used for measurement of free homocysteine. The
second aliquot was used for measurement of total plasma homocysteine.
Concentrations of total and free plasma homocysteine were determined by
high-pressure liquid chromatography with
fluorescence detection,30 and the
concentration of protein-bound homocysteine was calculated as the
difference between the 2 concentrations. Serum folate and
B12 were measured by MEIA (Abbott IMX system),
and lipid profiles were determined by use of an Olympus AU800
multichannel analyzer. For each subject, homocysteine and
vitamin samples were analyzed in one batch.
Data Processing and Statistical Analysis
Data were analyzed with the use of SPSS version 8.0
statistical package and are expressed as mean±SD. Continuous data were
analyzed by the independent-samples t test or the
paired-samples t test for comparisons between groups and
within subjects, respectively. The
2 test was
used for categorical data. Linear regression analysis was
conducted to examine the relationships between flow-mediated dilatation
and concentrations of plasma homocysteine, serum folate, and vitamin
B12. Statistical significance was inferred at a
value of P<0.05.
| Results |
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Brachial Artery Measurements
There were no significant differences between the vitamin and
placebo groups in flow-mediated dilatation at baseline (Table 2
, Figure
).
At the 8-week follow-up visit, flow-mediated dilatation was improved in
the vitamin group (1.5±3.5% change compared with baseline,
P=0.002). The increase in flow-mediated dilatation after B
vitamins was evident in the 13 subjects with initially elevated
homocysteine (>15 µmol/L; 2.2±2.3% change, P=0.01)
as well as in the 46 subjects with baseline homocysteine within the
reference range (1.2±3.7% change, P=0.03). In contrast,
flow-mediated dilatation was not altered by placebo (-0.3±2.5%
change compared with baseline, P=0.50). At 8 weeks,
flow-mediated dilatation was now significantly higher in the vitamin
compared with the placebo group (P=0.008; Table 2
,
Figure
).
|
|
NTG-induced dilatation, brachial artery diameter, and brachial artery
blood flow were similar in the vitamin and placebo groups at baseline.
These measures were unchanged after 8 weeks treatment with either
vitamins or placebo (Table 2
).
Biochemical Measurements
At baseline, concentrations of total and free plasma homocysteine
and of serum folate and vitamin B12 were similar
in the vitamin and placebo groups (Table 2
). After the treatment
period, concentrations of total, protein-bound, and free plasma
homocysteine fell, and serum folate and vitamin
B12 rose compared with baseline concentrations,
in the vitamin but not the placebo group (Table 2
). There were
no significant changes in blood pressure, fasting glucose, or lipid
profile between baseline and 8 weeks in either treatment group (data
not shown).
Determinants of Flow-Mediated Dilatation
In univariate analysis, flow-mediated
dilatation was inversely correlated with concentrations of free
homocysteine (r=-0.26, P=0.001), protein-bound
homocysteine (r=-0.20, P=0.008), and total
homocysteine (r=-0.24, P=0.002) and positively
correlated with levels of folate (r=0.17, P=0.03)
and vitamin B12 (r=0.12,
P=0.05). Free, protein-bound, and total plasma homocysteine,
folate, and vitamin B12 concentrations were also
closely intercorrelated (Table 3
).
|
In multivariate analysis, the inverse
relationship between flow-mediated dilatation and free homocysteine
remained significant after adjustment for concentrations of
protein-bound homocysteine, folate, and vitamin
B12 (Table 4
) and
after further adjustment for age, blood pressure, total and HDL
cholesterol, fasting glucose, and cigarette smoking
(P=0.02). In contrast, the relationships between
flow-mediated dilatation and protein-bound homocysteine, folate, and
vitamin B12 that were evident in
univariate analysis became nonsignificant after
adjustment for free plasma homocysteine concentrations (Table 4
).
|
| Discussion |
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In the present study, folic acid and vitamin B12 supplementation was associated with a significant improvement in brachial artery flowmediated dilatation. This effect was seen in patients with moderately raised homocysteine (>15 µmol/L) as well as in patients whose homocysteine concentrations were within the reference range. Regression analysis demonstrated an inverse relationship between flow-mediated dilatation and concentrations of plasma homocysteine, suggesting that the effect of B vitamins on endothelial function may be mediated through reduced homocysteine concentrations. The precise mechanisms underlying the relationship between plasma homocysteine and vascular endothelial dysfunction are not well understood. Because flow-mediated dilatation is endothelium dependent and largely mediated by the release of NO,29 our observations suggest an increase in the availability of NO after homocysteine lowering by B vitamins. The present study does not exclude a direct effect of folate or its related metabolites or an effect of vitamin B12 on endothelial function. However, the absence of a significant relationship between the levels of these vitamins and flow-mediated dilatation, after adjustment for plasma homocysteine concentrations, argues against this hypothesis.
