Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide–derived end products in hyperhomocysteinemic subjects

Holven, Kirsten B; Holm, Torbjørn; Aukrust, Pål; Christensen, Benedicte; Kjekshus, John; Andreassen, Arne K; Gullestad, Lars; Hagve, Tor Arne; Svilaas, Arne; Ose, Leiv; Nenseter, Marit S

« Previous Next »The American Journal of Medicine
Volume 110, Issue 7 , Pages 536-542, May 2001

Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide–derived end products in hyperhomocysteinemic subjects☆

Kirsten B Holven, PhD
- Lipid Clinic (KBH, AS, LO, MSN), University Hospital, Rikshospitalet, Oslo, Norway
Torbjørn Holm, MD
- Department of Cardiology (TH, JK, AKA, LG), Division of Heart and Lung Diseases, Research Institute for Internal Medicine and Section of Clinical Immunology and Infection Diseases, University Hospital, Rikshospitalet, Oslo, Norway
Pål Aukrust, MD, PhD
- Medical Department (PA), University Hospital, Rikshospitalet, Oslo, Norway
Benedicte Christensen, MD, PhD
- Department of Medical Genetics (BC), Ullevål University Hospital, Oslo, Norway
John Kjekshus, MD, PhD
- Department of Cardiology (TH, JK, AKA, LG), Division of Heart and Lung Diseases, Research Institute for Internal Medicine and Section of Clinical Immunology and Infection Diseases, University Hospital, Rikshospitalet, Oslo, Norway
Arne K Andreassen, MD, PhD
- Department of Cardiology (TH, JK, AKA, LG), Division of Heart and Lung Diseases, Research Institute for Internal Medicine and Section of Clinical Immunology and Infection Diseases, University Hospital, Rikshospitalet, Oslo, Norway
Lars Gullestad, MD, PhD
- Department of Cardiology (TH, JK, AKA, LG), Division of Heart and Lung Diseases, Research Institute for Internal Medicine and Section of Clinical Immunology and Infection Diseases, University Hospital, Rikshospitalet, Oslo, Norway
Tor Arne Hagve, MD, PhD
- Institute for Clinical Biochemistry (TAH), University Hospital, Rikshospitalet, Oslo, Norway
Arne Svilaas, MD
- Lipid Clinic (KBH, AS, LO, MSN), University Hospital, Rikshospitalet, Oslo, Norway
Leiv Ose, MD, PhD
- Lipid Clinic (KBH, AS, LO, MSN), University Hospital, Rikshospitalet, Oslo, Norway
Marit S Nenseter, PhD
- Lipid Clinic (KBH, AS, LO, MSN), University Hospital, Rikshospitalet, Oslo, Norway
- MSD Cardiovascular Research Center (MSN), University Hospital, Rikshospitalet, Oslo, Norway
- Requests for reprints should be addressed to Marit S. Nenseter, PhD, Lipid Clinic, University Hospital, Rikshospitalet, 0027 Oslo, Norway

Received 23 August 2000; received in revised form 17 January 2001; accepted 17 January 2001.

Abstract

PURPOSE: An elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases. In this study, we tested the hypothesis that hyperhomocysteinemia induces endothelial dysfunction mediated, at least in part, through nitric oxide–dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subjects.

SUBJECTS AND METHODS: Endothelial function was evaluated in healthy controls and hyperhomocysteinemic subjects by measuring plasma levels of the nitric oxide–derived end products nitrite and nitrate and by assessing vasodilatory responses in the skin microcirculation and forearm vasculature. In the subjects with hyperhomocysteinemia, these measurements were repeated after 6 weeks and 12 months of folic acid supplementation.

RESULTS: Compared with healthy controls, hyperhomocysteinemic subjects had significantly lower median plasma levels of nitric oxide–derived end products (12.1 μM [range 4.4 to 41.8] versus 24.6 μM [13.6 to 53.2]; P <0.001), a significantly lower endothelium-dependent vasodilatory response to acetylcholine (P <0.01), hyperemic response in the microcirculation (P <0.01), and total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response. Folic acid treatment for 12 months increased the plasma level of nitric oxide–derived end products by 121% (95% confidence interval [CI], 72% to 170%), the vasodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and the ischemia-mediated hyperemic responses in the microcirculation by 60% (95% CI, 25% to 96%) and in the forearm vasculature by 47% (95% CI, 21% to 73%).

CONCLUSIONS: Homocysteine appears to induce its atherogenic effect, at least in part, by depressing endothelial function, possibly through nitric oxide–dependent mechanisms. This effect can be reversed by folic acid supplementation.