Objective-High-density lipoprotein (HDL) is a heterogeneous lipoprotein class and there is no consensus on the value of HDL subspecies in coronary heart disease (CHD) risk assessment. We tested the hypothesis whether specific HDL subpopulations are significantly associated with CHD-prevalence. Methods and Results-ApoA-I concentrations (mg/dL) in HDL subpopulations were quantitatively determined by native 2d gel electrophoresis, immunoblotting, and image analysis in male participants in the Framingham Offspring Study (FOS). CHD cases (nϭ169) had higher pre␤-1 and ␣-3 particle and lower ␣-1, pre␣-3, and pre␣-1 particle levels than either all (nϭ1277) or HDL cholesterol-matched (nϭ358) controls. ␣-1 and pre␣-3 levels had an inverse association, whereas ␣-3 and pre␣-1 particle levels had a positive association with CHD prevalence after adjusting the data for established CHD risk factors. Standardized logit coefficients indicated that ␣-1 HDL was most significantly associated with CHD prevalence. Moreover, each mg/dL increase in ␣-1 particle level decreased odds of CHD by 26% (PϽ0.0001), whereas each mg/dL increase in HDL cholesterol decreased odds of CHD by 2% in a model including all established CHD risk factors. Conclusions-Specific HDL subpopulations were positively correlated, whereas others were inversely correlated with CHD prevalence in male subject in the FOS, indicating that the various HDL particles might have different roles in the cause of CHD. [1][2][3][4] Traditionally, HDL has been separated into major subclasses by polyanion precipitation, ultracentrifugation (HDL2 and HDL3), or by the apolipoprotein content, distinguishing particles containing only apoA-I (LpA-I), the major apolipoprotein of HDL, from particles containing both apoA-I and apoA-II (LpA-I:A-II). None of these techniques has provided any convincing evidence that 1 kind of HDL subfraction has any greater cardioprotective function than another. [5][6][7][8][9][10] The lack of agreement among these studies is probably related to the fact that all of these HDL subfractions are themselves heterogeneous, containing a variety of different HDL subspecies with possibly different physiological functions.Our laboratory uses native 2-dimensional gel electrophoresis, immunoblotting, and image analysis to separate HDL subpopulations quantitatively from plasma with highresolution based on electrophoretic charge and particle size. 11 We determine apoA-I content, not cholesterol, in these particles. This method has been useful in studies of HDL metabolism and cholesterol transport from cells because it separates intermediates in these processes. 12 A small casecontrol study indicated that coronary heart disease (CHD) patients not only had HDL deficiency but also had a major rearrangement in the apoA-I-containing HDL subpopulations with significantly lower levels of the large ␣-1 and pre␣-1 (Ϸ11 nm), and higher levels of the small ␣-3 (Ϸ8.4 nm) and pre␤-1 (Ϸ5.6 nm) HDL particles than controls. 13 Among these particles, ␣-3 contains both apoA-I and apoA-...

Objective-We examined the effects of simvastatin-niacin and antioxidant vitamins on changes in high-density lipoprotein (HDL) subpopulations and alterations in coronary artery stenosis, as assessed by angiography. Methods and Results-Lipids, lipoproteins, and HDL particles were measured on and off treatment in 123 subjects of the HDL-Atherosclerosis Treatment Study. Patients were assigned to 4 treatment groups, simvastatin-niacin, simvastatinniacin-antioxidant vitamins, antioxidant vitamins, and placebo. Subjects were followed for 3 years on treatment and then for 2 months off treatment. Simvastatin-niacin significantly increased the 2 large apoA-I-containing HDL subpopulations, ␣ 1 and pre␣ 1 , and significantly decreased the 2 smallest particles, pre␤ 1 and ␣ 3 , compared with values obtained from the same patients off treatment. Adding antioxidant vitamins to the lipid-modifying agents blunted these effects (not significant). A significant negative correlation (rϭϪ0.235; PϽ0.01) between the changes in ␣ 1 HDL particle concentration and coronary artery stenosis was noted. Subjects in the third tertile (157% increase in ␣ 1 ) had no progression of stenosis in the 3-year follow-up period, whereas subjects in the first tertile (15% decrease in ␣ 1 ) had an average of 2.1% increase in stenosis. Conclusions-Simvastatin-niacin therapy significantly increased the large apoA-I-containing ␣ 1 HDL particles. This increase was significantly associated with less progression of coronary stenosis even after adjusting for traditional risk factors.