Hyperhomocysteinemia is a risk factor for ischemic heart disease. Several other mechanisms apply also to dilative types of heart failure of various, non-ischemic etiologies. We hypothesized that hyperhomocysteinemia is associated with left ventricular (LV) dilatation and hypertrophy in dilative cardiomyopathy. Homocysteine was measured in 66 individuals with suspected cardiomyopathy. Cardiac magnetic resonance imaging was used to assess LV volume, mass, and wall stress. Hyperhomocysteinemia (> 12 micromol/L) was found in 45 patients (68%). LV mass was greater in these patients compared with individuals with normal homocysteine (83+/-27 vs. 67+/-19 g/m(2); p<0.02). Homocysteine was increased in patients with increased brain natriuretic peptide > or = 100 pg/mL (18.3+/-5.9 vs. 14.9+/-5.1 micromol/L; p=0.018). LV mass, LV end-diastolic and end-systolic volume (LVEDV, LVESV) were significantly increased in individuals in the upper quartile compared with the lower quartile (90+/-25 vs. 65+/-18 g/m(2), p=0.021; 114+/-50 vs. 71+/-23 mL/m(2), p=0.042; 76+/-51 vs. 36+/-22 mL/m(2), p=0.045). LV dilatation (LVEDV > or = 90 mL/m(2)) was more common in hyperhomocysteinemia (> 12 micromol/L, p=0.0166). Normalized LV mass was correlated with homocysteine (r=0.346, p=0.065). Homocysteine was not significantly correlated with LVEDV (r=0.229, p=0.065), LV end-diastolic wall stress (r=0.226, p=0.069) and LV ejection fraction. Hyperhomocysteinemia appears to be, at least in part, involved in a disproportional LV dilatation, where the ensuing hypertrophy is not sufficient to compensate for the increased wall stress. A potential mechanism is the hyperhomocysteinemia associated increase in oxidative stress that favors muscle fiber slippage.