Previous studies involving healthy volunteers22 23 24 and
patients with familial
hypercholesterolemia26 27 have not
shown a significant relationship between the improvement in
endothelial function and the change in plasma
homocysteine after B vitamin supplementation. The precise reasons for
this are not known; however, in all studies, total plasma homocysteine
concentrations were used as the sole index of homocysteine status. In
plasma, homocysteine exists in protein-bound (
70%) and free
(
30%) forms; the latter includes reduced homocysteine and
homocysteine disulfides.31 We found an independent
relationship between flow-mediated dilatation and concentrations of
free, but not protein-bound, homocysteine. Our results suggest that
free plasma homocysteine concentrations may be a more accurate index of
the biological activity of homocysteine in vivo. This is an important,
yet unrecognized, confounding factor that may limit interpretation of
previous experimental and clinical studies investigating the
relationship between homocysteine and endothelial
function. Evidence to support this assertion also comes from in vitro
data, which show that free homocysteine species inactivate
NO, promote the generation of oxygen-derived free radicals, induce
tissue factor release, and cause endothelial cell
injury.10 12 13 32
Our observations of improved vascular function after B vitamin supplementation in patients with established atherosclerosis are in contrast with previous findings in patients with end-stage renal disease25 and in animal models of atherosclerosis.21 33 The lack of improvement in endothelial function despite reduced homocysteine concentrations in these studies may be explained by the failure of folate supplementation to lower plasma homocysteine concentrations <20 µmol/L in patients with end-stage renal disease25 and the concurrent administration of an atherogenic diet in primates,21 factors that may have a continuing effect on endothelial function. In the present study, the doses of folate and vitamin B12 were identical to those currently being used in the largest prospective intervention trial, the Study of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and were selected to provide maximal homocysteine reduction.9 However, folate doses as low as 400 µg/d have been shown to have a similar homocysteine-lowering effect. The results of the present study lend support to the hypotheses that elevated homocysteine concentrations may have a key role in the development of atherosclerosis and that B vitamin supplementation may reduce cardiovascular risk in patients with CHD.
In summary, we have found that supplementation with folic acid and vitamin B12 improves brachial artery endothelium-dependent dilatation in patients with CHD and that this action may be mediated through reduced concentrations of free plasma homocysteine. These data provide evidence that dietary supplementation with B vitamins may reduce cardiovascular risk in patients with established atherosclerosis.
| Acknowledgments |
|---|
Received March 30, 2000; revision received June 16, 2000; accepted June 30, 2000.
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S. N. Doshi, I. F.W. McDowell, S. J. Moat, N. Payne, H. J. Durrant, M. J. Lewis, and J. Goodfellow Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering Circulation, January 1, 2002; 105(1): 22 - 26. [Abstract] [Full Text] [PDF] |
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M. Cattaneo, D. N. Kiortsis, M. S. Elisaf, K.M. English, P.J. Pugh, K.S. Channer, S. C. Clarke, P. M. Schofield, A. A. Grace, J. C. Metcalfe, et al. Does Tamoxifen Enhance Endothelial Function by Lowering the Plasma Levels of Homocysteine? Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis Response Circulation, December 11, 2001; 104 (24): e146 - e147. [Full Text] [PDF] |
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J. T. Kuvin, A. R. Patel, K. A. Sliney, N. G. Pandian, W. M. Rand, J. E. Udelson, and R. H. Karas Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1843 - 1849. [Abstract] [Full Text] [PDF] |
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J. C CHAMBERS and J. S KOONER Homocysteine: a novel risk factor for coronary heart disease in UK Indian Asians Heart, August 1, 2001; 86(2): 121 - 122. [Full Text] [PDF] |
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S. N. Doshi, I. F. W. McDowell, S. J. Moat, D. Lang, R. G. Newcombe, M. B. Kredan, M. J. Lewis, and J. Goodfellow Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide? Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1196 - 1202. [Abstract] [Full Text] [PDF] |
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J. Thambyrajah, M. J. Landray, H. J. Jones, F. J. McGlynn, D. C. Wheeler, and J. N. Townend A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1858 - 1863. [Abstract] [Full Text] [PDF] |
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J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner Association of Maternal Endothelial Dysfunction With Preeclampsia JAMA, March 28, 2001; 285(12): 1607 - 1612. [Abstract] [Full Text] [PDF] |
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J. C. Chambers, P. M. Ueland, M. Wright, C. J. Dore, H. Refsum, and J. S. Kooner Investigation of Relationship Between Reduced, Oxidized, and Protein-Bound Homocysteine and Vascular Endothelial Function in Healthy Human Subjects Circ. Res., July 20, 2001; 89(2): 187 - 192. [Abstract] [Full Text] [PDF] |
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