REGULAR ARTICLE Dynamic regulation of MTHFR mRNA expression and C677T genotype modulate mortality in coronary artery disease patients after revascularization Alexandre C. Pereira ⁎ , Ayumi A. Miyakawa, Neuza H.M. Lopes, Paulo R. Soares, Sergio A. de Oliveira, Luiz A.M. Cesar, Jose F. Ramires, Whady Hueb, Jose Eduardo Krieger Heart Institute, University of São Paulo Medical School, São Paulo, Brazil Received 31 October 2006; received in revised form 1 March 2007; accepted 6 March 2007 Available online 2 July 2007 Abstract Introduction: A large body of evidence links plasma homocysteine (Hcy) concentra- tions and cardiovascular disease. A common MTHFR polymorphism (C677T) leads to a variant with reduced activity and associated with increased Hcy levels. Coronary surgery precipitates a significant and sustained increase in the blood concentrations of Hcy and elevated levels of plasma Hcy have been associated to saphenous vein (SV) graft disease after CABG. However, the effects of MTHFR genotypes in the incidence of cardiovascular events after CABG have not been investigated prospectively. Here, we investigate whether MTHFR gene variants are associated with an increased cardiovascular risk in individuals submitted to CABG. We also propose a molecular mechanism to explain our findings. Methods: We performed MTHFR C677T genotypes in 558 patients with two or three vessel-disease and normal left ventricular function prospectively followed in the MASS II Trial, a randomized study to compare treatments for multivessel CAD and preserved left ventricle function. Follow-up time was 5 years. Survival curves were calculated with the Kaplan–Meier method, and evaluated with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, myocardial infarction and refractory angina using a Cox proportional hazards survival model. Finally, using an ex-vivo organ culture we have reproduced the arterialization of SV implants by culturing human SV either under venous hemodynamic condition (flow: 5 mL/min; no pressure) or arterial hemodynamic KEYWORDS MTHFR; CABG; Homocysteine ⁎ Corresponding author. Laboratorio de Genética e Cardiologia Molecular, InCor-Instituto do Coracao, HCFMUSP, Av. Dr. Eneas de Carvalho Aguiar, 44, Sao Paulo, 05403-000 SP Brazil. Tel./fax: +55 11 3069 5929. E-mail address: alexandre.pereira@incor.usp.br (A.C. Pereira). intl.elsevierhealth.com/journals/thre 0049-3848/$ - see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2007.03.004 Thrombosis Research (2007) 121, 25–32