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Among individuals with severe hyperhomocysteinaemia, there is a striking heterogeneity in the severity of the clinical features. This observation demonstrates that factors must exist that modulate the relationship between hyperhomocysteinaemia and clinical disease. Investigations of the association between mild-to-moderate hyperhomocysteinaemia and atherothrombotic disease also suggest heterogeneity in the association between plasma homocysteine levels and 1) clinical disease; 2) angiographic and echographic estimates of the extent of atherosclerosis; 3) arterial stiffness; 4) endothelial function; and 5) procoagulant status. The commonly held view that homocysteine is a vasculotoxic substance that promotes atherogenesis by causing endothelial damage is incomplete, because it cannot explain this heterogeneity. I suggest that homocysteine may have both prothrombotic and proatherogenic properties, but that there are strong, as yet unidentified enhancing and protective factors, the prevalence of which may differ among populations. This concept could account for some of the observed heterogeneity. Identifying these factors would be of major clinical importance and would provide crucial mechanistic insights.

Heterogeneity of the Association between Plasma Homocysteine and Atherothrombotic Disease: Insights from Studies of Vascular Structure and Function