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(Circulation. 2007;115:2262-2270.)
© 2007 American Heart Association, Inc.

Coronary Heart Disease

Global Improvement of Vascular Function and Redox State With Low-Dose Folic Acid

Implications for Folate Therapy in Patients With Coronary Artery Disease

Cheerag Shirodaria, MRCP^*; Charalambos Antoniades, MD, PhD^*; Justin Lee, MRCP; Clare E. Jackson, PhD; Matthew D. Robson, PhD; Jane M. Francis, DCR, DNM; Stuart J. Moat, PhD; Chandi Ratnatunga, FRCS; Ravi Pillai, FRCS; Helga Refsum, MD, PhD; Stefan Neubauer, MD, FRCP; Keith M. Channon, MD, FRCP

From the Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom (C.S., C.A., J.L., C.E.J., M.D.R., J.M.F., C.R., R.P., S.N., K.M.C.); Department of Medical Biochemistry, University Hospital of Wales, Cardiff, United Kingdom (S.J.M.); and Oxford Centre for Gene Function, Department of Physiology, Anatomy & Genetics, University of Oxford, United Kingdom and Institute of Basic Medical Sciences, University of Oslo, Norway (H.R.).

Correspondence to Prof Keith M. Channon, MD, FRCP, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom. E-mail keith.channon{at}cardiov.ox.ac.uk

Received November 27, 2006; accepted February 23, 2007.

Background— Although dietary folate fortification lowers plasma homocysteine and may reduce cardiovascular risk, high-dose folic acid therapy appears to not alter clinical outcome. Folic acid and its principal circulating metabolite, 5-methyltetrahydrofolate, improve vascular function, but mechanisms relating folate dose to vascular function remain unclear. We compared the effects of folic acid on human vessels using pharmacological high-dose versus low-dose treatment, equivalent to dietary folate fortification.

Methods and Results— Fifty-six non–folate-fortified patients with coronary artery disease were randomized to receive low-dose (400 µg/d) or high-dose (5 mg/d) folic acid or placebo for 7 weeks before coronary artery bypass grafting. Vascular function was quantified by magnetic resonance imaging before and after treatment. Vascular superoxide and nitric oxide bioavailability were determined in segments of saphenous vein and internal mammary artery. Low-dose folic acid increased nitric oxide–mediated endothelium-dependent vasomotor responses, reduced vascular superoxide production, and improved enzymatic coupling of endothelial nitric oxide synthase through availability of the cofactor tetrahydrobiopterin. No further improvement in these parameters occurred with high-dose compared with low-dose treatment. Whereas plasma 5-methyltetrahydrofolate increased proportionately with treatment dose of folic acid, vascular tissue 5-methyltetrahydrofolate showed no further increment with high-dose compared with low-dose folic acid.

Conclusions— Low-dose folic acid treatment, comparable to daily intake and dietary fortification, improves vascular function through effects on endothelial nitric oxide synthase and vascular oxidative stress. High-dose folic acid treatment provides no additional benefit. These direct vascular effects are related to vascular tissue levels of 5-methyltetrahydrofolate rather than plasma levels. High-dose folic acid treatment likely confers no further benefit in subjects already receiving folate supplementation.

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