HYPERHOMOCYSTEINEMIA AND CORONARY HEART DISEASE
Numerous studies have indicated that mild hyperhomocysteinemia is an independent risk factor for CHD. In the Physicians' Health Study, a total of 14,91.6 US male physicians, aged 40 - 84 yr, were followed up for 6 yr. Men with homocysteine levels above the 95th percentile 'based on control distribution) had a threefold increased risk of myocardial infarction compared with those within the bottom 90%. The findings were also statistically compatible with a graded risk increase across the distribution, a suggestion made by Perry and coworkers in a prospective study of stroke in middle-aged British men. Similar findings have been reported for myocardial infarction, carotid artery thickening, and angiographically defined coronary artery stenosis.
In addition, Selhub and associates demonstrated a gradual increase in the prevalence of carotid artery stenosis with increasing levels of homocysteine. A meta-analysis by Boushey and colleagues showed an increase in risk of CAD of about 70% for each 5 !lmol/L rise in fasting homocysteine. They concluded that a total of 10% of CAD risk appeared to be attributable to homocysteine. Two recent studies have confirmed the relevance of homocysteine as a risk factor for vascular disease. The first was a multicenter, case-control study where the risk of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) was examined, as well as the association of plasma tHcy with conventional risk factors.
The subjects comprised 750 cases and 800 controls, both male and female, below 60 yr of age. The relative risk (RR) for vascular disease in the top fifth of the fasting tHcy distribution, when compared with the bottom four-fifths, was 2.2 (95% confidence interval [CIl 1.6 - 2.9), and a dose-response effect was noted. This level of risk is similar to that observed for hypercholesterolemia and smoking. The second study examined the prognostic value of homocysteine in patients with established CAD. A total of 587 patients with angiographically confirmed CAD were followed-up for a median period of 4.6 yr. Homocysteine levels were strongly associated with levels of folate and vitamin B12, history of myocardial infarction, the left ventricular ejection fraction, and serum creatinine.
A strong, graded relationship was found between plasma tHcy and overall mortality. After 4 yr, 3.8% of patients with tHcy below 9 ),lmol/L had died compared with 24.7% of those with tHcy greater than 15 !lmol/L. The association was not altered significantly when adjusted for other, possibly con-founding, factors such as age, sex, serum creatinine, left ventricular ejection fraction, and history of myocardial infarction. However, not all studies examining the effect of homocysteine levels on the incidence of cardiovascular disease (CVD) have shown a positive association, highlighting the need for further investigation. An updated analysis of the Physicians' Health Study data yielded a relative risk for elevated tHey of only 1.3 (95% CI 0.5 - 3.1).
An analysis of the Multiple Risk Factor Intervention Trial (MRFIT) cohort showed no effect of tHey after adjustment for other variables (RR = 0.94; 95% CI 0.56 - 1.56). An analysis of tHey and CHD in the Caerphilly cohort showed tHey to be only weakly predictive of CHD events. Finally, the ARIC study showed no association between the incidence of CHD an tHey, although there was a possibility that vitamin B6 offered independent protection, a finding also suggested by others.
