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Experimental and observational studies support a role of plasma homocysteine levels (tHcy) in coronary artery disease (CAD). In the GENICA (Genetic and ENvironmental factors In Coronary Atherosclerosis) study, we found that high tHcy predicted cardiovascular mortality in hypertensive, but not in normotensive, patients independently of CAD and history of myocardial infarction. Moreover, despite not being associated with the coronary atherosclerotic burden, tHcy was inversely associated with left ventricular (LV) ejection fraction. This inverse relationship between LV systolic function and tHcy, which has been independently confirmed, might explain the association of tHcy with the risk of incident heart failure documented in the Framingham Heart Study. Thus, additional mechanistic investigation taking into consideration the effects of tHcy on LV function is necessary to further explore the potential therapeutic usefulness of tHcy lowering treatment in CAD.