(Circulation. 1999;99:1156-1160.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Demonstration of Rapid Onset Vascular Endothelial Dysfunction After Hyperhomocysteinemia
An Effect Reversible With Vitamin C Therapy
From the National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, UK (J.C.C., J.S.K.); the Department of Cardiology, Ealing Hospital, Middlesex, UK (A.M., J.J.-M.); and the Department of Human Nutrition, St Bartholomew's and the Royal London School of Medicine & Dentistry, Queen Mary and Westfield College, London, UK (O.A.O.).
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 jkooner{at}rpms.ac.uk
Background—Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin C.
Methods and Results—We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin C (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8±1.4; 2 hours, 25.4±2.5; and 4 hours, 31.2±3.1 µmol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3±0.7; 2 hours, 1.1±0.9; and 4 hours, -0.7±0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and flow-mediated dilatation (P<0.001). Pretreatment with vitamin C did not affect the rise in homocysteine concentrations after methionine (0 hours, 13.6±1.6; 2 hours, 28.3±2.9; and 4 hours, 33.8±3.7 µmol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4.0±1.0; 2 hours, 3.5±1.2 and 4 hours, 2.8±0.7%, P=0.02). GTN-induced endothelium independent brachial artery dilatation was not affected after methionine or methionine preceded by vitamin C.
Conclusions—We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that can be prevented by pretreatment with vitamin C in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.
Key Words: endothelium • arteriosclerosis • antoxidants • nitric oxide • blood flow
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