Heterogeneity of the association between plasma homocysteine and atherothrombotic disease: Insights from studies of vascular structure and function

Among individuals with severe hyperhomocysteinaemia, there is a striking he terogeneity in the severity of the clinical features. This observation demo nstrates that factors must exist that modulate the relationship between hyp erhomocysteinaemia 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 o f the extent of atherosclerosis; 3) arterial stiffness; 4) endothelial func tion; and 5) procoagulant status. The commonly held view that homocysteine is a vasculotoxic substance that promotes atherogenesis by causing endothel ial damage is incomplete, because it cannot explain this heterogeneity. I s uggest that homocysteine may have both prothrombotic and proatherogenic pro perties, but that there are strong, as yet unidentified enhancing and prote ctive factors, the prevalence of which may differ among populations. This c oncept could account for some of the observed heterogeneity. Identifying th ese factors would be of major clinical importance and would provide crucial mechanistic insights.