About half of all deaths are due to
cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and becoming larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases,
homocysteine, a "new" risk factor, is being viewed with mounting interest.
Homocysteine is a
sulfur-containing intermediate product in the normal metabolism of
methionine, an
essential amino acid.
Folic acid,
vitamin B(12), and
vitamin B(6) deficiency and reduced
enzyme activities inhibit the breakdown of
homocysteine, thus increasing the intracellular
homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild
hyperhomocysteinemia and
cardiovascular disease or all-cause mortality. Starting at a plasma
homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level.
Hyperhomocysteinemia as an independent risk factor for
cardiovascular disease is thought to be responsible for about 10 percent of total risk. Elevated plasma
homocysteine levels (> 12 micromol/l; moderate
hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10 percent of the general population and in up to 40 percent of patients with
vascular disease. Additional risk factors (smoking, arterial
hypertension, diabetes, and
hyperlipidemia) may additively or, by interacting with
homocysteine, synergistically (and hence overproportionally) increase overall risk.
Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial antithrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to
homocysteine-mediated oxidative stresses. Especially when acting as direct or indirect antagonists of cofactors and
enzyme activities, numerous agents, drugs, diseases, and life style factors have an impact on
homocysteine metabolism.
Folic acid deficiency is considered the most common cause of
hyperhomocysteinemia. An adequate intake of at least 400 microg of
folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these
folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated
homocysteine levels in high-risk individuals in general and patients with manifest
vascular disease in particular. Subjects of both populations should first have a baseline
homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of
hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma
homocysteine level of < 10 micromol/l. Based on various calculation models, reduction of elevated plasma
homocysteine concentrations may theoretically prevent up to 25 percent of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for and treatment of
hyperhomocysteinemia can be recommended for the apparently healthy general population.