Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial


 Dr Arduino A. Mangoni MD, Department of Health Care of the Elderly, Guy's, King's, and St Thomas' School of Medicine, East Dulwich Grove, London SE22 8PT, UK (fax: 0044 207 346 3441; e-mail:


Abstract.  Mangoni AA, Sherwood RA, Swift CG, Jackson SHD (Guy's, King's, and St Thomas' School of Medicine, King's College London, UK). Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med 2002; 252: 497–503.

Objective.  Cigarette smoking is associated with increased plasma homocysteine concentrations, endothelial dysfunction and arterial stiffening. Homocysteine per se induces endothelial dysfunction and arterial stiffening and might account, at least partly, for the vascular abnormalities observed in smokers. We sought to determine whether folic acid supplementation, by reducing plasma homocysteine concentrations, enhanced endothelial function and reduced arterial stiffness in smokers.

Design.  Double-blind, randomized controlled, parallel-group, trial.

Setting. Academic medical centre.

Subjects.  A consecutive sample of 24 healthy cigarette smokers (age 37.8 ± 2.5 years, mean ± SEM).

Intervention.  Subjects were randomly assigned to 4-week folic acid 5 mg day−1 or placebo.

Main outcome measures.  The following were measured before and after treatment: (i) peripheral vasoreactivity (forearm arterial blood flow, FABF) during intra-arterial administration of endothelium-dependent (acetylcholine 1.5, 4.5 and 15 μg min−1) and endothelium-independent (sodium nitroprusside 1, 2 and 4 μg min−1) vasodilators; (ii) carotid-femoral pulse-wave velocity (PWV); (iii) blood pressure (BP).

Results.  Folic acid reduced homocysteine concentrations (10.8 ± 0.6 vs. 8.2 ± 0.5 μmol L−1, P < 0.001) and enhanced endothelium-dependent vasodilatation during each acetylcholine infusion rate (ratio between the FABF in the infused and control arm during increasing infusion rates at baseline 1.09 ± 0.03 vs. 1.41 ± 0.09 after treatment, P < 0.01; 1.39 ± 0.07 vs. 1.83 ± 0.12, P < 0.01; 1.65 ± 0.16 vs. 2.72 ± 0.36, P < 0.05) whilst endothelium-independent vasodilatation was unaffected. A significant fall in BP was also observed (mean BP 88 ± 2 vs. 83 ± 1 mmHg, P < 0.01). By contrast, PWV did not significantly change (8.4 ± 0.3 vs. 7.8 ± 0.4 m s−1). No significant changes in plasma homocysteine concentrations, FABF, BP, and PWV were observed in the placebo group. A multiple regression analysis showed that changes in folic acid plasma concentrations independently predicted both FABF changes during maximal acetylcholine-mediated vasodilatation (P < 0.01) and BP changes (P = 0.01).

Conclusions.  Short-term folic acid supplementation significantly enhanced endothelial function and reduced BP in young chronic smokers. These effects were largely independent from the homocysteine lowering effects. Thus, a simple, nontoxic, and relatively inexpensive vitamin intervention might be useful in primary cardiovascular prevention in this high-risk group.