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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1031.)
© 2008 American Heart Association, Inc.

Editorials

The Homocysteine Paradox

Roman N. Rodionov; Steven R. Lentz

From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City.

Correspondence to Steven R. Lentz, MD, PhD, Department of Internal Medicine, C32 GH, The University of Iowa, Iowa City, IA 52242. E-mail steven-lentz@uiowa.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

There is little doubt that elevation of plasma total homocysteine is associated with increased cardiovascular risk. Over the past 2 decades, many large prospective studies have established that hyperhomocysteinemia predicts for an increased relative risk of coronary events, stroke, venous thromboembolism, and death.^1,2 Hyperhomocysteinemia also has been shown to produce abnormalities of vascular structure and function in animal models.³ Paradoxically, however, several intervention trials have failed to demonstrate any clinical benefit from homocysteine-lowering therapy.^4–8 What is the explanation for this paradox?

See accompanying article on page 1158

One possibility is that hyperhomocysteinemia is a clinically important risk factor only when plasma total homocysteine is elevated to extremely high levels. The hypothesis that homocysteine is a cardiovascular risk factor first arose from clinical and pathological observations in children and young adults with hereditary homocystinuria.⁹ If untreated, these individuals develop severe hyperhomocysteinemia, with plasma total homocysteine levels greater than 100 µmol/L, and they have a high risk of developing pathological vascular lesions and thromboembolic events at a young age.¹⁰ When placed on homocysteine-lowering therapy (high doses of vitamin B6, vitamin B12, folic acid, or betaine, along with dietary methionine restriction), their risk of adverse vascular events decreases markedly.¹¹ Improvement in vascular outcome occurs despite a moderate level of residual hyperhomocysteinemia.

In contrast to the clear clinical benefit of homocysteine-lowering therapy in severe hyperhomocysteinemia, its potential role in mild hyperhomocysteinemia remains unproven. All of the recent intervention trials of homocysteine-lowering therapy have been performed in subjects with relatively mild hyperhomocysteinemia (plasma total homocysteine . . . [Full Text of this Article]

Related Article:

Homocysteine or Renal Impairment: Which Is the Real Cardiovascular Risk Factor?

Kathleen Potter, Graeme J. Hankey, Daniel J. Green, John W. Eikelboom, and Leonard F. Arnolda
Arterioscler Thromb Vasc Biol 2008 28: 1158-1164. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				R. V. Milani and C. J. Lavie Homocysteine: The Rubik's Cube of Cardiovascular Risk Factors Mayo Clin. Proc., November 1, 2008; 83(11): 1200 - 1202. [Full Text] [PDF]

				L. M. Klevay Homocysteine Is Not So Paradoxical Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): e160 - e160. [Full Text] [PDF]

				R. N. Rodionov and S. R. Lentz Many Potential Explanations for the Homocysteine Paradox Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): e161 - e161. [Full Text] [PDF]

				S. Dayal, R. N. Rodionov, E. Arning, T. Bottiglieri, M. Kimoto, D. J. Murry, J. P. Cooke, F. M. Faraci, and S. R. Lentz Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H816 - H825. [Abstract] [Full Text] [PDF]