Homocysteine and cardiovascular disease: biological mechanisms, observational epidemiology, and the need for randomized trials

Am Heart J. 2004 Jul;148(1):34-40. doi: 10.1016/j.ahj.2004.02.004.


Basic research indicates that homocysteine causes endothelial dysfunction and damage, accelerates thrombin formation, inhibits native thrombolysis, promotes lipid peroxidation through free radical formation, and induces vascular smooth muscle proliferation and monocyte chemotaxis. Most, but not all, observational epidemiological studies indicate that individuals with higher homocysteine levels have increased risks of cardiovascular disease. The magnitude ranges from approximately 20% in prospective studies to approximately 80% in retrospective case-control studies. In all observational epidemiological studies, however, the amount of uncontrolled and uncontrollable confounding is as large as the postulated small to moderate effect size. Thus, the totality of evidence should include randomized trials of sufficient sample size and duration with clinical end points. Folic acid reduces levels of homocysteine, but at present, despite several plausible biological mechanisms and a large body of observational epidemiological data, it is unclear whether supplementation will reduce risks of cardiovascular disease. It is also unclear whether any benefit of folic acid is attributable to lowering homocysteine levels. The current evidence is necessary, but not sufficient to judge causality. Such judgments await the availability of data from large-scale randomized trials. The availability of such data would permit rational clinical decision-making for individual patients and policy decisions for the health of the general public.

Publication types

  • Review

MeSH terms

  • Cardiovascular Diseases / etiology*
  • Endothelium, Vascular / physiology
  • Homocysteine / blood
  • Homocysteine / physiology*
  • Humans
  • Hyperhomocysteinemia / complications*
  • Hyperhomocysteinemia / drug therapy
  • Risk Factors
  • Vitamin B Complex / therapeutic use


  • Homocysteine
  • Vitamin B Complex