Abstract
The possibility that modest elevations in the level of blood homocysteine (hyperhomocysteinaemia) could contribute to cardiovascular disease arose from investigation of patients with rare, severe homocysteine elevations caused by cystathionine beta-synthase deficiency. Such patients often had thromboembolic events before the age of 30 years. Since the established cardiovascular risk factors could only partly account for the occurrence and severity of vascular disease in the general population, other risk factors had to exist, and homocysteine elevation seemed to be a possible candidate. Australian case-control studies identified an association between mild homocysteine elevation and early-onset coronary disease, and also with chronic renal failure. Patients in the latter group have a high prevalence of unexplained vascular disease and particularly high homocysteine levels. Such elevations in levels of homocysteine in vascular patients could usually be normalised by daily supplementation with folic acid (1-5 mg) while in patients with chronic renal failure 5 mg of folic acid daily markedly reduced the increased concentrations of homocysteine. These initial observations have been confirmed by many investigators and biologically plausible mechanisms for homocysteine-induced vascular dysfunction, and particularly endothelial dysfunction, have been identified. However, associations between hyperhomocysteinaemia and other risk factors, such as smoking and hypertension, have also been documented and need to be controlled for when assessing any increase in risk that homocysteine may independently confer. Although it has been established that lowering the greatly elevated blood homocysteine levels in homocystinuria, due to cystathione beta-synthase deficiency, unquestionably reduces cardiovascular risk, it remains to be determined whether normalising mild homocysteine elevation could reduce cardiovascular risk. Trials to test this possibility have been initiated and others are planned.
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