Homocysteine lowering and cardiovascular disease risk: Lost in translation

Abstract

E levated plasma total homocysteine has been proposed as a risk factor for cardiovascular morbidity and mortality. The public health implications of homocysteine as a cardiovascular risk factor are particularly far-reaching, because homocysteine can be lowered effectively, inexpensively and safely by treatment with folic acid and other B vitamins. In patients with chronic kidney disease (CKD), homocysteine levels rise and cardiovascular risk increases as glomerular filtration rate declines, raising the question of whether hyperhomocysteinemia may be responsible, in part, for the high cardiovascular disease burden in this population. The reasons for increased homocysteine levels in CKD are not entirely understood, but probably relate to decreased renal clearance and metabolism of homocysteine.In the present paper, the following are reviewed: possible biological mechanisms underlying the role for homocysteine as a cardiovascular risk factor; observational studies examining the association between elevated homocysteine and cardiovascular risk in the general population and in patients with CKD; interventional studies of homocysteine-lowering therapy; possible reasons for the largely negative results from these trials; and the ongoing trials of homocysteine-lowering therapy.Pathophysiology of cardiovascular risk from elevated homocysteine levels Hyperhomocysteinemia is believed to promote atherogenesis and atherothrombosis via several mechanisms ( Figure 1) (1).Homocysteine metabolism generates reactive oxygen species that can directly injure the endothelium. Homocysteine has been shown to inhibit nitric oxide synthase activity, leading to endothelial dysfunction. Other proatherogenic mechanisms attributed to hyperhomocysteinemia include dysregulated methylation of proteins and DNA resulting in abnormal vascular smooth muscle cell proliferation, as well as increased lipid peroxidation.Observational studies of homocysteine levels and cardiovascular disease Data from observational studies examining the association between elevated homocysteine levels and cardiovascular morbidity and mortality in the general population have been inconsistent. Homocysteine was an independent risk factor for all-cause mortality in the Physicians' Health Study (2). Male physicians with the highest 5% of homocysteine levels demonstrated a five-year RR of 3.4 for acute myocardial infarction (MI) or death due to coronary disease compared with subjects with the lowest 90% of homocysteine levels. Two meta-analyses of observational data demonstrated a similar association. Wald et al (3) evaluated 20 prospective studies and concluded that lowering homocysteine concentrations by 3 μmol/L decreased the risk of ischemic heart disease by 16% and stroke by 24%. A second meta-analysis of 18 retrospective and 12 prospective studies (4) determined that a 25% reduction in homocysteine Studies of the general population have suggested that high homocysteine levels are associated with cardiovascular morbidity and mortality. In chronic kidney disease, homocys...

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