Value of High-Density Lipoprotein (HDL) Subpopulations in Predicting Recurrent Cardiovascular Events in the Veterans Affairs HDL Intervention Trial

OBJECTIVE: To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs HDL Intervention Trial (VA-HIT). METHODS AND RESULTS: Apolipoprotein A-I (apoA-I)-containing HDL subpopulations were quantitatively determined by nondenaturing 2D gel electrophoresis. Hazard ratios of recurrent CVD events were calculated by comparing VA-HIT subjects with (n=398) and without (n=1097) such events. Subjects with new CVD events had significantly lower HDL-C, apoA-I, and large cholesterol-rich HDL particle (alpha-1, alpha-2, pre-alpha-1, and pre-alpha-2) levels, significantly higher triglyceride, and small poorly lipidated HDL particle (pre-beta-1 and alpha-3) levels than subjects without such events. Multivariate analyses indicated that alpha-1 and alpha-2 particle levels were significant negative risk factors, whereas alpha-3 level was a significant positive risk factor for new CVD events. Pre-beta-1 level was a significant risk factor for new CVD events only in univariate analysis. A forward selection model indicated that alpha-1 was the most significant risk factor for recurrent CVD events among HDL particles. CONCLUSIONS: An altered HDL subpopulation profile marked with low alpha-1 and alpha-2 levels and a high alpha-3 level in coronary heart disease patients indicated an elevated risk for new CVD events. Moreover, alpha-1 and alpha-2 levels were superior to HDL-C levels in risk assessment in patients with low HDL-C in VA-HIT.