This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (161)  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Social Bookmarking   What's this?

Francesco Nappo, MD, PhD; Nicoletta De Rosa, MD, PhD; Raffaele Marfella, MD, PhD; Domenico De Lucia, MD; Diego Ingrosso, MD, PhD; Alessandra F. Perna, MD, PhD; Bartolomeo Farzati, MD; Dario Giugliano, MD

JAMA. 1999;281:2113-2118.

Context  Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function.

Objective  To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions.

Design and Setting  Observer-blinded, randomized crossover study conducted at a university hospital in Italy.

Subjects  Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years.

Interventions  Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins.

Main Outcome Measures  Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads.

Results  The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) µmol/L at baseline to 27.1 (6.7) µmol/L at 4 hours (P<.001). A similar increase was observed with the same load plus vitamins (10.0 [4.0] to 22.7 [7.8] µmol/L; P<.001) but no significant increase was observed with placebo (10.1 [3.7] to 10.4 [3.2] µmol/L; P=.75). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P<.05) but not after placebo or methionine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% [2.7%]; P<.001), platelet aggregation response to adenosine diphosphate (-11.4% [4.5%]; P=.009) and blood viscosity (-3.0% [1.2%]; P=.04) declined in these parameters 10 minutes after an L-arginine load (3 g) following placebo, the increase after methionine alone (-2.3% [1.5%], 4.0% [3.0%], and 1.5% [1.0%], respectively; P<.05), did not occur following methionine load with vitamin pretreatment (-6.3% [2.5%], -7.9% [3.5%], and -1.5% [1.0%], respectively; P=.24).

Conclusion  Our data suggest that mild to moderate elevations of plasma homocysteine levels in healthy subjects activate coagulation, modify the adhesive properties of endothelium, and impair the vascular responses to L-arginine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism.

Author Affiliations: Departments of Geriatrics and Metabolic Diseases (Drs Nappo, De Rosa, Marfella, and Giugliano) and Immunology (Dr Farzati), Institute of General Pathology and Oncology (Dr De Lucia), and Institute of Biochemistry of Macromolecules (Drs Ingrosso and Perna), Second University of Naples, Naples, Italy.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women: The Women's Antioxidant and Folic Acid Cardiovascular Study
Christen et al.
Arch Intern Med 2009;169:335-341.
ABSTRACT | FULL TEXT  

Traffic-related Particles Are Associated with Elevated Homocysteine: The VA Normative Aging Study
Park et al.
Am. J. Respir. Crit. Care Med. 2008;178:283-289.
ABSTRACT | FULL TEXT  

Homocysteine induces VCAM-1 gene expression through NF-{kappa}B and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants
Carluccio et al.
Am. J. Physiol. Heart Circ. Physiol. 2007;293:H2344-H2354.
ABSTRACT | FULL TEXT  

Lowering Homocysteine with B Vitamins Has No Effect on Blood Pressure in Older Adults
McMahon et al.
J. Nutr. 2007;137:1183-1187.
ABSTRACT | FULL TEXT  

Metabolic syndrome: Pathogenesis, medical care and dental implications
Friedlander et al.
Journal of the American Dental Association 2007;138:179-187.
ABSTRACT | FULL TEXT  

Effect of methionine loading on pulse wave analysis in elderly volunteers.
Hart et al.
Postgrad. Med. J. 2006;82:524-527.
ABSTRACT | FULL TEXT  

Aged Garlic Extract Improves Homocysteine-Induced Endothelial Dysfunction in Macro- and Microcirculation
Weiss et al.
J. Nutr. 2006;136:750S-754S.
ABSTRACT | FULL TEXT  

Dose-Related Association of MTHFR 677T Allele With Risk of Ischemic Stroke: Evidence From a Cumulative Meta-Analysis
Cronin et al.
Stroke 2005;36:1581-1587.
ABSTRACT | FULL TEXT  

Folic Acid Supplementation Can Reduce the Endothelial Damage in Rat Brain Microvasculature Due to Hyperhomocysteinemia
Lee et al.
J. Nutr. 2005;135:544-548.
ABSTRACT | FULL TEXT  

Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress
Clapp et al.
Cardiovasc Res 2004;64:172-178.
ABSTRACT | FULL TEXT  

Impairment of Coronary Circulation by Acute Hyperhomocysteinemia in Type 2 Diabetic Patients
Coppola et al.
Diabetes Care 2004;27:2055-2056.
FULL TEXT  

Treatment of coronary heart disease with folic acid: is there a future?
Moat et al.
Am. J. Physiol. Heart Circ. Physiol. 2004;287:H1-H7.
FULL TEXT  

Effect of Lifestyle Changes on Erectile Dysfunction in Obese Men: A Randomized Controlled Trial
Esposito et al.
JAMA 2004;291:2978-2984.
ABSTRACT | FULL TEXT  

Hyperhomocysteinemia as an independent risk factor for silent brain infarction
Kim et al.
Neurology 2003;61:1595-1599.
ABSTRACT | FULL TEXT  

