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Causal or Casual?

William G. Christen, ScD; Umed A. Ajani, MBBS; Robert J. Glynn, ScD; Charles H. Hennekens, MD

Arch Intern Med. 2000;160:422-434.

Background  Accumulating data from epidemiological studies suggest that individuals with elevated blood levels of homocysteine have increased risks of cardiovascular disease. We reviewed the currently available evidence of an association between homocysteine and cardiovascular disease and examined whether the strength of the evidence varies according to study design.

Methods  We used a computerized MEDLINE literature search, 1966 through September 1998, to identify all epidemiological studies that examined the relationship of homocysteine level with risks of coronary heart or cerebrovascular disease. Two measures of plasma homocysteine level and its association with risk of cardiovascular disease were extracted: mean homocysteine level in cases and controls, and relative risk of cardiovascular disease for elevated homocysteine level.

Results  A total of 43 studies were reviewed. Most cross-sectional and case-control studies indicated higher mean homocysteine levels (either fasting or after methionine load) and/or a greater frequency of elevated homocysteine level in persons with cardiovascular disease as compared with persons without cardiovascular disease. Results of most prospective studies, however, indicated smaller or no association. The few prospective studies that reported a positive association between homocysteine level and risks of cardiovascular disease included patients with preexisting vascular disease.

Conclusions  In contrast to cross-sectional and case-control studies, results of prospective studies indicated less or no predictive ability for plasma homocysteine in cardiovascular disease. Instead, elevated homocysteine level may be an acute-phase reactant that is predominantly a marker of atherogenesis, or a consequence of other factors more closely linked to risks of cardiovascular disease. Randomized trials are necessary to test reliably whether lowering homocysteine levels will decrease risks of cardiovascular disease.

From the Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (Drs Christen, Ajani, and Glynn), and Department of Biostatistics, Harvard School of Public Health (Dr Glynn), Boston, Mass. Dr Hennekens is now Visiting Professor of Medicine, and Epidemiology and Public Health, University of Miami School of Medicine, Miami, Fla.

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