EVIDENCE THAT HOMOCYSTEINE IS AN INDEPENDENT RISK FACTOR FOR ATHEROSCLEROSIS IN HYPERLIPIDEMIC PATIENTS

In 482 patients sequentially referred for diagnosis and therapy of hyperlipidemia, our specific aim was to determine the prevalence of homocysteinemia, to assess whether it was independently associated with atherosclerotic vascular disease, and to determine how effectively high homocysteine could be treated with folic acid and pyridoxine. Of the 482 patients, 18 (3.7%) had high homocysteine (greater than or equal to 16.2 mu mol/L, median = 19), 31 had high cystathionine (greater than or equal to 342 nmol/L) with normal homocysteine (median = 12), and 433 had normal cystathionine and homocysteine (median = 9). Of the 18 patients with high homocysteine, 13 (72%) had atherosclerotic vascular disease, much higher than the 44% (192 of 433 patients) with normal homocysteine (chisquare = 5.4, p = 0.02). In the 18 kindreds with a homocysteinemic proband, 14 (78%) had greater than or equal to 1 first degree relatives with arterosclerotic vascular disease age 65, compared with 50% (215 of 433) of the families where the proband had normal homocysteine (chi-square = 5.5, p = 0.02). In the 482 patients already at high risk for atherosclerotic vascular disease by virtue of hyperlipidemia, when assessed by logistic regression, homocysteine was an independent positive predictor of atherosclerotic vascular disease (p = 0.007); relative risk for atherosclerotic events was 2.8 times higher (p = 0.0004) in patients with top (greater than or equal to 1.4 mu mol/L) than with bottom (< 6.9 mu mol/L) quintile homocysteine. After 15 weeks of folic acid (5 mg/day) and pyridoxine (100 mg/day) therapy in 10 patients with high homocysteine, median homocysteine normalized, decreasing from 18 to 11 mu mol/L (p = 0.001). To best quantitate and ameliorate risk for atherosclerotic vascular disease, homocysteine should routinely be measured at least once in hyperlipidemic patients at high risk for atherosclerosis and, if high, should be treated.