The controversy over homocysteine and cardiovascular risk

Elevated plasma total homocysteine (tHcy) is a risk factor for occlusive ca rdiovascular disease (CVD), This concept is based on the observations of pr emature vascular disease in patients with homocystinuria, the relation betw een tHcy and both clinical CVD as well as preclinical atherosclerotic disea se, the relation between tHcy in children and CVD in their parents or relat ives, and reduction in CVD or surrogate endpoints after tHcy-lowering inter vention with B vitamins. Plausible mechanisms include the in vivo interfere nce with nitric oxide-dependent reactive vasodilatation. Some observations have raised questions about tHcy as a risk factor. 1) Some prospective stud ies showed a weak relation or no relation between tHcy and CVD. 2) Several traditional risk factors are associated with tHcy and may confound the rela tion between tHcy and CVD. 3) tHcy is related to renal function, and hyperh omocysteinemia may reflect early nephrosclerosis. 4) The C677T transition o f the methylenetetrahydrofolate reductase gene causes a moderate increase i n tHcy but no or only minor increased CVD risk. However, the strength of so me of these arguments can be questioned because there is increasing evidenc e that tHcy is a proximate risk factor provoking the acute event, it strong ly interacts with traditional risk factors, and it may predict CVD or death in patients with chronic renal failure. Furthermore, the studies of the C6 77T polymorphism lack statistical power, and the TT genotype may even modul ate CVD risk independently of homocysteine. Thus, only placebo-controlled i ntervention studies with tHcy-lowering B vitamins and clinical endpoints ca n provide additional valid arguments for the debate over whether tHcy is a causal CVD risk factor.