CLINICAL STUDY
Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease
Lawrence M. Title, MD*,
Peter M. Cummings, BA, MSc ,
Karen Giddens*,
Jacques J. Genest, Jr, MD and
Bassam A. Nassar, MB, PhD, BCh
* Division of Cardiology at the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
Department of Pathology and Laboratory Medicine at the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
Manuscript received December 6, 1999;
revised manuscript received February 22, 2000,
accepted April 11, 2000.
Reprint requests and correspondence: Dr. Lawrence Title, Division of Cardiology, Queen Elizabeth II Health Sciences Centre, 6896-1796 Summer Street, Halifax, Nova Scotia, Canada B3H 3A7
ltitle{at}is.dal.ca
OBJECTIVES
The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (CAD).
BACKGROUND
Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress.
METHODS
In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level  9 µmol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment.
RESULTS
Plasma folate, homocysteine and FMD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 ± 3.6% to 5.2 ± 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FMD from 2.6 ± 2.4% to 4.0 ± 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group.
CONCLUSIONS
Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | ANOVA | = analysis of variance | | CAD | = coronary artery disease | | FMD | = flow-mediated dilation | | MDA | = malondialdehyde | | NMD | = nitroglycerin-mediated dilation | | NO | = nitric oxide |
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