Increased serum homocysteine and sudden death resulting from coronary atherosclerosis with fibrous plaques

Introduction - Modest elevations of total homocysteine have been associated with increased risk for coronary atherosclerosis but correlation between elevated homocysteine and plaque morphology has not been described in humans. Methods - We determined serum homocysteine at postmortem from 87 men with coronary thrombus (62 of whom were diagnosed as acute), from 35 men with severe coronary disease without thrombus, and from 46 controls. In coronary deaths, atherosclerotic plaques at the sites of maximal luminal narrowing of the four epicardial coronary arteries were classified as fibrous plaques, fibrous cap atheromas, thin-cap atheromas, and healed ruptures, and macrophage infiltration was assessed semiquantitatively. Results - Median serum homocysteine postmortem as a result of acute thrombus was 10.4 μmol/L (P=0.4 versus controls), 12.1 μmol/L in men with organized thrombi (P=0.1 versus controls), 15.6 μmol/L in men without thrombus (P=0.007 versus controls), and 9.8 μmol/L in controls. The median homocysteine was 12.1 μmol/L in 65 men with healed infarcts (P=0.03 versus controls). The number of fibrous plaques was associated with log-normalized homocysteine (P=0.004), independent of age, albumin, smoking, hypertension, and serum cholesterol. Homocysteine levels in the upper tertile (>15 μmol/L) were associated with sudden death without acute or organized thrombus (odds ratio 3.8, P=0.03) independent of age and other risk factors; the coexistence of diabetes increased the association (odds ratio 25.1, P=0.009, versus lowest tertile ≤8.5 μmol/L). Conclusions - Increased serum homocysteine is associated with sudden death in the absence of acute coronary thrombosis, especially with concomitant diabetes, and with the presence of lipid-poor, fibrous plaques.