Review: Homocysteine, endothelial dysfunction and oxidative stress in type 1 diabetes mellitus
Wotherspoon et al.
British Journal of Diabetes & Vascular Disease 2003;3:334-340.
ABSTRACT  

The Use of B Vitamin Supplements and Peripheral Arterial Disease Risk in Men Are Inversely Related
Merchant et al.
J. Nutr. 2003;133:2863-2867.
ABSTRACT | FULL TEXT  

Potential role for adenosine in the pathogenesis of the vascular complications of hyperhomocysteinemia
Riksen et al.
Cardiovasc Res 2003;59:271-276.
ABSTRACT | FULL TEXT  

Hyperhomocysteinemia Induces Renal Hemodynamic Dysfunction: Is Nitric Oxide Involved?
Fischer et al.
J. Am. Soc. Nephrol. 2003;14:653-660.
ABSTRACT | FULL TEXT  

Homocysteine Determinants and the Evidence to What Extent Homocysteine Determines the Risk of Coronary Heart Disease
De Bree et al.
Pharmacol. Rev. 2002;54:599-618.
ABSTRACT | FULL TEXT  

Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia
Weiss et al.
Vasc Med 2002;7:227-239.
ABSTRACT  

Impaired Nitric Oxide-Mediated Flow-Induced Coronary Dilation in Hyperhomocysteinemia : Morphological and Functional Evidence for Increased Peroxynitrite Formation
Ungvari et al.
Am. J. Pathol. 2002;161:145-153.
ABSTRACT | FULL TEXT  

Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects
Zheng et al.
Arterioscler. Thromb. Vasc. Bio. 2002;22:e15-18.
ABSTRACT | FULL TEXT  

NUTRITION AS A MEDIATOR IN THE RELATION BETWEEN ORAL AND SYSTEMIC DISEASE: ASSOCIATIONS BETWEEN SPECIFIC MEASURES OF ADULT ORAL HEALTH AND NUTRITION OUTCOMES
Ritchie et al.
CROBM 2002;13:291-300.
ABSTRACT | FULL TEXT  

Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review
Gorelick
Stroke 2002;33:862-875.
ABSTRACT | FULL TEXT  

Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite
Bagi et al.
Arterioscler. Thromb. Vasc. Bio. 2002;22:28-33.
ABSTRACT | FULL TEXT  

Homocysteine and brain atrophy on MRI of non-demented elderly
den Heijer et al.
Brain 2002;126:170-175.
ABSTRACT | FULL TEXT  

Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness: A 2-Year, Randomized, Placebo-Controlled Trial
van Dijk et al.
Arterioscler. Thromb. Vasc. Bio. 2001;21:2072-2079.
ABSTRACT | FULL TEXT  

Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide?
Doshi et al.
Arterioscler. Thromb. Vasc. Bio. 2001;21:1196-1202.
ABSTRACT | FULL TEXT  

Chronic heart failure and micronutrients
Witte et al.
J Am Coll Cardiol 2001;37:1765-1774.
ABSTRACT | FULL TEXT  

Use of Bioimpedance Spectroscopy to Estimate Body Water Distribution in Rats Fed High Dietary Sulfur Amino Acids
Yokoi et al.
J. Nutr. 2001;131:1302-1308.
ABSTRACT | FULL TEXT  

Plasma Homocysteine Concentrations in the Acute and Convalescent Periods of Atherothrombotic Stroke
Meiklejohn et al.
Stroke 2001;32:57-62.
ABSTRACT | FULL TEXT  

Plasma Homocysteine Predicts Mortality Independently of Traditional Risk Factors and C-Reactive Protein in Patients With Angiographically Defined Coronary Artery Disease
Anderson et al.
Circulation 2000;102:1227-1232.
ABSTRACT | FULL TEXT  

Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease
Title et al.
J Am Coll Cardiol 2000;36:758-765.
ABSTRACT | FULL TEXT  

Potential Antiatherogenic Mechanisms of Ascorbate (Vitamin C) and {alpha}-Tocopherol (Vitamin E)
Carr et al.
Circ. Res. 2000;87:349-354.
ABSTRACT | FULL TEXT  

Does Folic Acid Decrease Plasma Homocysteine and Improve Endothelial Function in Patients With Predialysis Renal Failure?
Thambyrajah et al.
Circulation 2000;102:871-875.
ABSTRACT | FULL TEXT  

The controversy over homocysteine and cardiovascular risk
Ueland et al.
Am. J. Clin. Nutr. 2000;72:324-332.
ABSTRACT | FULL TEXT  

Homocysteine and atherothrombosis--mechanisms for injury
Thambyrajah and Townend
Eur Heart J 2000;21:967-974.
 

Hyperhomocysteinemia and Oxidative Stress : Time for a Reality Check?
Jacobsen
Arterioscler. Thromb. Vasc. Bio. 2000;20:1182-1184.
FULL TEXT  

The Effects of Hormone Replacement Therapy and Raloxifene on C-Reactive Protein and Homocysteine in Healthy Postmenopausal Women: A Randomized, Controlled Trial
Walsh et al.
J. Clin. Endocrinol. Metab. 2000;85:214-218.
ABSTRACT | FULL TEXT