A Prospective Study of Cholesterol, Apolipoproteins, and the Risk of Myocardial Infarction

BACKGROUND: The independent contributions of subfractions of high-density lipoprotein (HDL) cholesterol (HDL2 and HDL3) and apolipoproteins in predicting the risk of myocardial infarction are unclear. Prospective data are sparse, but HDL2 is widely believed to be a more important predictor than HDL3. METHODS: Blood samples were collected at base line from 14,916 men (ages, 40 to 84 years) who were participants in the Physicians' Health Study. After five years of follow-up, plasma samples from 246 men with new myocardial infarction (case subjects) were analyzed together with specimens from 246 men matched to them for age and smoking status who had not had a myocardial infarction. RESULTS: The levels of total cholesterol and apolipoprotein B-100 were significantly associated with an increased risk of myocardial infarction (data on levels of low-density lipoprotein cholesterol were unavailable). Both HDL cholesterol and HDL2 levels were associated with a substantially decreased risk of myocardial infarction, but the HDL3 level was the strongest predictor; the relative risk was 0.3 (95 percent confidence interval, 0.2 to 0.6) for those in the fifth of the group with the highest HDL3 levels, as compared with the fifth with the lowest levels. The benefit of a higher HDL cholesterol level was most pronounced among those with lower total cholesterol levels. Levels of apolipoprotein A-I and apolipoprotein A-II were also associated with decreased risk. However, the levels of HDL subfractions and apolipoproteins did not add significantly to the value of a multivariate model that included the ratio of total to HDL cholesterol in predicting myocardial infarction, whereas that ratio remained a significant independent predictor of risk. After adjustment for other risk factors, a change of one unit in the ratio of total to HDL cholesterol was associated with a 53 percent change in risk (95 percent confidence interval, 26 percent to 85 percent). CONCLUSIONS: This study underscores the importance of HDL cholesterol in predicting the risk of myocardial infarction and demonstrates protective effects of both the HDL3 and HDL2 subfractions of HDL cholesterol. We found little or no predictive value for the levels of apolipoproteins A-I, A-II, and B or HDL subfractions after conventional risk factors and the ratio of total to HDL cholesterol were considered.