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Paul M. Ridker, MD; JoAnn E. Manson, MD; Julie E. Buring, ScD; Jessie Shih, PhD; Matthew Matias; Charles H. Hennekens, MD

JAMA. 1999;281:1817-1821.

Context  Individuals with elevated levels of homocysteine tend to have higher prevalence of cardiovascular disease. However, prospective studies of homocysteine are inconsistent and data among women are limited.

Objective  To determine whether elevated homocysteine levels in healthy postmenopausal women predict risk of developing cardiovascular disease.

Design  Prospective, nested case-control study with a mean 3-year follow-up.

Setting  The Women's Health Study, an ongoing US primary prevention trial initiated in 1993.

Participants  From a total cohort of 28,263 postmenopausal women with no history of cardiovascular disease or cancer at baseline, 122 women who subsequently experienced cardiovascular events were defined as cases, and 244 age- and smoking status–matched women who remained free of disease during follow-up were defined as controls.

Main Outcome Measures  Incidence of death due to cardiovascular disease, nonfatal myocardial infarction (MI), stroke, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft by baseline homocysteine level.

Results  Of the 122 cases, there were 85 events of MI or stroke and 37 coronary revascularizations. Case subjects had significantly higher baseline homocysteine levels than controls (14.1 vs 12.4 µmol/L; P=.02). Subjects with homocysteine levels in the highest quartile had a 2-fold increase in risk of any cardiovascular event (relative risk [RR], 2.0; 95% confidence interval [CI], 1.1-3.8). This effect was largely due to an excess of cases with high levels of homocysteine; the RR for those with homocysteine levels at or higher than the 95th percentile (20.7 µmol/L) was 2.6 (95% CI, 1.1-5.7). Risk estimates were independent of traditional risk factors and were greatest for the end points of MI and stroke (RR for those with baseline homocysteine levels in the top quartile, 2.2; 95% CI, 1.1-4.6). Self-reported multivitamin supplement use at study entry was associated with significantly reduced levels of homocysteine (P<.001). However, the association between increasing quartile of homocysteine level and risk of MI or stroke remained significant in analyses controlling for baseline multivitamin supplement use (P=.003 for trend), and subgroup analyses limited to women who were (P=.02 for trend) or were not (P=.04 for trend) taking multivitamin supplements.

Conclusions  Among healthy postmenopausal US women, elevated levels of homocysteine moderately increased the risk of future cardiovascular disease. Whether lowering the homocysteine level reduces risk of cardiovascular events requires testing in randomized controlled trials.

Author Affiliations: Divisions of Cardiovascular Diseases (Dr Ridker) and Preventive Medicine (Drs Ridker, Manson, Buring, and Hennekens), Brigham and Women's Hospital, and the Department of Ambulatory Care and Prevention (Drs Buring and Hennekens), Harvard Medical School, Boston, Mass; and Abbott Laboratories, Abbott Park, Ill (Dr Shih and Mr Matias).

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