Fax +41 61 306 12 34 E-Mail: karger@karger.ch www.karger.com © 2004 S. Karger AG, Basel 1424-8832/04/0336-0345$21.0/0 Accessible online at: www.krager.com/pht Pathophysiol Haemost Thromb 2003/2004; 33: 345-347 Key Words Homocysteine · Risk factors · Cardiovascular disease Hyperhomocysteinemia Copyright © 2004 S. Karger AG, Base In the last couple of decades many studies have been car- ried out on the association of moderately high plasma levels of total homocysteine (tHcy) with coronary artery disease, cerebrovascular disease, peripheral artery disease and venous thromboembolism. Most studies showed a positive association between tHcy and thrombosis risk. However, despite this, many investigators are still skeptical about the importance of hyperhomocysteinemia as a thrombosis risk factor, because some important aspects of the association of hyperhomocysteinemia with cardiovascular diseases still need to be clarified. In the following few lines I will try to explain why I con- sider hyperhomocysteinemia a proven risk factor for cardio- vascular diseases and then I'll address the question of whether or not it is an important risk factor. Is Hyperhomocysteinemia a Proven Cardiovascular Risk Factor? Case-control, cross-sectional and prospective studies have clearly proven that there is a graded association between the plasma levels of total homocysteine (tHcy) and the risk for occlusive arterial and venous disease [1,2]. Despite this, hyperhomocysteinemia has not been universal- ly accepted yet as an established cardiovascular risk factor. The skepticism of some physicians and investigators stems from the lack of proof that hyperhomocysteinemia causes cardiovascular diseases and that lowering tHcy reduces the cardiovascular risk (which actually sounds tautological, for the reasons explained below). However, the association between a risk factor and a disease is not necessarily causal [3-5]. By definition, risk factors are nothing more than sta- tistical predictors of the risk for a disease. The demonstra- tion of their causal association with that disease is strictly dependent on the demonstration, within proper randomized trials, that their modification alters the risk [5]. The logical consequence is that causality can be indisputably proven only for those risk factors that are modifiable. The universal acceptance as cardiovascular risk factors of age, male sex, and family history for premature atherosclerotic disease, which cannot be modified, implies that it is universally accepted that causality is not a criterion to be necessarily fulfilled by a risk factor. I do not see any good reason to make exceptions for hyperhomocysteinemia. Marco Cattaneo Unita di Ematologia e Trombosi, Dipartimento di Medicina, Chirurgia e Odontoiatria, Ospedale San Paolo, Universita di Milano Via di Rudini, 8, 20142 Milano, Italy Fax: +39 0 25 03 20 723; E-mail: marco.cattaneo@unimi.it Is Hyperhomocysteinemia an Important Risk Factor of Cardiovascular Disease? Marco Cattaneo Unita di Ematologia e Trombosi, Ospedale San Paolo,Dipartimento di Medicina, Chirurgia e Odontoiatria, Universita di Milano