Nonfasting Plasma Total Homocysteine Levels and All-Cause and Cardiovascular Disease Mortality in Elderly Framingham Men and Women

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Abstract
IN 1969, the observations of McCully,1 who performed routine autopsy studies of children who died of homocystinuria due to distinct inborn errors of metabolism, led him to hypothesize that hyperhomocysteinemia may be linked to precocious arteriosclerosis. Registry data compiled by Mudd and colleagues2 subsequently confirmed that among children and young adults with homocystinuria and marked hyperhomocysteinemia due to cystathionine β-synthase deficiency, there was a dramatic excess risk of premature cardiovascular disease (CVD) morbidity and mortality. By 1976, Wilcken and Wilcken3 reported the first case-control findings indicating that much milder, long-term elevations in homocysteine (Hcy) might be associated with clinical arteriosclerosis in adults. Meta-analyses4-6 pooling essentially all the published literature from 1975 through 1998 strongly suggest that mild to moderate elevation in fasting, nonfasting, or post–methionine loading Hcy levels confers an independent risk for clinical arteriosclerotic outcomes among adults, comparable in magnitude to a mild to moderate elevation in total cholesterol levels.