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STATE-OF-THE-ART PAPER

Homocysteine Hypothesis for Atherothrombotic Cardiovascular Disease

Not Validated

Sanjay Kaul, MD^_*,,_*, Andrew A. Zadeh, MD^_*, and Prediman K. Shah, MD^_*,

^_* Division of Cardiology, Cedars-Sinai Medical Center
David Geffen School of Medicine, University of California, Los Angeles, California Drs. Kaul and Zadeh contributed equally to this work.

Manuscript received January 24, 2006; revised manuscript received March 28, 2006, accepted April 4, 2006.

^_* Reprint requests and correspondence: Dr. Sanjay Kaul, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048 (Email: kaul{at}cshs.org).

Homocysteine has been implicated in promoting atherosclerotic and thrombotic vascular disease. During the last decade, the utility of homocysteine in predicting risk for atherothrombotic vascular disease has been evaluated in several observational studies in a large number of patients. These studies show that the overall risk for vascular disease is small, with prospective, longitudinal studies reporting a weaker association between homocysteine and atherothrombotic vascular disease compared to retrospective case-control and cross-sectional studies. Furthermore, randomized controlled trials of homocysteine-lowering therapy have failed to prove a causal relationship. On the basis of these results, there is currently insufficient evidence to recommend routine screening and treatment of elevated homocysteine concentrations with folic acid and other vitamins to prevent atherothrombotic vascular disease. This review outlines the metabolism and pathophysiology of homocysteine, highlights the results of homocysteine observational and interventional trials, and presents areas of uncertainty and potential future work.

Abbreviations and Acronyms   CAD = coronary artery disease   CVD = cardiovascular disease   HOPE-2 = Heart Outcomes Prevention Evaluation-2 trial   IHD = ischemic heart disease   MACE = major adverse cardiac event   MI = myocardial infarction   MTHFR = methylene tetrahydrofolate reductase   NORVIT = Norwegian Vitamin Trial   tHcy = total homocysteine   VISP = Vitamin Intervention for Stroke Prevention study

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