Electrophysiology Hyperhomocysteinemia and vitamin B 6 deficiency: New risk markers for nonvalvular atrial fibrillation? Rossella Marcucci, PhD, Irene Betti, MD, Emanuele Cecchi, MD, Daniela Poli, MD, Betti Giusti, PhD, Sandra Fedi, BSc, Ilaria Lapini, BSc, Rosanna Abbate, MD, Gian Franco Gensini, MD, and Domenico Prisco, MD Florence, Italy Background A recent “ex-vivo” study showed that nonvalvular atrial fibrillation (NVAF) is associated with en- hanced activity of metalloproteinases at the atrial level, and in animal models homocysteine (Hcy) is able to activate met- alloproteinases. The aim of this case-control study was to investigate the association of total Hcy plasma levels, vitamin status (folate, vitamin B 6 , and vitamin B 12 ), and methylenetetrahydrofolate reductase C677T and CBS 844ins68 polymor- phisms with NVAF. Furthermore, the role of these variables in the occurrence of ischemic events was investigated. Methods We studied 310 NVAF patients on oral anticoagulant treatment (168 patients with previous ischemic events and 142 without) and 310 controls. Results Hyperhomocysteinemia (highest quartile) and vitamin B 6 deficiency (lowest quartile) were independently asso- ciated with NVAF after multivariate analysis (Hcy: odds ratio [OR] 6.40, 95% CI 3.29 –12.46; vitamin B 6 : OR 3.02, 95% CI 1.02– 8.95). A significant correlation was found between Hcy levels and left atrial diameter (r = 0.46; P  .001). As shown by multivariate analysis, elevated Hcy levels were an independent risk factor for ischemic complications during NVAF (OR 2.66, 95% CI 1.15– 6.20). Conclusions This study demonstrates a significant association of both elevated Hcy levels and low vitamin B 6 levels with the presence of NVAF; in addition, it confirms the role of Hcy as a risk factor for ischemic events during NVAF. (Am Heart J 2004;148:456 – 61.) Nonvalvular atrial fibrillation (NVAF) is the most common arrhythmia in clinical practice and is a poten- tial cause of thromboembolic events. 1 The molecular basis for the development of structural remodeling of fibrillating human atria is still a matter of debate and investigation. A recent “ex-vivo” study has shown that NVAF is associated with enhanced activity of matrix metalloproteinases (MMPs) at the atrium level, and in particular with an increase in the expression of ADAM (A Disintegrin And Metalloproteinases)10 and ADAM15. 2 In animal models it has been shown that MMPs are activated by homocysteine (Hcy) in both endocardial cells and arterial media. 3,4 Meta-analyses of studies suggest that elevated levels of Hcy confer an independent risk for cerebrovascular ischemic events. 5,6 Mild hyperhomocysteinemia may result from both acquired and genetic influences. 7 The acquired influ- ences include vitamin deficiencies, whereas the most common genetic defect leading to hyperhomocysteine- mia is the methylenetetrahydrofolate reductase (MTHFR) C677T variant, which is associated with a thermolabile variant of the enzyme with reduced activ- ity. 8 The 844ins68 variant in the cystathionine -syn- thase (CBS) gene, the key enzyme in the transulfura- tion of Hcy to cystathionine, may also be associated with hyperhomocysteinemia and premature vascular disease. 9 Only 2 preliminary reports 10,11 have suggested a pos- sible role of Hcy in the prediction of the risk of arte- rial ischemic events in NVAF, and a recent study has From the Department of Medical and Surgical Critical Care, University of Florence, Florence Italy. This work was supported by grants from the Ministero dell’Istruzione, dell’Universita `e della Ricerca, Rome, Italy. Submitted August 29, 2003; accepted March 25, 2004. Reprint requests: Professor Domenico Prisco, Thrombosis Center, Department of Medi- cal and Surgical Critical Care, University of Florence, Viale Morgagni, 85 50134 Firenze, Italy. E-mail: priscod@ao-careggi.toscana.it 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.03.017