Homocysteine and cardiovascular disease: cause or effect?

Both markedly and mildly elevated circulating homocysteine concentrations a re associated with increased risk of vascular occlusion. Here we review pos sible mechanisms that mediate these effects. Inborn errors of homocysteine metabolism result in markedly elevated plasma homocysteine (200-300 mu mol/ L) and thromboembolic (mainly venous) disease: treatment to lower but not t o normalize these concentrations prevents vascular events, Mild homocystein e elevation (>15 mu mol/L) occurs in approximate to 20-30% of patients with atherosclerotic disease. Usually, this is easily normalized with oral fola te and ongoing trials are assessing the effect of folate treatment on outco mes. Although there is evidence of endothelial dysfunction with both marked ly and mildly elevated homocysteine concentrations, the elevated homocystei ne concentration in atherosclerotic patients is also associated with most s tandard vascular risk factors, and importantly, with early decline in renal function, which is common in atherosclerosis. Decline in renal function al one causes elevated plasma homocysteine land cysteine). These observations suggest that mild hyperhomocysteinemia could often be an effect rather than a cause of atherosclerotic disease. Data on the common C677T methylenetetr ahydrofolate reductase polymorphism supports this, in that, although homozy gosity is a frequent cause of mild hyperhomocysteinemia when plasma folate is below median population concentrations, it appears not to increase cardi ovascular risk. Indeed, there is recent evidence suggesting an acute antiox idant effect of folic acid independent of its effect on homocysteine concen trations. This antioxidant mechanism may oppose an oxidant effect of homocy steine and be relevant to treatment of patients with vascular disease, espe cially those with chronic renal insufficiency. Such patients have moderatel y elevated plasma homocysteine and greatly increased cardiovascular risk th at is largely unexplained.