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European Heart Journal Advance Access originally published online on November 23, 2008
European Heart Journal 2009 30(1):6-15; doi:10.1093/eurheartj/ehn515
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials

Charalambos Antoniades*, Alexios S. Antonopoulos, Dimitris Tousoulis, Kyriakoula Marinou and Christodoulos Stefanadis

1st Cardiology Department, Athens University Medical School, Ilias 8, 153 44 Gerakas Attikis, Athens, Greece

Received 29 April 2008; revised 21 September 2008; accepted 23 October 2008; online publish-ahead-of-print 23 November 2008.

* Corresponding author. Tel: +30 6945904220, Fax: +30 2106616466, Email: antoniades{at}vodafone.net.gr

Plasma total homocysteine (Hcy) has been associated with cardiovascular risk in multiple large-scale epidemiological studies, and it has been considered as an independent risk factor for atherosclerosis. Homocysteine lowering, achieved after the introduction of the folate food fortification programme in North America, was accompanied by an accelerated decline of cardiovascular risk and especially of stroke. Although the initial clinical trials suggested that homocysteine-lowering treatment with folates and B vitamins induces coronary plaque regression, this finding was not confirmed by more recent clinical studies. Under the light of the findings from the recent large randomized clinical trials that failed to document a benefit of Hcy lowering on clinical outcome of patients with atherosclerosis, the role of Hcy as a risk factor and the efficacy of Hcy lowering against atherosclerosis have been questioned. Therefore, better understanding of the mechanisms relating Hcy and Hcy-lowering treatment with vascular function and atherogenesis is crucial, to help us understand why clinical trials failed to show a benefit from Hcy-lowering treatment. Are these therapeutic strategies ineffective because they fail to reduce intracellular Hcy levels and vascular redox state or should Hcy stop being considered as an independent risk factor for atherosclerosis from now on? In this review article, we provide a global approach of the molecular mechanisms relating Hcy with cardiovascular risk and introduce possible mechanistic explanations regarding the inability of clinical trials to detect any clinical benefit from Hcy-lowering treatment in secondary prevention. Finally, we provide clinical recommendations regarding the therapeutic strategies targeting homocysteine in the general population.

Key Words: Atherosclerosis • Homocysteine • Folate • Endothelium • Atherothrombosis


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